Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette's

Background  

Excessive sequential stereotypy of behavioral patterns (sequential super-stereotypy) in Tourette's syndrome and obsessive compulsive disorder (OCD) is thought to involve dysfunction in nigrostriatal dopamine systems. In sequential super-stereotypy, patients become trapped in overly rigid sequential patterns of action, language, or thought. Some instinctive behavioral patterns of animals, such as the syntactic grooming chain pattern of rodents, have sufficiently complex and stereotyped serial structure to detect potential production of overly-rigid sequential patterns. A syntactic grooming chain is a fixed action pattern that serially links up to 25 grooming movements into 4 predictable phases that follow 1 syntactic rule. New mutant mouse models allow gene-based manipulation of brain function relevant to sequential patterns, but no current animal model of spontaneous OCD-like behaviors has so far been reported to exhibit sequential super-stereotypy in the sense of a whole complex serial pattern that becomes stronger and excessively rigid. Here we used a hyper-dopaminergic mutant mouse to examine whether an OCD-like behavioral sequence in animals shows sequential super-stereotypy. Knockdown mutation of the dopamine transporter gene (DAT) causes extracellular dopamine levels in the neostriatum of these adult mutant mice to rise to 170% of wild-type control levels.     

Compensatory neural reorganization in Tourette syndrome

Children with neurological disorders may follow unique developmental trajectories whereby they undergo compensatory neuroplastic changes in brain structure and function that help them gain control over their symptoms. We used behavioral and brain imaging techniques to investigate this conjecture in children with Tourette syndrome (TS). Using a behavioral task that induces high levels of intermanual conflict, we show that individuals with TS exhibit enhanced control of motor output. Then, using structural (diffusion-weighted imaging) brain imaging techniques, we demonstrate widespread differences in the white matter (WM) microstructure of the TS brain that include alterations in the corpus callosum and forceps minor (FM) WM that significantly predict tic severity in TS. Most importantly, we show that task performance for the TS group (but not for controls) is strongly predicted by the WM microstructure of the FM pathways that lead to the prefrontal cortex and by the functional magnetic resonance imaging blood oxygen level-dependent response in prefrontal areas connected by these tracts. These results provide evidence for compensatory brain reorganization that may underlie the increased self-regulation mechanisms that have been hypothesized to bring about the control of tics during adolescence.     

A controlled study of Tourette syndrome. IV. Obsessions, compulsions, and schizoid behaviors.

To determine the frequency of obsessive, compulsive, and schizoid behaviors in Tourette syndrome (TS), we prospectively questioned 246 patients with TS, 17 with attention-deficit disorder (ADD), 15 with ADD due to a TS gene, and 47 random controls. The comparative frequency of obsessive, compulsive, and repetitive behaviors--such as obsessive unpleasant thoughts, obsessive silly thoughts, echolalia, palilalia, touching things excessively, touching things a specific number of times, touching others excessively, sexual touching, biting or hurting oneself, head banging, rocking, mimicking others, counting things, and occasional or frequent public exhibitionism--were significantly more common in TS patients than in controls. The frequency of each of these was much higher for grade 3 (severe) TS. Most of these behaviors also occurred significantly more often in individuals with ADD or in individuals with ADD secondary to TS (ADD 2(0) TS). When these features were combined into an obsessive-compulsive score, 45.4% of TS patients had a score of 4-15, whereas 8.5% of controls had a score of 4 or 5. These results indicate that obsessive-compulsive behaviors are an integral part of the expression of the TS gene and can be inherited as an autosomal dominant trait. Schizoid symptoms, such as thinking that people were watching them or plotting against them, were significantly more common in TS patients than in controls. Auditory hallucinations of hearing voices were present in 14.6% of TS patients, compared with 2.1% of controls (P = .02). These symptoms were absent in ADD patients but present in ADD 2(0) TS patients. These voices were often blamed for telling them to do bad things and were frequently identified with the devil. None of the controls had a total schizoid behavior score greater than 3, whereas 10.9% of the TS patients had scores of 4-10 (P = .02). This frequency increased to 20.6% in the grade 3 TS patients. These quantitative results confirm our clinical impression that some TS patients have paranoid ideations, often feel that people are out to get them, and hear voices.     

A family study of Gilles de la Tourette syndrome.

Previous studies have demonstrated that Gilles de la Tourette syndrome (TS) is a familial disorder and that chronic tics (CT) and obsessive compulsive disorder (OCD) appear to be etiologically related to the syndrome. In the present study we report the results from a study of 338 biological relatives of 86 TS probands, 21 biologically unrelated relatives of adopted TS probands, and 22 relatives of normal subjects. The 43 first-degree relatives of the adopted TS and normal probands constituted a control sample. The rates of TS, CT, and OCD in the total sample of biological relatives of TS probands were significantly greater than in the relatives of controls. In addition, the morbid risks of TS, OCD, and CT were not significantly different in families of probands with OCD when compared to relatives of probands without OCD. These findings provide further evidence that OCD is etiologically related to TS.     

抽动秽语综合征遗传学研究

抽动秽语综合症(Gilles de la Tourette’s syndrome,GTS,TS)是一种慢性复杂性神经精神障碍,多起病于儿童期,以多发性运动性抽动伴不自主发声为主要临床表现,并伴多种并发症及神经行为障碍.目前已有大量关于TS遗传学研究报道,但其主要遗传学基础尚未鉴定.在此就抽动秽语综合征的遗传学研究做一介绍.     

Stereoselective effect of morphine on antinociception and endogenous opioid peptide levels in plasma but not cerebrospinal fluid of dogs.

Morphine releases endogenous opioids into the circulation of dogs. To test the stereospecificity of this effect, as well as to determine whether morphine also releases endogenous opioids centrally, which might be involved in its antinociceptive action, the effects of (-)-morphine sulfate (10 mg/kg, sc) or (+)-morphine hydrobromide on antinociception in a dog tail-flick test, on semi-quantified morphine-induced signs of salivation, emesis, defecation and ataxia, and on the plasma and cerebrospinal fluid (CSF) levels of endogenous opioid peptides were studied. Plasma and CSF levels of immunoreactive beta-endorphin (i-BE), met-enkephalin (i-ME), leu-enkephalin (i-LE), and dynorphin (i-DY) were quantified by radioimmunoassay in octadecylsilyl-silica cartridge extracts. Immunoreactive morphine (i-M) levels were measured in unextracted samples. (-)-Morphine treatment significantly increased antinociception, morphine-induced signs, i-M levels in plasma and CSF, and i-BE, i-ME, and i-LE levels in plasma, but not CSF. Levels of i-DY remained constant in plasma and CSF. (+)-Morphine treatment did not alter any of these parameters, indicating that the effects of morphine on nociception, behavioral signs, and plasma endogenous opioids in dogs were stereoselective. It is concluded that morphine does not cause an increase in immunoreactive endogenous opioid peptides in the CSF at the time of its peak antinociceptive effect.     

Differential modulation of mouse brain biogenic amines by haloperidol and pimozide: implications in Tourette's syndrome

1. A comparison between the effect of equal dose regimens of Tourette's medications on mouse motor activity and regional brain monoamines suggests differential responses which may underlie drug-induced side-effects. 2. Haloperidol was more potent than pimozide in altering striatal dopamine concentration which may account for the greater incidence of haloperidol-induced extrapyramidal disorders compared to pimozide. 3. Pimozide, but not the haloperidol treatment, altered brain serotonin concentrations to suggest a decrease in turnover rate which may underlie pimozide-caused sedation in Tourette's syndrome. 4. Pimozide was more potent than haloperidol in duration of behavioral depression which suggests differential dopamine receptor subtypes blockade. 5. Pimozide was more potent than haloperidol in altering 3 of the 6 brain regions content of norepinephrine-derived normetanephrine which may be responsible for the increase in blood pressure reported during pimozide treatment.     

Cognitive and behavioral characteristics of turner syndrome: exploring a role for ovarian hormones in female sexual differentiation

To better understand factors contributing to behavioral development, we studied patients with Turner syndrome (TS), a disorder typically marked by prenatal onset of ovarian dysfunction. We compared girls and women (ages 12 and up) with TS (n = 21) to matched controls (n = 21) in cognitive and motor skills, as well as sex-typed personality characteristics and activity preferences. Measures were categorized (based on prior studies) as showing an average male advantage (male-superior measures), female advantage (female-superior measures), or no sex difference (sex-neutral measures). It was hypothesized that, if gonadal function contributes to behavioral development, effects of this deficiency would be more prominent on sexually differentiated than sex-neutral measures and thus that patient-control differences would be most marked for measures that show sex differences. Our findings indicated that TS patients and controls differed more on cognitive and motor domains that show sex differences than on sex-neutral domains. Patients also had more "undifferentiated" personalities and showed reduced sex-typed interests and activities. Differing experiences, as indexed by interests and activities, did not explain the observed cognitive and motor differences. These results are consistent with a role for ovarian hormones acting on the brain to influence cognitive and behavioral development, although they do not rule out other possible interpretations.     

The brain mechanism of error detection: the P.E.T. study

In present research, the brain maintenance of the error detection mechanism was studied in resting condition and while subjects consciously implemented incorrect actions (i.e. deception). Assessment of the regional cerebral blood flow revealed involvement of anterior cingulated cortex in deception. The obtained data indicate that it is impossible to consciously control the activity of the error detection mechanism. PET study of patients with obsessive compulsive disorder in resting condition revealed a decrease of brain glucose metabolism in the anterior cingulated cortex in comparison with healthy subjects. These data pointed to malfunctioning of the error detection mechanism. The findings support the formerly proposed hypothesis about the impact of the error detection mechanism in formation and support of obsessive compulsive disorder.     

Levallorphan and dynorphin improve motor dysfunction in Mongolian gerbils with unilateral carotid occlusion: the first application of the inclined plane method in the experimental cerebral ischemia

Levallorphan and dynorphin were effective on the motor dysfunction in the gerbil model of unilateral cerebral ischemia. The effect of opioids, levallorphan (mixed agonist-antagonist), dynorphin (kappa-receptor agonist) and naloxone (mu-receptor antagonist), on neurological impairment was evaluated using the unilateral cerebral ischemia model of gerbil. Motor function was evaluated quantitatively by using the inclined plane method. Both levallorphan-treated group and dynorphin-treated group showed a significant improvement of the motor dysfunction compared with saline-control group. On the other hand, naloxone-treated group did not differ from saline-control group. The beneficial effect of these opioids on motor dysfunction might be mediated by the kappa-opioid receptor. This study also showed the potential usefulness of the inclined plane method for the investigation on the cerebral ischemia.     

Enhanced cognitive control in young people with Tourette's syndrome

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by the presence of chronic vocal and motor tics. Tics are sudden, highly stereotyped, movements that can be simple or complex in appearance. Since patients with TS have difficulties preventing unwanted movements, one might expect that their ability to voluntarily control goal-directed movements would be similarly poor. Indeed, it has been suggested that TS sufferers are impaired at inhibiting reflexively triggered movements and in rapidly selecting or switching between different motor sets. This idea is consistent with current views on the neurological basis of TS that posit a dysfunction of the neural circuits linking the frontal lobes and the striatum. These circuits are known to be involved in the voluntary control of action. By using an oculomotor switching task, we show for the first time that young people with TS exhibit paradoxically greater levels of cognitive control over their movements than their age-matched controls. This finding is consistent with an increased need to monitor and control movements and may indicate a subcortical locus for the triggering of tics. It also suggests that the constant need to suppress tics could have resulted in an enhancement of the executive processes involved in inhibitory control.     

Hemodynamic responses of conscious rats following intrathecal injections of prodynorphin-derived opioids: independence of action of intrathecal arginine vasopressin

Experiments were conducted (i) to determine the hemodynamic (blood pressure and heart rate) responses of conscious rats following intrathecal (IT) administration of endogenous prodynorphin-derived opioids into the lower thoracic space, (ii) to identify the receptors involved in mediating their cardiovascular responses, and (iii) to reveal any possible hemodynamic interactions with the neuropeptide arginine vasopressin. Male Sprague-Dawley rats were surgically prepared with femoral arterial and venous catheters as well as a spinal catheter (into lower thoracic region, T9-T12). After recovery, hemodynamic responses were observed in conscious rats for 5-10 min after IT injections of artificial cerebrospinal fluid (CSF) solution, prodynorphin-derived opioids (dynorphin A, dynorphin B, dynorphin A (1-13), dynorphin A (1-10), alpha- and beta-neoendorphin, leucine enkephalin (LE), methionine enkephalin (ME), arginine vasopressin (AVP), or norepinephrine (NE)). IT injections of AVP (10 or 20 pmol), dynorphin A (1-13), or dynorphin A (10-20 nmol) caused pressor effects associated with a prolonged and significant bradycardia. Equimolar (20 nmol) concentrations of LE, ME, alpha- and beta-neoendorphin, and dynorphin A (1-10) caused no significant blood pressure or heart rate changes. Combined IT injections of dynorphin A (1-13) and AVP caused apparent additive pressor effects when compared with the same dose of either peptide given alone. IT infusion of the specific AVP-V1 antagonist d(CH2)5Tyr(Me)AVP before subsequent IT AVP, dynorphin A (1-13), or NE administration inhibited only the subsequent pressor responses to AVP. The kappa-opioid antagonist (Mr2266) infused IT blocked the pressor actions of subsequent dynorphin A administration and not AVP or NE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-Related Behavioral Phenotype of an Astrocytic Monoamine Oxidase-B Transgenic Mouse Model of Parkinson’s Disease

We have previously shown that increases in astrocytic monoamine oxidase-B (MAO-B) expression, mimicking that which occurs with aging and in neurodegenerative disease, in a doxycycline (dox)-inducible transgenic mouse model evokes neuropathological similarities to what is observed in the human parkinsonian brain. Additional behavioral and neuropathological studies could provide further validation for its usage as a model for Parkinson’s disease (PD). In the present study, we utilized a battery of behavioral tests to evaluate age-related phenotype in this model. In the open field test, we found that dox-induction impaired motor ability with decreases in movement and ambulatory function as well as diminished stereotypical, repetitive movement episodes in both young and old mice. Older mice also showed decreased motor performance in the pole test when compared to younger mice. Furthermore, dox-induced older mice displayed severe hindlimb clasping and the most significant loss of dopamine (DA) in the striatum when compared to young and non-induced animals. Additionally, increased MAO-B activity significantly correlated with decreased expression of striatal DA. The results of our study further confirms that the dox-inducible astrocytic MAO-B transgenic mouse displays similar age-related behavioral and neuropathological features to other models of PD, and could serve as a useful tool to study PD pathophysiology and for the evaluation of therapeutic interventions.     

Increased dynorphin immunoreactivity in spinal cord after traumatic injury

Opiate antagonists, at high doses, have been shown to improve physiological variables and outcome after experimental spinal injury. Dynorphin appears to be unique amongst opioids in producing hindlimb paralysis after intrathecal injection. Taken together, these findings suggest a possible pathophysiological role for endogenous opioids, particularly dynorphin, in spinal injury. In the present studies we examined the relationship between changes in dynorphin immunoreactivity (Dyn-ir) in rat spinal cord after traumatic injury and the subsequent motor dysfunction. Trauma was associated with significantly increased Dyn-ir at the injury site, but not distant from the lesion. Dyn-ir was found elevated as early as 2 h and as late as 2 weeks after trauma, and was significantly correlated with the degree of injury. These data are consistent with the hypothesis that dynorphin systems may be involved in the secondary injury that follows spinal trauma.     

Stress management and Gilles de la Tourette's syndrome

Tourette's syndrome is a lifelong disorder characterized by multiple motor and verbal tics. The present study examined relaxation training and desensitization training as a method of reducing the frequency and intensity of tics and the distress they caused in a young adult diagnosed with Tourette's syndrome. After a period of symptom monitoring the subject underwent 3 weeks of intensive training in relaxation skills and 5 weeks of desensitization training with situational cues previously identified as eliciting Tourette's symptoms. According to self-report monitoring, the experience of symptoms was decreased across 3 global dimensions: distress (48%), frequency (48%), and intensity (50%), and an hourly symptom count (50%). Collateral parental symptom report agreed with an observed decrease across distress (40%), frequency (41%), and intensity (40%). Inspection of data suggests that both components of stress management added to total treatment efficacy.     

Effects of the essential oil from Citrus aurantium L. in experimental anxiety models in mice

Citrus aurantium L. is popularly used to treat anxiety, among other indications suggesting central nervous system action. Previous studies showed anxiolytic effect in the essential oil from peel in mice evaluated on the elevated plus maze [Carvalho-Freitas, M.I.R., Costa, M., 2002. Anxiolytic and sedative effects of extracts and essential oil from Citrus aurantium L. Biological and Pharmaceutical Bulletin 25, 1629-1633.]. In order to better characterize the activity of the essential oil, it was evaluated in two other experimental models: the light-dark box and the marble-burying test, respectively related to generalized anxiety disorder and to obsessive compulsive disorder. Mice were treated acutely by oral route 30 min (single dose) or once a day for 15 days (repeated doses) before experimental procedures. In light-dark box test, single treatment with essential oil augmented the time spent by mice in the light chamber and the number of transitions between the two compartments. There were no observed alterations in the parameters evaluated in light-dark box after repeated treatment. Otherwise, single and repeated treatments with essential oil were able to suppress marble-burying behavior. At effective doses in the behavioral tests, mice showed no impairment on rotarod procedure after both single and repeated treatments with essential oil, denoting absence of motor deficit. Results observed in marble-burying test, related to obsessive compulsive disorder, appear more consistent than those observed in light-dark box.     

Stress management and Gilles de la Tourette's syndrome

Tourette's syndrome is a lifelong disorder characterized by multiple motor and verbal tics. The present study examined relaxation training and desensitization training as a method of reducing the frequency and intensity of tics and the distress they caused in a young adult diagnosed with Tourette's syndrome. After a period of symptom monitoring the subject underwent 3 weeks of intensive training in relaxation skills and 5 weeks of desensitization training with situational cues previously identified as eliciting Tourette's symptoms. According to self-report monitoring, the experience of symptoms was decreased across 3 global dimensions: distress (48%), frequency (48%), and intensity (50%), and an hourly symptom count (50%). Collateral parental symptom report agreed with an observed decreased across distress (40%), frequency (41%), and intensity (40%). Inspection of data suggests that both components of stress management added to total treatment efficacy.     

Ultrastructure of ependyma in brain third ventricle of the rats exposed to repeated tail-suspension. Scanning electron microscopical study

By means of scanning electron microscopy the ultrastructure of ependyma was studied in the brain third ventricle of the rats repeatedly exposed to 14-day tail-suspension (TS). Animals were subjected to TS for 30 days, then readapted to horizontal position during 30 days and again, repeatedly subjected to TS for 14 days simultaneously with the rats which were in TS for the first time during 14 days. Repeated TS of rats, inspite of repeated redistribution of body liquid mediums in cranial direction, results in considerably less expressed destructive changes in ultrastructure of ependymocyte cilia, then after primary 14- and 30-day TS, showing much greater cerebrospinal fluid (CSF) outflow from brain ventricles into sagittal venous sinus at postponed for a long time, repeated simulation of weightlessness effects in comparison with CSF outflow at primery one.     

Tourettesyndrome免疫病因学研究进展

多发性抽动症（Tourette syndrome）是一种慢性神经精神性疾病,好发于儿童和青少年,主要表现为一个或多个部位肌肉运动性或发声性抽动,发作期持续超过一年,间歇期不超过3个月。TS的病因和发病机制至今仍未明确,目前认为其发病与免疫因素,环境心理因素,遗传因素,生物化学因素等多种因素有关,目前,A族B溶血性链球菌与Ts的发生跟发展的关系已有所报道,较多研究是关于链球茵感染的,一些免疫相关研究发现与链球菌感染有关的小儿自身免疫性神经精神疾病会引发或加重抽动症状。另外,过敏性变态反应性疾病与Ts患儿的自身免疫应答活跃的关系也有所报道。神经．内分泌一免疫网络学说认为,外周免疫系统跟中枢神经系统之间,可通过直接接触或通过产生并释放出来的生物活性因子进行信息交流。细胞因子正是两大系统间相互作用的信使,不仅可以调节免疫,而且还可以调控神经元和神经胶质细胞的功能。细胞因子与神经介质、内分泌激素共同组成机体细胞间的信号分子,参与免疫系统并激活神经递质及激素间的信息传递,与精神障碍和心理机体反应密切相关。因此,有关免疫病因学异常可能是部分易感患儿发病的机制,文章从感染免疫学,过敏性变态反应性疾病,以及细胞因子调节网络等与免疫相关的几个方面加以综述。     

Electroconvulsive therapy for manic state with mixed and psychotic features in a teenager with bipolar disorder and comorbid episodic obsessive–compulsive disorder: a case report

Background

Comorbidity of bipolar disorder and obsessive–compulsive disorder is common in adolescence. Obsessive–compulsive disorder symptoms may be episodic and secondary to alterations in mood, and display specific features. Management of pediatric bipolar disorder-obsessive–compulsive disorder is challenging, as pharmacotherapy of obsessive–compulsive disorder may induce or exacerbate manic episodes and there is limited evidence of treatment efficacy. Electroconvulsive therapy is sparsely used in children and adolescents, but is documented to be a safe and efficacious intervention in adults with bipolar disorder. In view of the severity of symptoms in juvenile mania, studies on treatment strategies are warranted. We report a case of an adolescent with bipolar disorder-obsessive–compulsive disorder who was successfully treated with electroconvulsive therapy during an episode of severe mania.

Case presentation

A 16-year-old girl of Middle East origin first presented to us with depressed mood, irritability, and increased obsessive–compulsive disorder symptoms, which were initially interpreted in the context of acute stress secondary to migration. She had been diagnosed with bipolar disorder and obsessive–compulsive disorder in her previous home country, but had difficulties in accounting for earlier psychiatric history. During hospitalization her mood switched to a manic state with mixed and psychotic features, at times showing aggression toward others. Interruption in her lithium treatment for a short period and possibly the introduction of an atypical antipsychotic could in part have been triggering factors. After 8 weeks of in-patient care and psychotropic drug trials, electroconvulsive therapy was initiated and administered every second or third day for 4 weeks, with marked positive response. No apparent side effects were reported.

Conclusions

This case demonstrates the need for a detailed medical history, taking special note of periodicity and character of obsessive–compulsive disorder symptoms, in adolescents with mood disorders. When treating culturally diverse patients, extra consideration should be taken. Special concerns in the pharmacological treatment to avoid the patient’s condition from worsening must be addressed, including giving priority to mood stabilization before obsessive–compulsive disorder symptoms. There are potential benefits in considering electroconvulsive therapy in young patients with severe mania where first-line treatment options have failed.