Vitamin D and Hyperkinetic Movement Disorders: A Systematic Review.

Background: The importance of vitamin D deficiency in Parkinson's disease, its negative influence on bone health, and even disease pathogenesis has been studied intensively. However, despite its possible severe impact on health and quality of life, there is not a sufficient understanding of its role in other movement disorders. This systematic review aims at providing an overview of the prevalence of vitamin D deficiency, bone metabolism alterations, and fractures in each of the most common hyperkinetic movement disorders (HKMDs). Methods: The study search was conducted through PubMed with keywords or Medical Related Subjects (MeSH) of common HKMDs linked with the terms of vitamin D, osteoporosis, injuries, and fractures. Results: Out of 1585 studies screened 40 were included in our review. They show that there is evidence that several HKMDs, including Huntington disease, Restless Legs Syndrome, and tremor, are associated with low vitamin D serum levels in up to 83% and 89% of patients. Reduced bone mineral density associated with vitamin D insufficiency was described in Huntington disease. Discussion: Our survey suggests that vitamin D deficiency, bone structure changes, and fractures are important but yet under-investigated issues in HKMDs. HKMDs-patients, particularly with a history of previous falls, should have their vitamin D-levels tested and supplemented where appropriate. Highlights: Contrary to Parkinson's disease, vitamin D deficiency, and bone abnormalities are under-investigated in hyperkinetic movement disorders (HKMDs). Several HKMDs, including essential tremor, RLS, and Huntington disease, are associated with vitamin D deficiency in up to 89%, the latter also with reduced bone mineral density. Testing and where appropriate supplementation is recommended.

A Case of Neuromuscular Electrical Stimulation for Childhood Stroke Hyperkinesis: A Brief Report.

AIM: Some conditions within specific populations are so rare rigorous evidence is unavailable. Childhood hyperkinesis is one example, yet presents an opportunity to examine sensation's contribution to motor function. METHODS: The patient experienced functional difficulty from hyperkinesis as a result of childhood stroke. Home-based passive neuromuscular electrical stimulation (NMES) was implemented an hour/day, six days/week, over 6 weeks (36 hours). Clinical and robotic measures (Assisting Hand Assessment, Box and Block Test, Jebsen Taylor Test of Hand Function, Kinarm) were administered before and after the intervention and at 9 months. RESULTS: NMES was feasible and well tolerated. Clinically important gains of arm function were maintained at 9 months. Robotic measures showed improved hyperkinesis, namely reduced movement segmentation and improved target approximation, in addition to improved proprioceptive function after NMES. CONCLUSION: This case study illustrates the use of NMES within a previously unexplored population and highlights the potential importance of sensory systems to motor gains.

Basal ganglia oscillations as biomarkers for targeting circuit dysfunction in Parkinson's disease.

Oscillations are a naturally occurring phenomenon in highly interconnected dynamical systems. However, it is thought that excessive synchronized oscillations in brain circuits can be detrimental for many brain functions by disrupting neuronal information processing. Because synchronized basal ganglia oscillations are a hallmark of Parkinson's disease (PD), it has been suggested that aberrant rhythmic activity associated with symptoms of the disease could be used as a physiological biomarker to guide pharmacological and electrical neuromodulatory interventions. We here briefly review the various manifestations of basal ganglia oscillations observed in human subjects and in animal models of PD. In this context, we also review the evidence supporting a pathophysiological role of different oscillations for the suppression of voluntary movements as well as for the induction of excessive motor activity. In light of these findings, it is discussed how oscillations could be used to guide a more precise targeting of dysfunctional circuits to obtain improved symptomatic treatment of PD.

Maternal B vitamin intake during pregnancy and childhood behavioral problems in Japan: The Kyushu Okinawa Maternal and Child Health Study.

Objectives: The current prebirth cohort study investigated the relationship between maternal B vitamin intake during pregnancy and behavioral problems in Japanese children aged 5 years. Methods: Subjects were 1199 mother-child pairs. Dietary intake was assessed using a diet history questionnaire. Emotional problems, conduct problems, hyperactivity problems, peer problems, and low prosocial behavior were examined using the Japanese parent-report version of the Strengths and Difficulties Questionnaire. Adjustment was made for maternal age, gestation at baseline, region of residence, number of children, maternal and paternal education, household income, maternal depressive symptoms, alcohol intake, vitamin B complex supplement use, smoking during pregnancy, child's birth weight, child's sex, breastfeeding duration, and smoking in the household during the first year of life. Results: Maternal folate intake during pregnancy was independently inversely associated with childhood low prosocial behavior: the adjusted odds ratio (OR) (95% confidence interval [CI], P for trend) between extreme quartiles was 0.55 (0.37-0.80, 0.0002). Maternal vitamin B6 intake during pregnancy was independently inversely related to childhood hyperactivity problems and low prosocial behavior: the adjusted ORs (95% CIs, P for trend) between extreme quartiles were 0.57 (0.34-0.94, 0.01) and 0.58 (0.40-0.85, 0.0009), respectively. Maternal vitamin B2 intake during pregnancy was independently inversely associated with childhood emotional problems: the adjusted OR (95% CI, P for trend) between extreme quartiles was 0.58 (0.33-0.99, 0.11). Conclusions: Maternal intake of folate, vitamin B6, and vitamin B2 during pregnancy may be protective against childhood low prosocial behavior, hyperactivity problems and low prosocial behavior, and emotional problems, respectively.

Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca2+ imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.

Arginine Vasopressin and Arginine Vasopressin Receptor 1b Involved in Electroacupuncture-Attenuated Hypothalamic-Pituitary-Adrenal Axis Hyperactivity in Hepatectomy Rats.

OBJECTIVE: The study aims to know the effect of electroacupuncture (EA) in maintenance of the homeostasis of the neuroendocrine system in hepatectomy rats and the involvement of arginine vasopressin (AVP) signaling in hypothalamus after EA was observed. MATERIALS AND METHODS: Rats were randomly assigned to four groups, including the intact group, model group, sham-EA group, and EA group. EA was given during the perioperative period at the Zusanli (ST36) and Sanyinjiao (SP6) points after hepatectomy. The serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were detected via radioimmunoassay. The expression of AVP, arginine vasopressin receptor 1a (AVPR1a), arginine vasopressin receptor 1b (AVPR1b), and glucocorticoid receptor (GR) was detected by Western blot after surgery. RESULTS: Compared with the intact group, the ACTH and CORT levels in the serum of model group were increased, whereas the ACTH and CORT levels were decreased in the EA group compared with the model group. Moreover, AVP and AVPR1b protein levels in the pituitary gland were increased in the model group and decreased in the EA group. Further, a distinct increase in the AVP and AVPR1a protein levels was observed in the model group, whereas they were significantly decreased in the EA group. Blockade of AVPR1b by nelivaptan reduced the increase of ACTH and CORT. D [Leu(4) , Lys(8) ] vasopressin can inhibit the effect of EA in rectification of the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. CONCLUSIONS: EA application at ST36 and SP6 can ameliorate the hyperactivity of the HPA axis via AVP signaling during the perioperative period.

Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children.

OBJECTIVES: Autism spectrum disorder (ASD) is a developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and non-verbal communication, and stereotyped patterns of interests and activities. Vitamin-D deficiency was previously reported in autistic children. However, the data on the relationship between vitamin D deficiency and the severity of autism are limited. METHODS: We performed a case-controlled cross-sectional analysis conducted on 122 ASD children, to assess their vitamin D status compared to controls and the relationship between vitamin D deficiency and the severity of autism. We also conducted an open trial of vitamin D supplementation in ASD children. RESULTS: Fifty-seven percent of the patients in the present study had vitamin D deficiency, and 30% had vitamin D insufficiency. The mean 25-OHD levels in patients with severe autism were significantly lower than those in patients with mild/moderate autism. Serum 25-OHD levels had significant negative correlations with Childhood Autism Rating Scale (CARS) scores. Of the ASD group, 106 patients with low-serum 25-OHD levels (<30 ng/ml) participated in the open label trial. They received vitamin D3 (300 IU/kg/day not to exceed 5000 IU/day) for 3 months. Eighty-three subjects completed 3 months of daily vitamin D treatment. Collectively, 80.72% (67/83) of subjects who received vitamin D3 treatment had significantly improved outcome, which was mainly in the sections of the CARS and aberrant behavior checklist subscales that measure behavior, stereotypy, eye contact, and attention span. CONCLUSION: Vitamin D is inexpensive, readily available and safe. It may have beneficial effects in ASD subjects, especially when the final serum level is more than 40 ng/ml. TRIAL REGISTRATION NUMBER: UMIN-CTR Study Design: trial Number: R000016846.

Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism.

OBJECTIVE: Preliminary evidence suggests that omega-3 fatty acids may reduce hyperactivity in children with autism spectrum disorder (ASD). We sought to examine the feasibility of a novel, Internet-based clinical trial design to evaluate the efficacy of this supplement. METHOD: E-mail invitations were sent to parents of children aged 5 to 8 years enrolled in the Interactive Autism Network. All study procedures, including screening, informed consent, and collection of outcome measures took place over the Internet. The primary outcome measures were parent- and teacher-rated changes in hyperactivity on the Aberrant Behavior Checklist (ABC-H). RESULTS: During the 6-week recruitment period, 57 children from 28 states satisfied all eligibility criteria and were randomly assigned to 1.3 grams of omega-3 fatty acids or an identical placebo daily for 6 weeks. Outcome assessments were obtained from all 57 participants and 57 teachers, and the study was completed in 3 months. Children in the omega-3 fatty acid group had a greater reduction in hyperactivity (-5.3 points) compared to the placebo group (-2.6 points), but the difference was not statistically significant (1.9-point greater improvement in the omega-3 group, 95% CI = -2.2 to 5.2). Adverse events were rare and not associated with omega-3 fatty acids. Participant feedback was positive. CONCLUSION: Internet-based, randomized controlled trials of therapies in children with ASD are feasible and may lead to marked reductions in the time and cost of completing trials. A larger sample size is required to definitively determine the efficacy of omega-3 fatty acids. Clinical trial registration information-Omega-3 Fatty Acids for Hyperactivity Treatment in Autism Spectrum Disorder; http://clinicaltrials.gov; NCT01694667.

Reducing GABAA α5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome.

Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABA(A) α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABA(A) α5 NAMs to treat cognitive dysfunction in DS.

Rosmarinus officinalis L. hydroalcoholic extract, similar to fluoxetine, reverses depressive-like behavior without altering learning deficit in olfactory bulbectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Rosemary, Rosmarinus officinalis L., has several therapeutic applications in folk medicine for the treatment of a wide range of diseases, including depression. AIM OF THE STUDY: To evaluate the ability of Rosmarinus officinalis hydroalcoholic extract (ROHE), as compared to the positive control fluoxetine, to reverse behavioral (hyperactivity, anhedonic behavior and learning deficit in water maze) and biochemical alterations (serum glucose level and acetylcholinesterase, AChE, activity) induced by an animal model of depression, the olfactory bulbectomy (OB) in mice. MATERIALS AND METHODS: Locomotor and exploratory behavior was assessed in the open-field, novel object and novel cage tests, anhedonic behavior was assessed in the splash test; cognitive deficits were evaluated in the water maze task. For the first set of experiments, ROHE (10-300 mg/kg) or fluoxetine (10mg/kg) was administered once daily (p.o.) for 14 days after OB and the behavioral tests were performed. For the second set of experiments, serum glucose and hippocampal and cerebrocortical AChE activity were determined in OB and SHAM-operated mice treated orally with ROHE (10mg/kg), fluoxetine (10mg/kg) or vehicle. RESULTS: ROHE (10-300 mg/kg), similar to fluoxetine, reversed OB-induced hyperactivity, increased exploratory and anhedonic behavior. OB needed significantly more trials in the training session to acquire the spatial information, but they displayed a similar profile to that of SHAM mice in the test session (24h later), demonstrating a selective deficit in spatial learning, which was not reversed by ROHE or fluoxetine. A reduced serum glucose level and an increased hippocampal AChE activity were observed in bulbectomized mice; only the latter effect was reversed by fluoxetine, while both effects were reversed by ROHE. CONCLUSIONS: ROHE exerted an antidepressant-like effect in bulbectomized mice and was able to abolish AchE alterations and hypoglycemia, but not spatial learning deficit induced by OB. Overall, results suggest the potential of Rosmarinus officinalis for the treatment of depression, validating the traditional use of this plant.

Complex behavioral and synaptic effects of dietary branched chain amino acids in a mouse model of amyotrophic lateral sclerosis.

SCOPE: We hypothesized that chronic supplementation with branched chain amino acids (BCAAs) affects neurobehavioral development in vulnerable gene backgrounds. METHODS AND RESULTS: A murine model of amyotrophic lateral sclerosis (ALS), G93A mice bearing the mutated human superoxide dismutase 1 (SOD1) gene, and control mice received from 4 to 16 wk of age dietary supplementation with BCAAs at doses comparable to human usage. Motor coordination, exploratory behaviors, pain threshold, synaptic activity and response to glutamatergic stimulation in primary motor cortex slices were evaluated between the 8th and 16th week. The glial glutamate transporter 1 (GLT-1) and metabotropic glutamate 5 receptor (mGlu5R) were analyzed by immunoblotting in cortex, hippocampus and striatum. BCAAs induced hyperactivity, decreased pain threshold in wild-type mice and exacerbated the motor deficits of G93A mice while counteracting their abnormal pain response. Electrophysiology on G93A brain slices showed impaired synaptic function, reduced toxicity of GLT-1 blocking and increased glutamate toxicity prevented by BCAAs. Immunoblotting indicated down-regulation of GLT-1 and mGlu5R in G93A, both effects counteracted by BCAAs. CONCLUSION: These results, though not fully confirming a role of BCAAs in ALS-like etiology in the genetic model, clearly indicate that BCAAs' complex effects on central nervous system depend on gene background and raise alert over their spread use.

Coffee consumption during pregnancy and the risk of hyperkinetic disorder and ADHD: a prospective cohort study.

AIM: Based on hypotheses from experimental studies, we studied the association between intrauterine exposure to coffee and the risk of clinically verified hyperkinetic disorder and attention-deficit hyperactivity disorder (ADHD). METHODS: A cohort study with prospectively collected data from the Aarhus Birth Cohort, Denmark. We included 24 068 singletons delivered between 1990 and 1998. Linkage was performed with three Danish longitudinal registers: The Danish Psychiatric Central Register, The Integrated Database for Labour Market Research and The Danish Civil Registration System. We identified 88 children with hyperkinetic disorder and ADHD. Information about coffee consumption during pregnancy was obtained at 16 weeks of gestation from self-administrated questionnaires. Potential confounding factors were evaluated using Cox regression analyses. RESULTS: We found that intrauterine exposure to 10 or more cups of coffee per day was associated with a threefold increased risk of hyperkinetic disorder and ADHD. After adjustments for a number of confounding factors, the risk decreased and became statistically insignificant (RR 2.3, 95% CI 0.9-5.9). CONCLUSION: Prenatal exposure to high levels of coffee did not significantly increase the risk of clinically verified hyperkinetic disorder and ADHD in childhood.

Electrical stimulation in the lateral hypothalamus in rats in the activity-based anorexia model.

OBJECT: One quarter of patients with anorexia nervosa have a poor outcome and continue to suffer chronically or die. Electrical brain stimulation may be of therapeutic benefit in some of these patients; however, the brain target for inducing symptom relief is unknown. In this study, the authors evaluated the effects of acute and chronic electrical stimulation in the lateral hypothalamus on food intake, locomotor activity, and survival time in rats in an activity-based anorexia model. METHODS: In an acute experiment, the authors electrically stimulated at 100 Hz and 0, 25, 50 and 75% of the maximal stimulation amplitude (that is, the amplitude leading to severe side effects) in the lateral hypothalamus on consecutive days during 4 test sessions in 10 rats and evaluated food intake and locomotor activity. In a chronic experiment, they compared food intake, wheel revolutions, and survival time between 6 rats that underwent electrical stimulation in the lateral hypothalamus (50% of maximal stimulation amplitude) and 8 rats that did not undergo stimulation. RESULTS: In the acute experiment, overall electrical stimulation (25, 50, and 75% combined) and stimulation at 75% of the maximal stimulation amplitude significantly decreased the locomotor activity. However, if the authors omitted results of 1 rat, in which the electrode tip was not located in the lateral hypothalamus on one side but rather in the supraoptic chiasm, the remaining results did not yield significance. No other differences were observed. CONCLUSIONS: When the findings of the current study are extrapolated to patients with anorexia nervosa, the authors do not expect major effects on symptoms with electrical stimulation at high frequency in the lateral hypothalamus.

Implication of the endocannabinoid system in the locomotor hyperactivity associated with congenital hypothyroidism.

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB(1)) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB(1) receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB(1) receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.

Protective effect of quercetin on alcohol abstinence-induced anxiety and convulsions.

Chronic administration of ethanol (2 g/kg, p.o.) on days 1-6 and its withdrawal produced an anxiogenic reaction in mice as assessed in the mirrored-chamber test. Daily administration of quercetin (25 or 50 mg/kg, p.o.) prior to ethanol for 6 days prevented withdrawal-induced anxiety in mice. However, acute administration of a single dose of quercetin (50 mg/kg) to animals withdrawn from ethanol, i.e., on day 7, did not prevent withdrawal-induced anxiety. Ethanol withdrawal also induced a significant increase in the locomotor activity of mice indicating an anxiogenic response. Daily administration of quercetin (25 or 50 mg/kg, p.o.) prior to ethanol for 6 days prevented withdrawal-induced increased locomotor activity. Ethanol withdrawal also sensitized the convulsogenic reaction to pentylenetetrazole (PTZ). A non-convulsive dose (40-60 mg/kg) of PTZ produced full-blown convulsions and increased mortality in ethanol-withdrawn mice. Both acute and chronic administration of quercetin (25 or 50 mg/kg, p.o.) produced a significant protection against ethanol withdrawal-induced reduction in PTZ threshold in mice. The result suggests the protective effect of this safe drug, quercetin, in the management of ethanol withdrawal reactions.

An association of Ephedra use with psychosis and autonomic hyperactivity.

Ephedra extract is used in a number of dietary supplements taken for a variety of purposes including weight loss. Although recent events have led to calls for Ephedra to be removed from the market and the FDA has had over 18,000 adverse event reports, newspaper reports cite only a few instances of clearly associated adverse events associated with Ephedra use. In this communication, we review the literature and present a case report of Ephedra use associated with the onset of psychosis and autonomic hyperactivity after administration of risperidone. We conclude that the behavioral effects of Ephedra are a public health concern.

Involuntary vocalisations and a complex hyperkinetic movement disorder following left side thalamic haemorrhage.

A variety of involuntary speech phenomena as for example palilalia have been described as consequences of neurological disorders. Palilalia is the involuntary repetition of syllabels, words and phrases in ongoing speech. We describe a 73 year old woman who suffered from a hypertensive thalamic haemorrhage. MRI revealed that the lesion was predominantly located within the pulvinar, extending to the lateroposterior thalamic nuclei and to the pretectal area with possible involvement of the medial geniculate body. Few months after the event she developed involuntary vocalisations with whole words and meaningless syllables being rapidly reiterated. In contrast to typical palilalia these vocalisations were not meaningfully related to the ongoing speech of the patient. In addition, the patient developed a complex hyperkinetic movement disorder with right-sided painful hemidystonia and bilateral clonic jerks and a right-sided postural tremor.

Hyperkinetic movement disorder in an 11-year-old child treated with bilateral pallidal stimulators.

Pallidal stimulation is widely used in the treatment of movement disorder in adults but is less well reported in the treatment of dystonia in children. Despite inconsistent results in the past, its use in dystonia in Parkinson's disease is again attracting interest with promising results. Bilateral as well as unilateral pallidotomies have been performed and are felt to be required in some cases of dystonia. Use of depth electrodes to provide long-term electrical stimulation to pallidum and other basal ganglia structures has recently become more widespread. This technique is felt to have a lower morbidity, especially in bilateral procedures. Here we present the case of an 11-year-old boy with severe hyperkinetic movement disorder who showed sustained improvement after bilateral pallidal stimulation implantation.

[Treatment of children with hyperkinetic disorders (ADHD) based on communications- and systems analysis]. / Neues vom "Zappelphilipp"--Die Therapie bei Kindern mit hyperkinetischen Störungen (ADHD) auf der Basis von Kommunikations- und Systemtheorie.

Inquired for a therapeutic mode changing hyperactive behavior without application of drugs or diets we analyzed the patterns of cognition, communication and system behavior related to such disturbed children and their families. Following our observations we created a clinically useful therapy basing on a special view to system- and communication theory. We applied our therapeutic mode generally to as hyperactive identified primary school children and collected in N = 46 cases catamnestic data about five years later. In more than 80% out of the sample we found successful developments after application of in means 8 therapeutic sessions during 9 months. About 53% out of the successful treatment children show a splendid school success. Our results are demanding for an extended discussion of relations and family constellations including hyperactive behavior of one child. Searching for the possibilities of change in the view of system theory it seems to be more appropriate to consider relations but individual behavior.