An Open Source Automated Bar Test for Measuring Catalepsy in Rats.

Catalepsy bar tests are widely used to measure the failure to correct an imposed posture resulting from muscular rigidity. Procedures for measuring catalepsy vary greatly in the published literature, but one commonly used test measures the time it takes for a rodent to remove one or both of its forelimbs from a bar. The following paper describes an affordable, adjustable, open-source bar test that automatically measures and logs the time it takes for a rat to remove itself from a bar. While commercially available automated bar tests are prohibitively expensive, requiring proprietary software and hardware to operate, the proposed apparatus runs on an Arduino-based microcontroller making it low-cost and customizable. This 3D-printed design costs less than 65 United States dollars to build and is simple to assemble and operate. The beam-break sensor design also eliminates many of the pitfalls of the "complete-the-circuit"-based approach to recording catalepsy. The paper further describes the successful validation of the design using adult male rats injected with different doses of haloperidol to demonstrate a dose-dependent cataleptic effect. This design provides a versatile, low-cost solution to standardizing and automating measurement of catalepsy in rodents.

Chronic oral treatment with risperidone impairs recognition memory and alters brain-derived neurotrophic factor and related signaling molecules in rats.

Antipsychotic drugs (APDs) are essential for the treatment of schizophrenia and other neuropsychiatric illnesses such as bipolar disease. However, they are also extensively prescribed off-label for many other conditions, a practice that is controversial given their potential for long-term side effects. There is clinical and preclinical evidence that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although the molecular mechanisms of these effects are unknown. The purpose of the rodent studies described here was to evaluate a commonly prescribed APD, risperidone, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with risperidone (2.5 mg/kg/day) or vehicle (dilute acetic acid solution) in their drinking water for 30 or 90 days. Subjects were then evaluated for drug effects on recognition memory in a spontaneous novel object recognition task and protein levels of BDNF-related signaling molecules in the hippocampus and prefrontal cortex. The results indicated that depending on the treatment period, a therapeutically relevant daily dose of risperidone impaired recognition memory and increased the proBDNF/BDNF ratio in the hippocampus and prefrontal cortex. Risperidone treatment also led to a decrease in Akt and CREB phosphorylation in the prefrontal cortex. These results indicate that chronic treatment with a commonly prescribed APD, risperidone, has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function.

Carvacrol prevents impairments in motor and neurochemical parameters in a model of progressive parkinsonism induced by reserpine.

Parkinson's disease (PD) is a neurodegenerative disease characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compact (SNpc), with consequent depletion of dopamine in the striatum, which gives rise to the characteristic motor symptoms of PD. Although its etiology is unknown, several studies have suggested that oxidative stress plays a critical function in the pathophysiology of PD, and antioxidant agents could be helpful to slown down the dopaminergic neurodegeneration. Carvacrol (CA) is a phenolic monoterpene found in essential oils of many aromatic plants that presents antioxidant and neuroprotective effects. This study aimed to assess the effect of CA in a reserpine (RES)-induced rat model of PD. Male Wistar rats received 15 s.c. injections of 0.1 mg/kg RES or vehicle, every other day, concomitantly to daily i.p. injections of CA (12.5 or 25 mg/kg) or vehicle. Across the treatment, the animals were submitted to behavioral evaluation in the catalepsy test (performed daily), open field test (7th day) and assessment of vacuous chewing movements (12th, 20th and 30th days). Upon completion of behavioral tests, rats were perfused and their brains underwent tyrosine hydroxylase (TH) immunohistochemical analysis. Our results showed that CA (12.5 e 25 mg/kg) prevented the increase in catalepsy behavior and number of vacuous chewing movements, but failed to revert the decreased open-field locomotor activity induced by RES. In addition, CA in both doses prevented the decrease in TH immunostaining induced by RES in the SNpc and dorsal striatum. Taken together, our results suggest that CA shows a protective effect in a rat model of PD, preventing motor and neurochemical impairments induced by RES. Thus, the use of CA as a promising new strategy for the prevention and/or treatment of PD may be considered.

[Narcolepsy in childhood and adolescence: symptoms, diagnosis, and therapy. A case report]. / Narkolepsie im Kindes- und Jugendalter: Symptome, Diagnostik und Therapie. Ein Fallbericht.

Narcolepsy is a rare, multifactorial disease of the hypothalamus characterized by its leading symptoms of excessive daytime sleepiness and cataplexy. Sleep-EEG and a HLA-DR-genotype serve to secure the diagnosis. We report here on a 14-year-old girl suffering from anxieties, depression, school refusal, social withdrawal as well as very frequent attacks of sleep during the day and cataplexy. Currently, there is no approved drug for children and adolescents suffering from narcolepsy. Our patient benefited significantly and quickly from an off-label treatment with methylphenidate in combination with psychoeducation, cognitive behavioral therapy, and family therapy. Narcolepsy is a very rare but probably underestimated differential diagnosis applied to unclear daytime sleepiness, anxieties, or depression in childhood and adolescence. Both the key symptoms and the comorbid symptoms improve significantly under treatment with stimulants, albeit at a higher dosage.

Misdiagnosis of narcolepsy.

BACKGROUND: Narcolepsy is a chronic primary sleep disorder, characterized by excessive daytime sleepiness and sleep dysfunction with or without cataplexy. Narcolepsy is uncommon, with a low prevalence rate which makes it difficult to diagnose definitively without a complex series of tests and a detailed history. The aim of this study was to review patients referred to a tertiary sleep centre who had been labelled with a diagnosis of narcolepsy prior to referral in order to assess if the diagnosis was accurate, and if not, to determine the cause of diagnostic misattribution. METHODS: All patients seen at a sleep centre from 2007-2013 (n = 551) who underwent detailed objective testing including an MSLT PSG, as well as wearing an actigraphy watch and completing a sleep diary for 2 weeks, were assessed for a pre-referral and final diagnosis of narcolepsy. RESULTS: Of the 41 directly referred patients with a diagnostic label of narcolepsy, 19 (46 %) were subsequently confirmed to have narcolepsy on objective testing and assessment by a sleep physician using ICSD-2 criteria. CONCLUSIONS: The diagnosis of narcolepsy was incorrectly attributed to almost 50 % of patients labelled with a diagnosis of narcolepsy who were referred for further opinion by a variety of specialists and generalists. Accurate diagnosis of narcolepsy is critical for many reasons, such as the impact it has on quality of life, driving, employment, insurance and pregnancy in women as well as medication management.

Pharmacological blockade of dopamine D2 receptors by aripiprazole is not associated with striatal sensitization.

The partial agonist profile of novel antipsychotics such as aripiprazole has hardly been demonstrated in biochemical assays on animal tissues. As it is established that responses induced by dopamine D2 receptor agonists are increased in models of dopaminergic sensitization, this paradigm was used in order to facilitate the detection of the partial agonist properties of aripiprazole. At variance with all other partial and full agonists tested, the partial agonist properties of aripiprazole were not revealed in guanosine 5'-O-(γ-[³5S]thiotriphosphate ([³5S]GTPγS) binding assays on striatal membranes from haloperidol-treated rats. Hence,aripiprazole behaved as an antagonist, efficiently inhibiting the functional response to dopamine. Similarly, in behavioural assays, aripiprazole dose-dependently inhibited the stereotypies elicited by apomorphine. However, at variance with haloperidol, repeated administrations of aripiprazole(3 weeks) at the doses of 10 and 30 mg/kg did not induce any up-regulation or hyperfunctionality of the dopamine D2 receptors in the striatum. These data highlight the putative involvement of other pharmacological targets for aripiprazole that would support in the prevention of secondary effects commonly associated with the blockade of striatal dopamine D2 receptors. Hence, in additional experiments, aripiprazole was found to efficiently promote [³5S]GTPγS binding in hippocampal membranes through the activation of 5-HT(1A) receptors. Further experiments investigating the second messenger cascades should be performed so as to establish the functional properties of aripiprazole and understand the mechanism underlying the prevention of dopamine receptor regulation in spite of the observed antagonism.

Secondary enuresis & body dysmorphic disorder in a caucasian male with catatonic schizophrenia: a case report.

We describe a patient with Schizophrenia and secondary enuresis. The enuresis settled with resolution of his psychotic symptoms but later remerged after starting Clozapine. We explore the mechanisms of incontinence in Schizophrenia and those due to Clozapine. This case highlights the need to inquire about incontinence in patients with schizophrenia prior to prescribing clozapine.

Narcolepsy--master of disguise: evidence-based recommendations for management.

Narcolepsy is a neurological disorder affecting the regulation of sleep and wakefulness. It is characterized by excessive daytime sleepiness, cataplexy, and other rapid eye movement (REM) sleep-associated manifestations (eg, hypnagogic hallucinations and sleep paralysis). The recognition of this disorder is usually delayed by 10 to 15 years, largely because of its protean manifestations, insidious nature, and lack of physician awareness. Delayed diagnosis is associated with poor quality of life, depression, and increased likelihood of accidents. Health care providers should include narcolepsy in the differential diagnosis of patients with excessive sleepiness, chronic fatigue, sleep-disordered breathing, depression, and attention-deficit/hyperactivity disorder. Narcolepsy is a lifelong disorder that often requires pharmacological treatments, which may include wake-promoting stimulants for excessive sleepiness and gamma-hydroxybutyrate (sodium oxybate) and antidepressants for REM sleep-associated manifestations. This article presents a case of a 47-year-old man with long-standing sleepiness and cataplexy who was eventually diagnosed with narcolepsy 30 years after the first onset of symptoms. The presenting manifestations of narcolepsy, diagnostic criteria, and its management are also discussed.

Narcolepsy in childhood.

Narcolepsy is a chronic disease commonly diagnosed in middle adulthood. However, the first symptoms often appear in childhood and/or adolescence. Pediatric cases of narcolepsy are among the most often underrecognised and underdiagnosed diseases. This fact raises questions about the reasons for such diagnostic delay from the clinical point of view, and what kind of help can be expected from auxiliary diagnostic examinations. The aim of the review is to stress some specific features of the clinical picture in children, to discuss the role of auxiliary examinations at the onset of the disease including sleep studies, tests for human leukocyte antigens (HLAs), and cerebrospinal fluid hypocretin (Hcrt) measurement, and to draw attention to the most common cases of pediatric misdiagnosis. Frequent cataplectic attacks at an early age should lead to detailed clinical, neuroimaging and genetic examinations to rule out a secondary etiology. Beside the typical symptoms (excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations), some additional features including obesity and nocturnal bulimia can appear. Also poor school performance and emotional disorder are common complaints. Treatment should start as early as possible to avoid the development of problems with progress at school, and close cooperation between school and family should be maintained.

J.-M. Charcot and simulated neurologic disease: attitudes and diagnostic strategies.

BACKGROUND: Neurologists have long wrestled with the diagnosis of elaborated or feigned disease. Studies have not focused on early techniques utilized to diagnose malingering. OBJECTIVE: To analyze cases of purposeful neurologic malingering among patients treated by the 19th century neurologist J.-M. Charcot, describe his attitudes, and study his methods to separate malingering from primary neurologic diseases. METHODS: A study was conducted of Charcot's printed and original documents from the Bibliothèque Charcot, Paris, and added documents on American neurology. RESULTS: Charcot recognized that purposeful simulation occurred in isolation as well as in established neurologic disorders. Charcot was strict with subjects motivated by greed or spite, but showed forbearance and wonder in those who created illness as "art for art's sake." Charcot developed diagnostic equipment that measured inspiratory depth and muscle activity as a strategy to identify malingerers. His approach strikingly contrasted with contemporary military medical treatises on malingering and S.W. Mitchell's civilian neurologic approaches that unmasked patients through more aggressive strategies. CONCLUSION: Charcot provided an academically professional approach to the assessment of neurologic malingering, with a stern, often patronizing attitude, but without categorical condemnation. His diagnostic techniques are echoed by contemporary approaches and emphasized an attention to enhanced and inconsistent patterns of behaviors by malingerers.

A novel automated rat catalepsy bar test system based on a RISC microcontroller.

Catalepsy tests performed in rodents treated with drugs that interfere with dopaminergic transmission have been widely used for the screening of drugs with therapeutic potential in the treatment of Parkinson's disease. The basic method for measuring catalepsy intensity is the "standard" bar test. We present here an easy to use microcontroller-based automatic system for recording bar test experiments. The design is simple, compact, and has a low cost. Recording intervals and total experimental time can be programmed within a wide range of values. The resulting catalepsy times are stored, and up to five simultaneous experiments can be recorded. A standard personal computer interface is included. The automated system also permits the elimination of human error associated with factors such as fatigue, distraction, and data transcription, occurring during manual recording. Furthermore, a uniform criterion for timing the cataleptic condition can be achieved. Correlation values between the results obtained with the automated system and those reported by two independent observers ranged between 0.88 and 0.99 (P<0.0001; three treatments, nine animals, 144 catalepsy time measurements).

Narcolepsy in Singapore: is it an elusive disease?

INTRODUCTION: The aims of the study were to determine the demographic, clinical, and polysomnographic characteristics of narcolepsy, and to address the difficulties in diagnosing narcolepsy and cataplexy, which is a cardinal symptom. We also ventured to investigate the differences between narcolepsy with and without cataplexy. MATERIALS AND METHODS: Data were collected retrospectively from patients diagnosed with narcolepsy at the Sleep Disorder Unit of Singapore General Hospital over 5 years. Each patient had had a detailed clinical evaluation and overnight polysomnography (PSG) followed by a multiple sleep latency test (MSLT). RESULTS: A total of 28 cases were studied. Males made up 85.7% of the total and females, 14.3%. The mean age was 30.9 years. All had excessive daytime sleepiness. Other manifestations were cataplexy (48.1%), sleep paralysis (51.9%), hypnogogic hallucinations (84%), disturbed night sleep (29.2%), automatisms (17.4%) and catnaps (95.8%). The mean duration of symptoms was 7.24 years. In the MSLT, the mean values for mean sleep latency and number of sleep onset rapid eye movement (REM) periods (SOREMP) were 4.3 minutes and 2.7, respectively. Narcolepsy was associated with obstructive sleep apnoea and periodic limb movement disorder (35.7%). All the variables were compared between those who had narcolepsy with cataplexy and without cataplexy. The duration of presenting complaint, REM latency, respiratory disturbance index, number of SOREMPs and the presence of sleep paralysis were significantly different in the 2 groups. CONCLUSIONS: Narcolepsy predominantly affects young males. Concurrence of other sleep disorders is not uncommon. Some differences are evident between those who have narcolepsy with and without cataplexy.

[Nacrolepsy manifesting initially as cataplexy and sleep paralysis: usefulness of CSF hypocretin-1 examination for early diagnosis].

We report a 24-year-old man with narcolepsy initially suffered from cataplexy and sleep paralysis. From May 2000, at age 23 he experienced two kinds of recurrent episodes of weakness without altered consciousness; one was provoked by emotion and excitement, the other occurred spontaneously on onset of sleep without hallucination. He denied having daytime sleepiness and did not experience hypnagogic hallucinations. In July 2000, at our hospital he received the first medical examinations, of which physical and neurological results were unremarkable. A magnetic resonance imaging scan of the brain also gave unremarkable results. The initial diagnosis was epilepsy, and anti-convulsant drugs were begun in August 2000. The weakness episodes were not lessened by the treatment with carbamazepine, sodium valproate or clonazepam, and he was admitted to our clinic in April 2001 for further examinations. Human leukocyte antigen testing was positive for DR15 (DR2) and DQ6 (DQ1). The routine electroencephalographam detected no epileptic discharge or paradoxical alpha blocking. A polysomnogram showed a sleep onset REM sleep period and sleep fragmentation, but there was no apnea or periodic leg movements. A multiple sleep latency test showed a mean sleep latency of 1.8 min and REM sleep in three of five naps. These findings suggested probable narcolepsy, so we examined the hypocretin-1 (orexin A) concentration in his cerebrospinal fluid (CSF). It was below the detection limit of the assay (< 40 pg/mL). The final diagnosis in April 2001 was narcolepsy. Making an initial diagnosis of incomplete or atypical narcolepsy is difficult for clinicians. A delay in diagnosis, however, may produce personal and social problems for narcoleptic patients. We believe that an examination of CSF hypocretin-1 aids in the early diagnosis of narcolepsy.

[Diagnostic difficulties in the narcolepsy-catalepsy syndrome: with reference to our series of cases]. / Dificultades diagnósticas en el síndrome narcolepsia-cataplejía: a propósito de nuestra casuística.

The narcolepsy-cataplexy syndrome is a disorder of unknown aetiology, characterized by excessive daytime sleepiness associated with cataplexy and other REM sleep phenomena. Diagnosis is based on the clinical findings, although this may be difficult especially with respect to confirming the cataplexy. Objective tests, such as typing for HLA, DR2DQ1 (DRw15DQw6, WHO90) and above all TMLS (average latency < 5 mn and two or more onsets of sleep in the phases REM and SOREMP's) is of great help. However, the exact diagnostic significance of some aspects of these tests and their parameters is still under discussion. In this paper we review our series of cases consisting of fourteen patients who fulfil the clinical diagnostic criteria required in the ICSD-1990. TMLS and HLA typing was done for all. Of the HLA types, DQ1 was present in all our patients, unlike DR2 which was not found in two patients. Regarding TMLS, the average latency < 5 mn is a parameter met by all cases, although one did not have SOREMP's. The findings of the objective tests done on our patients are in agreement with those described by other authors. They underline the significance of the support they lend to the diagnosis. However, they are not the definite answer to the problem.

Catalepsy tests: what do they tell us?

In a survey of 200 clinicians regarding their use of catalepsy tests, three fourths of the respondents indicated that they used these tests. In light of this response, and considering both the scientific importance of being able to identify the presence of hypnosis and the fact that catalepsy may account for up to eight of the other indications of hypnosis in use, it is relevant to inquire into the reliability and validity of catalepsy tests. It was found that of the three tests of catalepsy currently in use, only one has the potential for being a test of hypnosis proper and can also justifiably be said to be "of catalepsy." This one test, however, has many serious weaknesses that need to be eliminated if it is to be truly useful.

A clinical picture of child and adolescent narcolepsy.

Although narcolepsy is rarely diagnosed before adulthood, symptoms often begin much earlier and can easily mimic psychiatric disorders in children and adolescents. Clinical experience from a pediatric sleep center is reviewed in 16 consecutive cases of polysomnographically proven narcolepsy with onset of symptoms by age 13 years. Only 1 of the 16 patients presented with the classic clinical tetrad of symptoms (sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis). Behavioral and emotional disturbances were present in 12 of 16 cases, with four patients appearing to have been misdiagnosed with a psychiatric disorder before recognition of the narcolepsy. Obesity appeared as an unexpected association in this case series, with 11 of the 16 narcoleptic patients found to be overweight at the time of diagnosis. The varied clinical presentations, polysomnographic findings, family history, and associated psychiatric symptoms are described. The importance of considering narcolepsy in the differential diagnosis of any child or adolescent with excessive sleepiness is emphasized.

Stability of cataplexy over several months--information for the design of therapeutic trials.

Twenty-seven narcoleptic patients severely affected with cataplexy completed four symptom diaries over a 4-month period in order to clarify some of the controversies surrounding assessment of anticataplectic medications. The home diary method was found to be a viable model for the assessment of anticataplectic activity. Assessment of reliability in 1-, 2-, 3-, 4-, 5- and 10-day intervals indicated that reliability increases with the number of days included. A 10-day design was found to be optimal. Reliability decreased, however, with each successive diary over the 4-month period. Power analysis indicates that two groups of 30-40 subjects in a parallel design, or one group of 30-40 subjects in a crossover design, would be sufficient to demonstrate a significant therapeutic anticataplectic effect in most cases. A "first diary effect" was observed, suggesting that a training period prior to the actual trial might improve reliability. Whether the patient was treated or untreated with stimulant medications did not affect severity or fluctuation of cataplexy, suggesting that both groups of patients could be included in therapeutic trials. No time-of-day fluctuation was observed in the daily distribution of cataplexy attacks. Sudden increases in cataplexy were often, although not always, caused by unusual emotional events or sleepiness. The finding of a long-lasting "precataplectic" feeling or "aura" pointed to the need to carefully clarify the symptom prior to beginning a therapeutic trial.