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Aim: Spinocerebellar ataxia type 2 (SCA2) is a trinucleotide repeat disorder characterized by mutations in the ataxin-2 gene. Although the primary symptoms of this disease are related to cerebellar involvement, such as ataxia and dysarthria, cognitive disorders associated with supratentorial involvement, depression, and extrapyramidal symptoms are also common. The aim of this study was to investigate volumetric changes in patients with SCA2. Materials and Methods: Nine SCA2 patients and sixteen age and gender-matched healthy controls were included in the study. Voxel-based morphometry (VBM) was used to explore changes in whole brain gray and white matter, while surface-based morphometry (SBM) was employed to investigate changes in cortical thickness (CT), local gyrification index (LGI), sulcal depth (SD), and fractal dimension (FD). Deep learning methods were utilized for the automatic segmentation of subcortical gray matter structures and extrapyramidal system structures. Comparisons between groups were made using GLM, T-Test, and Mann-Whitney U test. Results: VBM results showed widespread gray matter loss in the cerebellum and widespread white matter loss in the brain stem (Cluster size: 25918 voxels for gray matter, 24557 voxels for white matter). SBM findings indicated a decrease in cortical thickness (Cluster size:19276 vertices for left hemisphere; 17276 vertices for right hemisphere), more pronounced in the supratentorial frontoparietal region, while FD, LGI, and SD did not differ between groups. Volume loss was observed in the subthalamic nucleus, globus pallidus internus and externus, and red nucleus in SCA2 patients. Conclusion: SCA2 patients exhibit white and gray matter volume loss in the infratentorial region. Additionally, they show a decrease in frontoparietal cortical thickness, while FD, LGI, and SD do not show any changes. Moreover, atrophy is also observed in the extrapyramidal system structures. [ABSTRACT FROM AUTHOR]

The corticospinal and rubrospinal tracts are the predominant tracts for controlling skilled hand function. Injuries to these tracts impair grasping but not gross motor functions such as overground locomotion. The aim of the present study was to determine whether or not, after damage to both the corticospinal and rubrospinal tracts, other spared subcortical motor pathway can mediate the recovery of skilled hand function. Adult rats received a bilateral injury to the corticospinal tract at the level of the medullar pyramids and a bilateral ablation of the rubrospinal axons at C4. One group of rats received, acutely after injury, two injections of chondroitinase-ABC at C7, and starting at 7days post-injury were enrolled in daily reaching and grasping rehabilitation (CHASE group, n=5). A second group of rats received analogous injections of ubiquitous penicillinase, and did not undergo rehabilitation (PEN group, n=5). Compared to rats in the PEN group, CHASE rats gradually recovered the ability to reach and grasp over 42days after injury. Overground locomotion was mildly affected after injury and both groups followed similar recovery. Since the reticulospinal tract plays a predominant role in motor control, we further investigated whether or not plasticity of this pathway could contribute to the animal's recovery. Reticulospinal axons were anterogradely traced in both groups of rats. The density of reticulospinal processes in both the normal and ectopic areas of the grey ventral matter of the caudal segments of the cervical spinal cord was greater in the CHASE than PEN group. The results indicate that after damage to spinal tracts that normally mediate the control of reaching and grasping in rats other complementary spinal tracts can acquire the role of those damaged tracts and promote task-specific recovery.

Objective: To explore the microstructural damage of extrapyramidal system gray matter nuclei in Parkinson disease (PD) using diffusion kurtosis imaging (DKI).Materials and Methods: We enrolled 35 clinically confirmed PD patients and 23 healthy volunteers. All patients underwent MR examination with conventional MRI scan sequences and an additional DKI sequence. We subsequently reconstructed the DKI raw images and analyzed the data. A radiologist in our hospital collected the Mini-Mental State Examination (MMSE) score of all subjects.Results: In the PD group, the mean kurtosis and axial kurtosis level decreased in the red nucleus (RN) and thalamus; the radial kurtosis increased in the substantia nigra (SN) and globus pallidus (GP). Fractional anisotropy decreased in the putamen. The largest area under the ROC curve of mean diffusion in GP was 0.811. Most kurtosis parameters demonstrated a positive correlation with the MMSE score, while several diffusion parameters showed a negative correlation with the same.Conclusion: DKI can qualitatively distinguish PD from healthy controls; furthermore, DKI-derived parameters can quantitatively evaluate the modifications of microstructures in extrapyramidal system gray matter nucleus in PD.

Objective: To explore the microstructural damage of extrapyramidal system gray matter nuclei in Parkinson disease (PD) using diffusion kurtosis imaging (DKI). Materials and Methods: We enrolled 35 clinically confirmed PD patients and 23 healthy volunteers. All patients underwent MR examination with conventional MRI scan sequences and an additional DKI sequence. We subsequently reconstructed the DKI raw images and analyzed the data. A radiologist in our hospital collected the Mini-Mental State Examination (MMSE) score of all subjects. Results: In the PD group, the mean kurtosis and axial kurtosis level decreased in the red nucleus (RN) and thalamus; the radial kurtosis increased in the substantia nigra (SN) and globus pallidus (GP). Fractional anisotropy decreased in the putamen. The largest area under the ROC curve of mean diffusion in GP was 0.811. Most kurtosis parameters demonstrated a positive correlation with the MMSE score, while several diffusion parameters showed a negative correlation with the same. Conclusion: DKI can qualitatively distinguish PD from healthy controls; furthermore, DKI-derived parameters can quantitatively evaluate the modifications of microstructures in extrapyramidal system gray matter nucleus in PD. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the safety of 3-monthly paliperidone palmitate (PP3M) vs once-monthly paliperidone palmitate (PP1M) treatment with regard to extrapyramidal symptom (EPS)-related treatment-emergent adverse events (TEAEs) in patients with schizophrenia, previously stabilized on PP1M treatment.Patients and methods: Data on overall incidence, time to onset (TTO), and time to resolution (TTR) of EPS-related TEAEs (overall, subclasses such as dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor) from a randomized double-blind (DB) non-inferiority study were compared between PP3M and PP1M. Subgroup analysis was performed by age (18–25, 26–50, and 50+ years) and final open-label (OL) dose (50/75, 100, and 150 mg eq.).Results: Overall incidence of spontaneously reported EPS-related TEAEs decreased from 12.6% (PP1M) in OL phase to 8.3% (PP3M) and 7.4% (PP1M) in the DB phase; overall median TTO and TTR values were comparable between both groups. Among patients with reported EPS-related TEAEs, the median TTO for all EPS-related TEAEs was 17 days (PP1M) in OL phase and 115 days (PP3M) and 98.5 days (PP1M) in DB phase; median TTR was 36.5 days (PP1M) in OL phase and 91 days (PP3M) and 85.5 days (PP1M) in DB phase. No clear dose- or age-related differences in TTO and TTR of EPS-related TEAEs were noted.Conclusion: Despite differences in apparent half-life and pharmacokinetic profiles (peak plasma exposure of PP3M formulation is 70% higher than that of PP1M formulation), both PP3M and PP1M formulations exhibited comparable incidence of EPS-related TEAEs, TTO, and TTR in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Motor abnormalities (MAs) may be already evidenced long before the beginning of illness and are highly prevalent in psychosis. However, the extent to which the whole range of MAs are related to cognitive impairment in psychosis remains understudied. This study aimed to examine comparatively the relationships between the whole range of motor abnormalities and cognitive impairments in the first-episode of psychosis (FEP), their unaffected siblings and healthy control subjects. Fifty FEP patients, 21 of their healthy siblings and 24 age- and sex matched healthy controls were included. Motor assessment included catatonic, extrapyramidal and neurological soft signs (NSS) by means of standardized instruments. An exhaustive neuropsychological battery was also performed to extract the 7 cognitive dimensions of MATRICS initiative. Higher scores on NSS but not on extrapyramidal and catatonic signs showed significant associations with worse cognitive performance in the three study groups. However, the pattern of associations regarding specific cognitive functions was different among the three groups. Moreover, extrapyramidal signs showed significant associations with cognitive impairment only in FEP patients but not in their unaffected siblings and healthy controls. Catatonic signs did not show any significant association with cognitive functioning in the three study groups. These findings add evidence to the associations between motor abnormalities, particularly NSS and extrapyramidal signs, and cognitive impairment in first-episode psychosis patients. In addition, our results suggest that the specific pattern of associations between MAs and cognitive functioning is different in FEP patients from those of the unaffected siblings and healthy subjects. [ABSTRACT FROM AUTHOR]

Abstract: The hyperdirect pathway of the basal ganglia bypasses the striatum, and delivers cortical information directly to the subthalamic nucleus (STN). In rodents, the STN excites the two output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and the substantia nigra reticulata (SNr). Thus, during hyperdirect pathway activation, the STN drives EP firing inhibiting the thalamus. We hypothesized that STN activity could induce long‐term changes to the STN‐>EP synapse. To test this hypothesis, we recorded in the whole‐cell mode from neurons in the EP in acute brain slices from rats while electrically stimulating the STN. Repetitive pre‐synaptic stimulation generated modest long‐term depression (LTD) in the STN‐>EP synapse. However, pairing EP firing with STN stimulation generated robust LTD that manifested for pre‐before post‐as well as for post‐ before pre‐synaptic pairing. This LTD was highly sensitive to the time difference and was not detected at a time delay of 10 ms. To investigate whether post‐synaptic calcium levels were important for LTD induction, we made dendritic recordings from EP neurons that revealed action potential back‐propagation and dendritic calcium transients. Buffering the dendritic calcium concentration in the EP neurons with EGTA generated long term potentiation instead of LTD. Finally, mild LTD could be induced by post‐synaptic activity alone that was blocked by an endocannabinoid 1 (CB1) receptor blocker. These results thus suggest there may be an adaptive mechanism for buffering the impact of the hyperdirect pathway on basal ganglia output which could contribute to the de‐correlation of STN and EP firing. [ABSTRACT FROM AUTHOR]

Objective: Frameless stereotactic aspiration of a hematoma can be the one of the treatment options for spontaneous intracerebral hemorrhage in the basal ganglia. Postoperative hematoma enlargement, however, can be a serious complication of intracranial surgery that frequently results in severe neurological deficit and even death. Therefore, it is important to identify the risk factors of postoperative hematoma growth. Methods: During a 13-year period, 101 patients underwent minimally invasive frameless stereotactic aspiration for basal ganglia hematoma. Patients were classified into two groups according to whether or not they had postoperative hematoma enlargement in a computed tomography scan. Baseline demographic data and several risk factors, such as hypertension, preoperative hematoma growth, antiplatelet medication, presence of concomitant intraventricular hemorrhage (IVH), were analysed via a univariate statistical study. Results: Nine of 101 patients (8.9%) showed hematoma enlargement after frameless stereotactic aspiration. Among the various risk factors, concomitant IVH and antiplatelet medication were found to be significantly associated with postoperative enlargement of hematomas. Conclusion: In conclusion, our study revealed that aspirin use and concomitant IVH are factors associated with hematoma enlargement subsequent to frameless stereotactic aspiration for basal ganglia hematoma. [ABSTRACT FROM AUTHOR]

The present study aimed to observe the structural changes of the extracorticospinal tract in Parkinson's disease (PD) using susceptibility-weighted imaging (SWI) and diffusion tensor imaging (DTI) magnetic resonance (MR) scans. The association of DTI parameters and brain-iron accumulation with PD was examined and imaging signs useful in the diagnosis of PD were explored. The study included 30 patients with PD and 30 age- and gender-matched healthy controls who underwent routine MR, SWI and DTI scans. The corrected phase (CP) values of the substantia nigra (SN), red nucleus (RN), globus pallidus (GP) and putamen (PUT) were measured, and fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained. Significant differences were found in the CP values between the PD and control groups in the SN, RN and PUT, but there were no differences in other regions of interest (ROIs). The FA values of the SN and PUT in the PD group were significantly decreased compared with those of the control group, but there was no significant difference in the FA values of the GP. Furthermore, there was no significant inter-group difference in the ADC values of any ROIs. In conclusion, SWI is a method useful for evaluating brain-iron deposition in PD. Increasing iron storage levels have previously been shown to be associated with PD pathogenesis but not with the degree of PD severity. FA values may be useful for diagnosing PD, and DTI may offer some insight into PD pathomechanisms and clinical diagnosis. [ABSTRACT FROM AUTHOR]

OBJETIVO: A presença de síndromes psiquiátricas, incluindo demência, associada a distúrbios motores tem sido cada vez mais reconhecida durante a última década, com destaque para o prejuízo cognitivo na doença de Parkinson idiopática. Esta revisão enfocará a epidemiologia, os aspectos clínicos, diagnósticos diferenciais, mecanismos subjacentes e o tratamento da demência na doença de Parkinson idiopática. MÉTODO: Uma revisão da literatura dos estudos que investigaram a demência da doença de Parkinson idiopática foi realizada. RESULTADOS: A demência é altamente prevalente na doença de Parkinson idiopática. O protótipo da demência na doença de Parkinson idiopática consiste numa síndrome disexecutiva com comprometimento da atenção, funções executivas e, secundariamente, a memória. Neuroquimicamente, o déficit mais significativo parece ser colinérgico; a demência se correlaciona com a presença de corpos de Lewy corticais e límbicos. Evidências preliminares sugerem que os anticolinesterásicos podem ser efetivos na demência da doença de Parkinson idiopática. CONCLUSÕES: O prejuízo cognitivo na doença de Parkinson idiopática é associado a características próprias e é responsável por importante incapacidade nestes pacientes.OBJECTIVE: The concomitant presence of psychiatric syndromes, including dementia, with motor disturbance has been increasingly recognized during the last decade, with emphasis on cognitive impairment in idiopatic Parkinson's disease. This review will focus on the epidemiology, clinical aspects, differential diagnosis, underlying mechanisms and treatment of dementia in Parkinson's disease. METHOD: A literature review of the studies that investigated the dementia in Parkinson's disease was performed. RESULTS: Dementia is highly prevalent in Parkinson's disease. The prototype of dementia in Parkinson's disease is a dysexecutive syndrome with impaired attention, executive functions and secondarily impaired memory. Neurochemically the most significant deficit seems to be cholinergic; dementia seems to correlate best with cortical and limbic Lewy bodies. Preliminary evidence suggests that cholinesterase inhibitors may be effective in Parkinson's disease dementia. CONCLUSIONS: Cognitive impairment in Parkinson's disease is associated to specific features and is responsible for substantial disability in these patients.

Inhibition of phosphodiesterase 10A (PDE10A) results in activation of a dopamine D 1 receptor-mediated direct pathway in addition to a dopamine D 2 receptor-mediated indirect pathway in the striatum. Therefore, PDE10A inhibitors could be novel therapeutics for schizophrenia, which differ from the currently available antipsychotics that directly block the dopamine D 2 receptor. Previously, we found that a novel PDE10A inhibitor, PDM-042, had antipsychotic-like activity similar to currently available antipsychotics and minimal cataleptic effects in rats. The purpose of the present study was to examine the pharmacological effects of PDM-042 on cognitive function and extrapyramidal side effect. In addition, we aimed to examine whether these effects were mediated by activation of dopamine D 1 signaling in rats. PDM-042 (1–3 mg/kg) resulted in better discrimination of a novel object from a familiar one 48 h after the acquisition trial, suggesting that PDM-042 increased object recognition memory. A dopamine D 1 receptor antagonist, SCH23390 (0.1 mg/kg), significantly blocked the enhancement of the object recognition memory induced by PDM-042 (3 mg/kg) without affecting the recognition index by itself. We also found that the cataleptic effect of PDM-042 (1 mg/kg) was significantly enhanced by SCH23390 (0.01–0.03 mg/kg). These results indicate that PDM-042 has the potential to increase object recognition memory and that the cognitive enhancing and cataleptic effects of PDM-042 are mediated at least by activation of dopamine D 1 signaling. [ABSTRACT FROM AUTHOR]

Motor speech disorders are common in a number of neurological conditions including diseases involving impairment of the pyramidal, extrapyramidal, and cerebellar pathways, cranial nerves, muscular apparatus, neuromuscular plaque, and of cognitive, symbolic and mnestic activities. The diagnosis of speech disorders, namely the dysarthrias, involves the assessment of characteristic structural cerebral, prosodic, phonetic and phonemic changes, often flanked by concomitant functional, clinical, neuroradiological, neurophysiological and behavioral impairment. This paper presents a brief outline of the most significant associations to facilitate prompt differential diagnosis and thereby reduce the number of instrumental examinations required for diagnostic testing. [ABSTRACT FROM AUTHOR]

Attention can be conceptualized as comprising the functions of alerting, orienting, and executive control. Although the independence of these functions has been demonstrated, the neural mechanisms underlying their interactions remain unclear. Using the revised attention network test and functional magnetic resonance imaging, we examined cortical and subcortical activity related to these attentional functions and their interactions. Results showed that areas in the extended frontoparietal network (FPN), including dorsolateral prefrontal cortex, frontal eye fields (FEF), areas near and along the intraparietal sulcus, anterior cingulate and anterior insular cortices, basal ganglia, and thalamus were activated across multiple attentional functions. Specifically, the alerting function was associated with activation in the locus coeruleus (LC) in addition to regions in the FPN. The orienting functions were associated with activation in the superior colliculus (SC) and the FEF. The executive control function was mainly associated with activation of the FPN and cerebellum. The interaction effect of alerting by executive control was also associated with activation of the FPN, while the interaction effect of orienting validity by executive control was mainly associated with the activation in the pulvinar. The current findings demonstrate that cortical and specific subcortical areas play a pivotal role in the implementation of attentional functions and underlie their dynamic interactions. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder that is hallmarked by pathological changes associated with the death of dopaminergic neurons, particularly in the extrapyramidal system (substantia nigra pars compacta, striatum) of the brain. Although the causes of slow neuronal death in PD are unknown, both genetic and environmental factors are likely involved. Endogenous isoquinolines, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), present in the human brain have been previously reported to participate in the pathogenesis of PD. The chronic administration of 1BnTIQ induced parkinsonism in primates, and this effect might be associated with idiopathic PD. However, another endogenous derivative of tetrahydroisoquinoline, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), displays clear neuroprotective properties in the brain. In the present study, we investigated the neuroprotective effects of 1MeTIQ (25 and 50 mg/kg) in an animal model of PD after the chronic administration of 1BnTIQ (25 mg/kg). Behavioral analyses demonstrate that both acute and repeated treatment with 1MeTIQ completely antagonized 1BnTIQ-induced changes in rat locomotor activity. Neurochemical experiments indicate that 1MeTIQ co-administered with 1BnTIQ completely antagonized 1BnTIQ-induced reduction in the dopamine (DA) concentration in rat brain structures. In conclusion, the results demonstrate that 1MeTIQ possesses important neuroprotective properties in the animal model of PD and that the rats did not develop tolerance after its chronic administration. [ABSTRACT FROM AUTHOR]

Objective To evaluate damage to the extracorticospinal tract in Wilson disease (WD) patients using diffusion tensor imaging (DTI). Methods 70 patients with WD, including 50 with cerebral type and 20 with hepatic type, and 20 age-matched healthy controls were enrolled. Neurological symptoms were scored using the modified Young Scale. Patients with cerebral type WD were divided into four subgroups: those with (1) hypokinesia, (2) parkinsonism, (3) mouth and throat dystonia, and (4) psychiatric symptoms. All study subjects underwent DTI of the brain. Five regions of interest (ROIs) were chosen. Fractional anisotropy (FA) and fiber volumes between ROIs were determined, and the relationships between DTI metrics and clinical status were evaluated. Results FA values and fiber volumes between subcortical nuclei were lower in WD patients. Fiber volumes between the putamen (PU) and the globus pallidus (GP), substantia nigra (SN), and thalamus (TH); between the head of the caudate nucleus (CA) and the GP and TH; and between the TH and cerebellum were lower in group 1 than in the other groups of WD patients. Fiber volumes between the GP and the SN and TH were lower in group 2, and fiber volumes between the SN and TH were lower in group 3. DTI metrics differed between patients with the cerebral and hepatic types of WD. Conclusions DTI can reconstruct the network of the extracorticospinal tract. Fiber projection between subcortical nuclei was abnormal in WD patients. Damage to fiber connections may correlate with neurological symptoms in WD patients. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [ 3 H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [ 3 H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (K D ) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [ 3 H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident. [ABSTRACT FROM AUTHOR]

The author presents insights on the function of claustrum in information processing in the visual system. Topics discussed include the intrinsic excitatory connectivity of claustrum, the structural discontinuities in the anatomical structure of the claustrum, and how the brain operates in perception and cognition.

This study aimed to examine the functional networks related to the extrapyramidal system using a temporal oscillation signal correlation analysis method based on critical nodes in the substantia nigra (SN), red nucleus (RN) and dentate nucleus (DN). Nineteen healthy subjects underwent resting-state fMRI and susceptibility weighted imaging (SWI). For the brain network analysis, the SN, RN and DN were positioned on susceptibility weighted images and used as seeds for temporal correlations analyzed via BOLD data. T -tests were performed for the correlation coefficients of each seed. We demonstrated that the SN, RN and DN were functionally connected to each other, and, in general, their connectivity maps overlapped in a series of subcortical extrapyramidal structures and regions of cerebral cortices. A Granger causality analysis indicated that the effective connectivity graphs within extrapyramidal structures mainly exhibited a spacial up-down pattern for the positive and negative influences, respectively. Our findings suggest that extensive regions involved in the extrapyramidal system constituted a relatively exclusive network via spatial-temporal correlation signals that analogously corresponded to the anatomical structures. The investigation of extrapyramidal system networks may have potential clinical implications. [ABSTRACT FROM AUTHOR]

Many studies showed that abnormal oscillations in the cortical-basal ganglia loop is involved in the pathophysiology of Parkinson’s disease (PD). In contrast to the well-studied beta synchronization, high-voltage spindles (HVSs), another type of abnormal oscillation observed in PD, are neglected. To explore the role of subthalamic nucleus-deep brain stimulation (STN-DBS) in HVSs regulation, we simultaneously recorded the local field potential (LFP) in the globus pallidus (GP) and electrocorticogram (ECoG) in the primary motor cortex(M1) in freely moving 6-hydroxydopamine (6-OHDA) lesioned or control rats before, during, and after STN-DBS. Consistent with our previous study, HVSs occurrence, duration, and relative power and coherence between the M1 cortex and GP increased in 6-OHDA lesioned rats. We found that high but not low frequency stimulation restored the abnormal HVSs activity and motor deficit. These results suggest that the STN is involved in the abnormal oscillation between the M1 cortex and GP. [ABSTRACT FROM AUTHOR]

Altered mitochondrial function in the basal ganglia has been hypothesized to underlie cellular senescence and promote age-related motor decline. We tested this hypothesis in a nonhuman primate model of human aging. Six young (6–8 years old) and 6 aged (20–25 years old) female Rhesus monkeys ( Macaca mulatta ) were behaviorally characterized from standardized video records. Additionally, we measured mitochondrial bioenergetics along with calcium buffering capacity in the substantia nigra and putamen (PUT) from both age groups. Our results demonstrate that the aged animals had significantly reduced locomotor activity and movement speed compared with younger animals. Moreover, aged monkeys had significantly reduced ATP synthesis capacity (in substantia nigra and PUT), reduced pyruvate dehydrogenase activity (in PUT), and reduced calcium buffering capacity (in PUT) compared with younger animals. Furthermore, this age-related decline in mitochondrial function in the basal ganglia correlated with decline in motor function. Overall, our results suggest that drug therapies designed to enhance altered mitochondrial function may help improve motor deficits in the elderly. [ABSTRACT FROM AUTHOR]

The article examines the adverse effect of metoclopramide on the central nervous system (CNS) of the horse. Topics discussed include toxicity of Lidocaine CNS and cardiovascular system; health issues associated with drug overdose; and use of antihistaminic drugs as alternative treatments for metoclopramide-induced extrapyramidal effects.

Background: The use of antipsychotic drugs, particularly quetiapine, has increased at an unprecedented rate in the last decade, primarily in relation to nonpsychotic indications. This increased use is concerning because of the high rates of metabolic and extrapyramidal side effects and inadequate monitoring of these complications. The purpose of this study was to measure the use of quetiapine and other second-generation antipsychotics by primary care physicians and psychiatrists and the most common diagnoses associated with quetiapine recommendations. Methods: We analyzed data on antipsychotic use from the IMS Brogan Canadian CompuScript Database and the Canadian Disease and Treatment Index, with a focus on quetiapine. We looked at the number of dispensed prescriptions for second-generation antipsychotics written by primary care physicians and psychiatrists and the diagnoses associated with recommendations for quetiapine from 2005 to 2012. Results: Between 2005 and 2012, there was a 300% increase in dispensed prescriptions for quetiapine ordered by family physicians: from 1.04 million in 2005 to 4.17 million in 2012. In comparison, dispensed prescriptions from family physicians for risperidone increased 37.4%: from 1.39 million in 2005 to 1.91 million in 2012; those for olanzapine increased 37.1%, from 0.97 million in 2005 to 1.33 million in 2012. Dispensed prescriptions for quetiapine ordered by psychiatrists increased 141.6%: from 0.87 million in 2005 to 2.11 million in 2012. The top 4 diagnoses associated with quetiapine in 2012 were mood disorders, psychotic disorders, anxiety disorders and sleep disturbances. A 10-fold increase in quetiapine recommendations for sleep disturbances was seen over the study period, with almost all coming from family physicians. Interpretation: These findings indicate a preferential increase in the use of quetiapine over other antipsychotic drugs and show that most of the increased use is a result of off-label prescribing by family physicians. [ABSTRACT FROM AUTHOR]

Goal-directed decision making in biological systems is broadly based on associations between conditional and unconditional stimuli. This can be further classified as classical conditioning (correlation-based learning) and operant conditioning (reward-based learning). A number of computational and experimental studies have well established the role of the basal ganglia in reward-based learning, where as the cerebellum plays an important role in developing specific conditioned responses. Although viewed as distinct learning systems, recent animal experiments point toward their complementary role in behavioral learning, and also show the existence of substantial two-way communication between these two brain structures. Based on this notion of co-operative learning, in this paper we hypothesize that the basal ganglia and cerebellar learning systems work in parallel and interact with each other. We envision that such an interaction is influenced by reward modulated heterosynaptic plasticity (RMHP) rule at the thalamus, guiding the overall goal directed behavior. Using a recurrent neural network actor-critic model of the basal ganglia and a feed-forward correlation-based learning model of the cerebellum, we demonstrate that the RMHP rule can effectively balance the outcomes of the two learning systems. This is tested using simulated environments of increasing complexity with a four-wheeled robot in a foraging task in both static and dynamic configurations. Although modeled with a simplified level of biological abstraction, we clearly demonstrate that such a RMHP induced combinatorial learning mechanism, leads to stabler and faster learning of goal-directed behaviors, in comparison to the individual systems. Thus, in this paper we provide a computational model for adaptive combination of the basal ganglia and cerebellum learning systems by way of neuromodulated plasticity for goal-directed decision making in biological and bio-mimetic organisms. [ABSTRACT FROM AUTHOR]

Rationale: Self-injurious behaviour is not one of the three core symptoms that define autism. However, children on the autism spectrum appear to be particularly vulnerable. Afflicted children typically slap their faces, punch or bang their heads, and bite or pinch themselves. These behaviours can be extremely destructive, and they interfere with normal social and educational activities. However, the neurobiological mechanisms that confer vulnerability in children with autism have not been adequately described. Objectives: This review explores behavioural and neurobiological characteristics of children with autism that may be relevant for an increased understanding of their vulnerability for self-injurious behaviour. Methods: Behavioural characteristics that are co-morbid for self-injurious behaviour in children with autism are examined. In addition, the contributions of social and environmental deprivation in self-injurious institutionalized orphans, isolated rhesus macaques, and additional animal models are reviewed. Results: There is extensive evidence that social and environmental deprivation promotes self-injurious behaviour in both humans (including children with autism) and animal models. Moreover, there are multiple lines of convergent neuroanatomical, neurophysiological, and neurochemical data that draw parallels between self-injurious children with autism and environmentally deprived humans and animals. Conclusions: A hypothesis is presented that describes how the core symptoms of autism make these children particularly vulnerable for self-injurious behaviour. Relevant neurodevelopmental pathology is described in cortical, limbic, and basal ganglia brain regions, and additional research is suggested. [ABSTRACT FROM AUTHOR]

Chunking allows the brain to efficiently organize memories and actions. Although basal ganglia circuits have been implicated in action chunking, little is known about how individual elements are concatenated into a behavioral sequence at the neural level. Using a task in which mice learned rapid action sequences, we uncovered neuronal activity encoding entire sequences as single actions in basal ganglia circuits. In addition to neurons with activity related to the start/stop activity signaling sequence parsing, we found neurons displaying inhibited or sustained activity throughout the execution of an entire sequence. This sustained activity covaried with the rate of execution of individual sequence elements, consistent with motor concatenation. Direct and indirect pathways of basal ganglia were concomitantly active during sequence initiation, but behaved differently during sequence performance, revealing a more complex functional organization of these circuits than previously postulated. These results have important implications for understanding the functional organization of basal ganglia during the learning and execution of action sequences. [ABSTRACT FROM AUTHOR]

Highlights: [•] We review disinhibition, rebound, and entrainment modes of basal ganglia output. [•] We propose a unifying framework for three types of basal ganglia–thalamic transmission. [•] We propose a resolution to the paradox of pallidothalamic coactivation. [•] Excitatory inputs to the thalamus determine the mode of the thalamic firing. [•] Pallidal interspike intervals are discrete units of basal ganglia output. [ABSTRACT FROM AUTHOR]

Serotonin2C (5-HT) receptors are expressed in the basal ganglia, a group of subcortical structures involved in the control of motor behaviour, mood and cognition. These receptors are mediating the effects of 5-HT throughout different brain areas via projections originating from midbrain raphe nuclei. A growing interest has been focusing on the function of 5-HT receptors in the basal ganglia because they may be involved in various diseases of basal ganglia function notably those associated with chronic impairment of dopaminergic transmission. 5-HT receptors act on numerous types of neurons in the basal ganglia, including dopaminergic, GABAergic, glutamatergic or cholinergic cells. Perhaps inherent to their peculiar molecular properties, the modality of controls exerted by 5-HT receptors over these cell populations can be phasic, tonic (dependent on the 5-HT tone) or constitutive (a spontaneous activity without the presence of the ligand). These controls are functionally organized in the basal ganglia: they are mainly localized in the input structures and preferentially distributed in the limbic/associative territories of the basal ganglia. The nature of these controls is modified in neuropsychiatric conditions such as Parkinson's disease, tardive dyskinesia or addiction. Most of the available data indicate that the function of 5-HT receptor is enhanced in cases of chronic alterations of dopamine neurotransmission. The review illustrates that 5-HT receptors play a role in maintaining continuous controls over the basal ganglia via multiple diverse actions. We will discuss their interest for treatments aimed at ameliorating current pharmacotherapies in schizophrenia, Parkinson's disease or drugs abuse. [ABSTRACT FROM AUTHOR]

Electrophysiology studies routinely investigate the relationship between neural oscillations and task performance. However, the sluggish nature of the BOLD response means that few researchers have investigated the spectral properties of the BOLD signal in a similar manner. For the first time we have applied group ICA to fMRI data collected during a standard working memory task (delayed match-to-sample) and using a multivariate analysis,we investigate the relationship between working memory performance (accuracy and reaction time) and BOLD spectral power within functional networks. Our results indicate that BOLD spectral power within specific networks (visual, temporal-parietal, posterior default-mode network, salience network, basal ganglia) correlated with task accuracy. Multivariate analyses show that the relationship between task accuracy and BOLD spectral power is stronger than the relationship between BOLD spectral power and other variables (age, gender, head movement, and neuropsychological measures). A traditional General Linear Model (GLM) analysis found no significant group differences, or regions that covaried in signal intensity with task accuracy, suggesting that BOLD spectral power holds unique information that is lost in a standard GLM approach. We suggest that the combination of ICA and BOLD spectral power is a useful novel index of cognitive performance that may be more sensitive to brain-behavior relationships than traditional approaches. [ABSTRACT FROM AUTHOR]

The 'applause sign' is a motor perseveration described in focal and neurodegenerative disorders and characterized by fronto-subcortical dysfunction. Most previous formal investigations focused on Parkinson's disease or progressive supranuclear palsy. We assessed the prevalence of the applause sign in patients affected by Alzheimer's disease (AD), Lewy body dementia (LBD), corticobasal syndrome (CBS), and posterior cortical atrophy (PCA), with the aim to verify its contribution to the differential diagnosis. We enrolled 20 patients with AD, 20 with LBD, 16 with CBS, and ten with PCA, and 30 healthy controls. The three clap test (TCT) was used to elicit the applause sign, and was scored by raters blinded to the diagnosis. Correlation with motor (extrapyramidal) and cognitive measures was also performed. A maximum 40 % prevalence of a positive applause sign was found in the two parkinsonian syndromes, which could be discriminated from the two cortical groups with a positive predictive value of 82 % and a negative predictive value of 55 %. According to our findings, a diagnosis of LBD or CBS, rather than of AD or PCA, is highly probable in the presence of an abnormal TCP, but cannot be ruled out based on a negative result. No relevant correlates emerged that could clarify the origin and nature of the applause sign. [ABSTRACT FROM AUTHOR]

Background: Producing sounds by a musical instrument can lead to audiomotor coupling, i.e. the joint activation of the auditory and motor system, even when only one modality is probed. The sonification of otherwise mute movements by sounds based on kinematic parameters of the movement has been shown to improve motor performance and perception of movements. Results: Here we demonstrate in a group of healthy young non-athletes that congruently (sounds match visual movement kinematics) vs. incongruently (no match) sonified breaststroke movements of a human avatar lead to better perceptual judgement of small differences in movement velocity. Moreover, functional magnetic resonance imaging revealed enhanced activity in superior and medial posterior temporal regions including the superior temporal sulcus, known as an important multisensory integration site, as well as the insula bilaterally and the precentral gyrus on the right side. Functional connectivity analysis revealed pronounced connectivity of the STS with the basal ganglia and thalamus as well as frontal motor regions for the congruent stimuli. This was not seen to the same extent for the incongruent stimuli. Conclusions: We conclude that sonification of movements amplifies the activity of the human action observation system including subcortical structures of the motor loop. Sonification may thus be an important method to enhance training and therapy effects in sports science and neurological rehabilitation. [ABSTRACT FROM AUTHOR]

Abstract: Some 5-HT3 antagonists such as ondansetron have shown beneficial effects on negative symptoms of patients with schizophrenia. We aimed to evaluate the efficacy of granisetron (another 5-HT3 antagonist) add-on therapy in the treatment of negative symptoms of patients with stable schizophrenia. In a randomized, double-blind, and placebo-controlled study, forty stable patients with schizophrenia (DSM-IV-TR), were randomized to either granisetron (1 mg twice daily) or placebo (twice daily) in addition to risperidone up to 6 mg/day for eight weeks. The patients were assessed using positive and negative syndrome scale (PANSS) and extrapyramidal symptom rating scale (ESRS) at baseline, week 4 and 8. Hamilton depression rating scale (HDRS) was used to assess depression at baseline and week 8. Thirty-eight patients completed the trial. Granisetron group showed a significantly greater improvement on negative subscale than the placebo group at endpoint [t(38) = 6.046, mean difference (±95% CI) = 3.2(1.8–3.7), P < 0.001]. The same effect was observed for total score [t(38) = 4.168, mean difference (95% CI) = 3.2(1.6–4.7), P < 0.001]. However the placebo and granisetron groups did not differ in their reduction of positive and general psychopathology symptoms scores. HDRS scores and its changes did not differ between the two groups. The ESRS score at week 4 was significantly lower in the granisetron than the placebo group while the two groups showed similar ESRS score at week 8. Frequency of other side effects was similar between the two groups. In summary, granisetron add-on can safely and effectively reduce the primary negative symptoms of patients with schizophrenia. [Copyright &y& Elsevier]

Background Patients with obsessive-compulsive disorder (OCD) have highly idiosyncratic triggers. To fully understand which role this idiosyncrasy plays in the neurobiological mechanisms behind OCD, it is necessary to elucidate the impact of individualization regarding the applied investigation methods. This functional magnetic resonance imaging (fMRI) study explores the neural correlates of contamination/washing-related OCD with a highly individualized symptom provocation paradigm. Additionally, it is the first study to directly compare individualized and standardized symptom provocation. Methods Nineteen patients with washing compulsions created individual OCD hierarchies, which later served as instructions to photograph their own individualized stimulus sets. The patients and 19 case-by-case matched healthy controls participated in a symptom provocation fMRI experiment with individualized and standardized stimulus sets created for each patient. Results OCD patients compared to healthy controls displayed stronger activation in the basal ganglia (nucleus accumbens, nucleus caudatus, pallidum) for individualized symptom provocation. Using standardized symptom provocation, this group comparison led to stronger activation in the nucleus caudatus. The direct comparison of between-group effects for both symptom provocation approaches revealed stronger activation of the orbitofronto-striatal network for individualized symptom provocation. Conclusions The present study provides insight into the differential impact of individualized and standardized symptom provocation on the orbitofronto-striatal network of OCD washers. Behavioral and neural responses imply a higher symptom-specificity of individualized symptom provocation. [ABSTRACT FROM AUTHOR]

Phenytoin is one of the commonly used antiepileptic drugs. The common dose dependent and reversible neurological side effects of phenytoin are nystagmus, diplopia, dysarthria, ataxia, incoordination, chorioathetosis, orofacial dyskinesias and drowsiness. Persistent cerebellar dysfunction with cerebellar atrophy is a well known complication of long term phenytoin use. There are several mechanisms proposed including hypoxia due to frequent seizures or toxic effects of phenytoin on cerebellar Purkinje cells. However, irreversible cerebellar dysfunction following acute phenytoin intoxication is rare. We report a 20 year old female who presented with nystagmus, dysarthria, limb and truncal ataxia with orofacial dyskinesias and chorea. She also had cognitive and affective symptoms in the form of reduced attention, slow responses, lalling speech, blunting of affect, inappropriate laughter, reduced self care and executive dysfunction. The symptoms started 2 weeks following the initiation of phenytoin 300mg/ day, given prophylactically following left basal ganglia bleed. Her serum phenytoin was in toxic range, hence phenytoin was stopped. Her PET scan revealed bilateral cerebellar hypometabolism. At 6 months follow up, she had persistent ataxia with cognitive and affective dysfunction and follow up MRI showed diffuse cerebellar atrophy. The clinical and radiological findings suggest that acute phenytoin intoxication is responsible for persistent ataxia and cerebellar cognitive affective syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Hyperglycaemia (HG) occurs in 30-40% of the patients with acute ischaemic stroke and is associated with larger infarct size and poor functional outcome. It is unknown whether HG is also associated with larger perfusion deficits in the acute stage of ischaemic stroke. As perfusion computed tomography (CT) is a reliable technique to determine the infarct core and ischaemic penumbra, we aimed to determine if patients with acute ischaemic stroke and HG have larger perfusion deficits or infarct cores on admission perfusion CT than patients with normoglycaemia (NG). Methods: We identified 80 consecutive patients (mean age 69 ± 11 years, 58% men) with acute supratentorial non-lacunar ischaemic stroke in whom CT showed a perfusion deficit within 24 h after stroke onset. The size of the total perfusion deficit area (mean transit time of >145% compared to the contralateral hemisphere) and the infarct core area (cerebral blood volume of <2.0 ml/100 g) at the level of the basal ganglia (level 1) and at the level of the corona radiata (level 2) were compared between patients with HG (admission glucose ≥7.0 mM) and patients with NG with a MANOVA. Clinical outcome [modified Rankin Scale (mRS) score] after 6 months was correlated to glucose levels at admission. Results: Admission HG was present in 33 of the 80 patients (41%). A perfusion deficit was present in 79 (40% HG) patients at level 1 and 75 (43% HG) at level 2. The total area with a perfusion deficit (level 1 HG 22.1 ± 11.3 and NG 23.3 ± 12.3 cm2; level 2 HG 27.1 ± 12.3 and NG 25.4 ± 12.0 cm2) and the proportion of the infarct core (level 1 HG 31 ± 30% and NG 25 ± 22%; level 2 HG 33 ± 27% and NG 26 ± 23%) did not differ significantly between the groups. HG was associated with worse outcome (mRS ≥3) at 6 months (OR 2.6, 95% CI 0.72-9.1). Conclusions: As compared to patients with NG, patients with HG did not have larger perfusion deficits in the acute stage of ischaemic stroke. Nevertheless, functional outcome was worse in patients with HG, which means that poor clinical outcome in stroke patients with HG could not be explained by a larger perfusion deficit in the acute stage. Therefore, our study suggests that there might be a window of opportunity for glucose-lowering therapy in the future. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Motor tics are brief, repetitive, involuntary movements that interfere with behavior and appear in multiple neural disorders, most notably, Tourette syndrome. Converging evidence from different lines of research point to the involvement of the corticobasal ganglia system in tics, but the neural mechanism underlying motor tics is largely unknown. An animal model directly linking basal ganglia dysfunction and motor tics indicated that local disinhibition within the basal ganglia input structure, the striatum, induces the appearance of motor tics in both rats and monkeys. Recordings of neuronal activity from multiple brain regions performed in this model during the expression of motor tics showed that tics are associated with phasic changes of neuronal activity throughout the corticobasal ganglia pathway, culminating in the disinhibition of the cortex and the release of a tic. This line of research provides a mechanistic description of the underlying neurophysiology of motor tics and may supply the much needed infrastructure for methodical hypothesis-driven studies of novel clinical treatments. [ABSTRACT FROM PUBLISHER]

Key points The excitatory afferents to the striatum from the cortex and thalamus are critical in the expression of basal ganglia function., Thalamostriatal afferents are markedly heterogeneous and arise in different subnuclei of the intralaminar thalamus., We used an optogenetic approach, to isolate and selectively activate thalamostriatal afferents arising in the central lateral or parafascicular thalamic nuclei, and to study the properties of their synapses with principal striatal neurons, the medium-spiny neurons., Thalamostriatal synapses differ in many aspects and our data suggest that inputs from the central lateral nucleus are efficient drivers of medium-spiny neuron action potential firing, whereas inputs from the parafascicular nucleus are likely to be modulatory., These results suggest distinct roles for thalamostriatal inputs from different subnuclei of the thalamus and will help us understand how the striatal circuit operates in health and disease., Abstract To understand the principles of operation of the striatum it is critical to elucidate the properties of the main excitatory inputs from cortex and thalamus, as well as their ability to activate the main neurons of the striatum, the medium spiny neurons (MSNs). As the thalamostriatal projection is heterogeneous, we set out to isolate and study the thalamic afferent inputs to MSNs using small localized injections of adeno-associated virus carrying fusion genes for channelrhodopsin-2 and YFP, in either the rostral or caudal regions of the intralaminar thalamic nuclei (i.e. the central lateral or parafascicular nucleus). This enabled optical activation of specific thalamic afferents combined with whole-cell, patch-clamp recordings of MSNs and electrical stimulation of cortical afferents, in adult mice. We found that thalamostriatal synapses differ significantly in their peak amplitude responses, short-term dynamics and expression of ionotropic glutamate receptor subtypes. Our results suggest that central lateral synapses are most efficient in driving MSNs to depolarization, particularly those of the direct pathway, as they exhibit large amplitude responses, short-term facilitation and predominantly express postsynaptic AMPA receptors. In contrast, parafascicular synapses exhibit small amplitude responses, short-term depression and predominantly express postsynaptic NMDA receptors, suggesting a modulatory role, e.g. facilitating Ca2+-dependent processes. Indeed, pairing parafascicular, but not central lateral, presynaptic stimulation with action potentials in MSNs, leads to NMDA receptor- and Ca2+-dependent long-term depression at these synapses. We conclude that the main excitatory thalamostriatal afferents differ in many of their characteristics and suggest that they each contribute differentially to striatal information processing. [ABSTRACT FROM AUTHOR]

Abstract: The term “extrapyramidal” originally described a collection of tegmentospinal pathways that conveyed the propagation of cortically-induced seizures to the spinal cord of dogs with bilateral transection of the pyramidal tracts. The extrapyramidal concept developed into unwarranted avenues to include forebrain structures involved in motor control, such as the basal ganglia, or as a broad synonym of clinical syndromes characterized by nonparalytic abnormal involuntary movements and postures. Clinicians and pathologists assumed that, similarly to mammals in general, the human extrapyramidal system was also organized in parallel with the pyramidal tracts. Several inconsistencies of this model, as applied to humans, were overlooked despite compelling clinicoanatomic evidence showing that (i) bilateral damage to the pyramidal tracts at any level from the pontomedullary transition to the motor cortex produces the locked-in syndrome and (ii) the extrapyramidal tracts are sparse in man. In the present essay I advance the hypothesis that the human extrapyramidal system is fundamentally different from its mammalian counterparts both anatomically and functionally. To test this hypothesis, a systematic analysis of the residual motor patterns observed on a natural model of a bilateral section of the human pyramidal tracts, the locked-in syndrome, is provided. This analysis reveals that the human extrapyramidal system underpins the organization of the following categories of motor synergies: (i) oculofacial and oculocephalic, (ii) faciorespiratory, (iii) axial-appendicular, and (iv) plurisegmental. Anatomically, these functional repertoires of motor integration are mediated by six collections of axons defined by their brainstem nuclei of origin and spinal cord destinations: reticulospinal (medial and lateral), vestibulospinal (medial and lateral), rubrospinal (lateral only), and tectospinal (medial only) fiber systems. I conclude that the extrapyramidal concept can reliably be extended to humans, albeit its physiological and anatomical scope is considerably narrower than traditionally assumed. [Copyright &y& Elsevier]

Background: It has been suggested that neither dose titration nor the use of a loading dose was required for amisulpride and that 800 mg/day could be given from the first day with a low risk of extrapyramidal symptoms (EPS). However, no direct study of the need for dose titration has been conducted. Objective: This study aimed to compare the efficacy, tolerability and subjective experience of amisulpride between a group receiving an initial dose of 800 mg/day (AMI-800 group) and a group titrating up from an initial dose of 400 mg/day (AMI-400 group) over a period of 6 weeks. Methods: A total of 68 patients with acute exacerbations of schizophrenia participated in this 6-week randomized, multicentre, open-label study of amisulpride. Thirty patients were randomly assigned to the group that received an initial dose of 400 mg/day, which was then titrated up during the first 4 weeks following a fixed schedule. Thirty-eight patients were randomly assigned to the group receiving an initial dose of amisulpride 800 mg/day, which they took until the end of the fourth week. During the fifth and sixth weeks, the doses were adjusted flexibly in both groups. Our primary outcome measures were the Clinical Global Impression (CGI) scale and the changes over time in the total and subscale scores of the Positive and Negative Syndrome Scale (PANSS). Results: We found no significant between-group differences in clinical improvement on the CGI and the PANSS. However, when responders were defined as those patients who experienced at least a 30 % reduction in the PANSS total scores obtained at baseline, a higher proportion of those in the AMI-800 group met the criterion for responsiveness from week 4 (week 4: 68.4 % vs 40.0 %, p = 0.02; week 6: 71.1 % vs 43.3 %, p = 0.02). Irrespective of treatment group, significant proportions of patients developed hyperprolactinaemia (86 %) and EPS (35 %). However, no statistically significant differences in the overall incidence of adverse events were observed between the two treatment groups. There were also no group differences in subjective quality of life and attitudes toward antipsychotic medication. Conclusion: These results suggest that it may be useful to begin therapy, especially for acute exacerbations of schizophrenia, with an initial dose of amisulpride 800 mg/day to obtain maximal efficacy without any significant side effects. [ABSTRACT FROM AUTHOR]

Introduction. Extrapyramidal syndromes are significant side effects of antipsychotic therapy due to their severity, frequent occurrence and complications. This paper gives a brief of the literature with the emphasis on epidemiology, etiology, diagnosis and differential diagnosis, as well as the treatment of extrapyramidal disorders induced by antipsychotics. Dystonia. Sustained muscle contractions cause twisting and repetitive movements or abnormal postures. It may appear either as an acute or delayed, i.e. tardive sign. The incidence of dystonia is 2-3% among the patients treated with antipsychotics, and 50% among the ones cured with conventional antipsychotics. Akathisia. The main feature of this curious adverse effect is the psychomotor restlessness and the inability to remain motionless. Although akathisia is not very frequent, its incidence and prevalence ranges from 5 to 50% among the treated patients. It is most probably a result of the blockage of dopaminergic receptors. Parkinsonism. The most frequent secondary Parkinsonism is the one caused by drugs. The characteristic parkinsonian signs regress 4 to 16 weeks after the discontinuation of antipsychotic therapy. In the era of atypical antipsychotics this adverse effect appears less frequently. Tardive dyskinesia. Involuntary choreatic movements may appear days and months after the introduction of continuous use of antipsychotics. The individual susceptibility may play the major role in the development of this side effect. Conclusion. Numerous studies have compared conventional and atypical antipsychotics as well as atypical ones with one another in order to decrease the risk of development of extrapyramical side effects as well as to prevent their occurrence and improve their treatment. [ABSTRACT FROM AUTHOR]

Small protein fragments, and not just residues, can be used as basic building blocks to reconstruct networks of coevolved amino acids in proteins. Fragments often enter in physical contact one with the other and play a major biological role in the protein. The nature of these interactions might be multiple and spans beyond binding specificity, allosteric regulation and folding constraints. Indeed, coevolving fragments are indicators of important information explaining folding intermediates, peptide assembly, key mutations with known roles in genetic diseases, distinguished subfamily-dependent motifs and differentiated evolutionary pressures on protein regions. Coevolution analysis detects networks of fragments interaction and highlights a high order organization of fragments demonstrating the importance of studying at a deeper level this structure. We demonstrate that it can be applied to protein families that are highly conserved or represented by few sequences, enlarging in this manner, the class of proteins where coevolution analysis can be performed and making large-scale coevolution studies a feasible goal. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Many chronic inpatients with schizophrenia demonstrate enduring psychiatric symptoms and various side effects of antipsychotic drugs. Several biological markers such as prolactin, thyroid hormones and brain-derived neurotrophic factor (BDNF) are reportedly associated with psychiatric symptoms and/or antipsychotic side effects in patients with schizophrenia but to date findings are inconsistent. The objective of the present study was to comprehensively investigate the association of psychiatric and extrapyramidal symptoms with hormones and BDNF in chronic schizophrenia. Methods: In this study, 93 chronic inpatients with schizophrenia were comprehensively investigated in order to examine the association of psychiatric and extrapyramidal symptoms with prolactin, thyroid hormones (free triiodothyronine (T3), free thyroxine (T4), thyroid stimulating hormone), cortisol and BDNF. Symptoms were assessed via the Positive and Negative Syndrome Scale (PANSS), Mini-Mental State Examination (MMSE), and drug-induced extrapyramidal symptoms scale (DIEPSS). Results: Multiple regression analyses revealed that antipsychotic dose was the only variable that predicted significant variance in PANSS positive subscale scores, that BDNF and free T3 predicted significant variance in MMSE scores, and that prolactin and free T3 predicted significant variance in DIEPSS scores. Conclusion: These findings suggest that BDNF, free T3, and prolactin may be associated with cognitive function and/or extrapyramidal symptoms in patients with chronic schizophrenia. Notably, free T3 may be possibly associated with better cognitive function and less extrapyramidal symptoms, although our cross-sectional study could not reveal a causal relationship. [Copyright &y& Elsevier]