Neurobiological mechanisms associated with antipsychotic drug-induced dystonia.

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.

Spastic Paraplegia Accompanied by Extrapyramidal Sign and Frontal Cognitive Dysfunction.

A complicated form of spastic paraplegia is a neurodegenerative disorder presenting as progressive spasticity in the bilateral lower limbs accompanied by some clinical features. The present case showed spastic paralysis and hyperreflexia in all extremities as well as lead pipe rigidity in the neck and bilateral upper extremities (R < L), decreased scores on frontal cognitive tests, a decreased accumulation of the right dorsal putamen on a DAT scan, and hypoperfusion of the bilateral frontal lobes on 99mTc-ECD single photon emission computed tomography (SPECT). The present case provides a new spectrum of spastic paraplegia based on the evidence of clinical scores and the findings of brain functional imaging.

The Relationship Between Enhanced Reticulospinal Outflow and Upper Limb Function in Chronic Stroke Patients.

BACKGROUND: Recent evidence from both monkey and human studies suggests that the reticulospinal tract may contribute to recovery of arm and hand function after stroke. In this study, we evaluated a marker of reticulospinal output in stroke survivors with varying degrees of motor recovery. METHODS: We recruited 95 consecutive stroke patients presenting 6 months to 12 years after their index stroke, and 19 heathy control subjects. Subjects were asked to respond to a light flash with a rapid wrist flexion; at random, the flash was paired with either a quiet or loud (startling) sound. The mean difference in electromyogram response time after flash with quiet sound compared with flash with loud sound measured the StartReact effect. Upper limb function was assessed by the Action Research Arm Test (ARAT), spasticity was graded using the Modified Ashworth Scale (MAS) and active wrist angular movement using an electrogoniometer. RESULTS: StartReact was significantly larger in stroke patients than healthy participants (78.4 vs 45.0 ms, P < .005). StartReact showed a significant negative correlation with the ARAT score and degree of active wrist movement. The StartReact effect was significantly larger in patients with higher spasticity scores. CONCLUSION: We speculate that in some patients with severe damage to their corticospinal tract, recovery led to strengthening of reticulospinal connections and an enhanced StartReact effect, but this did not occur for patients with milder impairment who could use surviving corticospinal connections to mediate recovery.

Longitudinal assessment of brain-derived neurotrophic factor in Sardinian psychotic patients (LABSP): a protocol for a prospective observational study.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) plays a crucial role in neurodevelopment, synaptic plasticity and neuronal function and survival. Serum and plasma BDNF levels are moderately, but consistently, decreased in patients with schizophrenia (SCZ) compared with healthy controls. There is a lack of knowledge, however, on the temporal manifestation of this decline. Clinical, illness course and treatment factors might influence the variation of BDNF serum levels in patients with psychosis. In this context, we propose a longitudinal study of a cohort of SCZ and schizophrenic and schizoaffective disorder (SAD) Sardinian patients with the aim of disentangling the relationship between peripheral BDNF serum levels and changes of psychopathology, cognition and drug treatments. METHODS AND ANALYSIS: Longitudinal assessment of BDNF in Sardinian psychotic patients (LABSP) is a 24-month observational prospective cohort study. Patients with SAD will be recruited at the Psychiatry Research Unit of the Department of Medical Science and Public Health, University of Cagliari and University of Cagliari Health Agency, Cagliari, Italy. We will collect BDNF serum levels as well as sociodemographic, psychopathological and neurocognitive measures. Structured, semistructured and self-rating assessment tools, such as the Positive and Negative Syndrome Scale for psychopathological measures and the Brief Assessment of Cognition in Schizophrenia for cognitive function, will be used. ETHICS AND DISSEMINATION: This study protocol was approved by the University of Cagliari Health Agency Ethics Committee (NP2016/5491). The study will be conducted in accordance with the principles of good clinical practice, in the Declaration of Helsinki in compliance with the regulations. Participation will be voluntary and written informed consent will be obtained for each participant upon entry into the study. We plan to disseminate the results of our study through conference presentations and publication in international peer-reviewed journals. Access to raw data will be available in anonymised form upon request to the corresponding author.

Severity of illness and extra pyramidal symptoms as predictors for oral diseases among patients with schizophrenia.

OBJECTIVE: The study explores the association between severity of illness (positive, negative, depressive and cognitive symptoms) and extra pyramidal symptoms (EPS) with dental caries, periodontal disease and prosthetic needs among patients with schizophrenia. MATERIAL AND METHODS: A total of 71 schizophrenic patients diagnosed based on ICD-10 criteria participated in the study. Clinical Global Impression - Schizophrenia (CGI-SCH) scale was used to evaluate positive, negative, depressive, cognitive symptoms and overall severity of schizophrenia. Simpson-Angus Scale (SAS) was used for assessment of EPS. Dental examinations were conducted as per WHO (1997) criterion. RESULTS: Mean DMFT and CPI scores with periodontal pockets were 5.57 ± 2.12 and 2.37 ± 0.74; significant differences being noted among those with and without EPS (p < 0.001). Positive and EPS associated with dental caries with odds ratio of 5.26 (1.05, 26.2) and 8.52 (2.31, 31.4) (p < 0.001). Depressive and EPS were associated with periodontal disease with odds ratio of 4.19 (1.53, 32.5) and 5.27 (1.29, 21.5), respectively (p < 0.001). Cognitive and EPS were associated with dental prosthetic needs with odds ratio of 4.33 (1.47, 31.2) (p < 0.001) and 7.78 (1.43, 42.2), respectively (p < 0.001). CONCLUSIONS: Patients with schizophrenia had high dental caries, periodontal disease and unmet dental prosthetic needs. Severity of the schizophrenic and EPS was associated with poor oral health. Efforts need to be focused on strengthening the evidence of its association with oral health indicators through further studies including cohort investigations.

Circuits regulating pleasure and happiness in major depression.

The introduction of selective serotonin reuptake inhibitors has gradually changed the borders of the major depression disease class. Anhedonia was considered a cardinal symptom of endogenous depression, but the potential of selective serotonin reuptake inhibitors to treat anxiety disorders has increased the relevance of stress-induced morbidity. This shift has led to an important heterogeneity of current major depressive disorder. The complexity can be disentangled by postulating the existence of two different but mutually interacting neuronal circuits regulating the intensity of anhedonia (lack of pleasure) and dysphoria (lack of happiness). These circuits are functionally dominated by partly closed limbic (regulating misery-fleeing behaviour) and extrapyramidal (regulating reward-seeking behaviour) cortico-striato-thalamo-cortical (CSTC) circuits. The re-entry circuits include the shell and core parts of the accumbens nucleus, respectively. Pleasure can be considered to result from finding relief from the hypermotivation to exhibit rewarding behaviour, and happiness from finding relief from negative or conflicting circumstances. Hyperactivity of the extrapyramidal CSTC circuit results in craving, whereas hyperactivity of the limbic system results in dysphoria.

Extrapyramidal Reactions Associated with Serotonergic Antidepressants.

OBJECTIVE: Extrapyramidal reactions (EPRs) associated with serotonergic antidepressant treatments have been reported since 1958. These reactions can be distressing for patients and complicate treatment. Our objective was to complete a follow-up review of published EPR cases reported for serotonergic antidepressants. DATA SOURCES: Published cases between January 1998 and May 2015 were collected through a medical literature search. Citation reference lists were also searched manually. STUDY SELECTION AND DATA EXTRACTION: Identified cases were reviewed for patient age, gender, psychiatric diagnosis, dosage, time to reaction onset, concurrent medications, and EPR description. Cases were excluded when there was not a clear description, if descriptions were not consistent with accepted definitions, or if the written English was poor. We included cases of akathisia, dystonia, dyskinesia, parkinsonism, or mixed EPRs. Authors scored each case using the Naranjo adverse drug reaction probability scale. DATA SYNTHESIS: We identified 86 published reports involving 91 patients; selective serotonin reuptake inhibitors were implicated in 80.2% of cases. All EPR types were reported: 17 akathisia cases, 18 dyskinesia cases, 27 dystonia cases, 19 parkinsonism cases, and 10 mixed EPR cases. EPRs typically occurred within 30 days of either treatment initiation or dose increase. Age, gender, antidepressant dosing, or concurrent antipsychotic treatment did not appear to broadly contribute to EPR risk. Naranjo scores ranged from 2 to 8. CONCLUSIONS: Case reports associating serotonergic antidepressants with EPRs continue to be published. Practitioners are advised that monitoring for such is important. Rigorous research efforts are needed to better understand the clinical risk factors for these adverse drug reactions.

Plasticity of subcortical pathways promote recovery of skilled hand function in rats after corticospinal and rubrospinal tract injuries.

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.