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.

A role of diffusion tensor imaging fiber tracking in deep brain stimulation surgery: DBS of the dentato-rubro-thalamic tract (drt) for the treatment of therapy-refractory tremor.

INTRODUCTION: Deep brain stimulation (DBS) can alleviate tremor of various origins. A number of regions are targeted. In recent work our group was able to show the involvement of the dentato-rubro-thalamic tract (drt) in tremor control with fiber tracking techniques. Here we report for the first time the successful use of magnetic resonance tractography in combination with traditional landmark-based targeting techniques to perform the implantation of a bilateral DBS system in a patient with dystonic head tremor. METHODS: We report on a 37-year-old female with long-standing pure head tremor from myoclonus dystonia. She was identified as a candidate for thalamic DBS. The use of head fixation in a stereotactic frame would blur target symptoms (head tremor) during surgery and was therefore avoided. Her dentate-rubro-thalamic tracts were visualized with preoperative diffusion tensor imaging (DTI) and tractography, and then directly targeted stereotactically with DBS electrodes. RESULTS: Three months after implantation, tremor control was excellent (>90%). A close evaluation of the active electrode contact positions revealed clear involvement of the drt. CONCLUSION: This is the first time that direct visualization of fiber tracts has been employed for direct targeting and successful movement disorder tremor surgery. In the reported case, additional knowledge about the position of the drt, which previously has been shown to be a structure for modulation to achieve tremor control, led to a successful implantation of a DBS system, although there was a lack of intra-operatively testable tremor symptoms. In concordance with studies in optogenetic neuromodulation, fiber tracts are the emerging target structures for DBS. The routine integration of DTI tractography into surgical planning might be a leading path into the future of DBS surgery and will add to our understanding of the pathophysiology of movement disorders. Larger study populations will have to prove these concepts in future research.

Preferential and bidirectional labeling of the rubrospinal tract with adenovirus-GFP for monitoring normal and injured axons.

The rodent rubrospinal tract (RST) has been studied extensively to investigate regeneration and remodeling of central nervous system (CNS) axons. Currently no retrograde tracers can specifically label rubrospinal axons and neurons (RSNs). The RST can be anterogradely labeled by injecting tracers into the red nucleus (RN), but accurately locating the RN is a technical challenge. Here we developed a recombinant adenovirus carrying a green fluorescent protein reporter gene (Adv-GFP) which can preferentially, intensely, and bi-directionally label the RST. When Adv-GFP was injected into the second lumbar spinal cord, the GFP was specifically transported throughout the entire RST, with peak labeling seen at 2 weeks post-injection. When Adv-GFP was injected directly into the RN, GFP was anterogradely transported throughout the RST. Following spinal cord injury (SCI), injection of Adv-GFP resulted in visualization of GFP in transected, spared, or sprouted RST axons bi-directionally. Thus Adv-GFP could be used as a novel tool for monitoring and evaluating strategies designed to maximize RST axonal regeneration and remodeling following SCI.

Pyramidal and extrapyramidal scale (PEPS): a new scale for the assessment of motor impairment in vascular cognitive impairment associated with small vessel disease.

OBJECTIVE: Vascular cognitive impairment associated with small vessel disease (sVCI) may manifest as both cognitive and motor dysfunctions. However, few instruments exist for systematically assessing motor symptoms in sVCI, even though many neuropsychological tests exist to evaluate cognitive function. We developed a new scale for assessing motor impairments and evaluated the reliability and validity of the scale in patients with sVCI. METHODS: A new motor scale, called the PEPS (Pyramidal and Extra Pyramidal Scale for sVCI), consisted of 34 items (for 60 total points) with 5 subdomains: corticospinal, corticobulbar, extrapyramidal signs, gait abnormalities, and gait severity. The PEPS was compared between 75 patients with sVCI and 73 control patients who had dementia or mild cognitive impairment (MCI) without ischemia. RESULTS: The PEPS had good interrater and test-retest reliability, and it was moderately to highly correlated with the UPDRS, NIHSS, MMSE, CDR, and ADL scales. An optimal cut-off score of PEPS to discriminate dementia or MCI patients with ischemia from those without ischemia was 6.5 with a sensitivity of 88% and a specificity of 100%. CONCLUSION: The PEPS is a reliable and valid scale that can be used to assess and monitor motor impairment in patients with vascular cognitive impairment due to small vessel disease.

Progressive supranuclear palsy syndrome presenting as progressive nonfluent aphasia: a neuropsychological and neuroimaging analysis.

There is currently considerable interest in the clinical spectrum of progressive nonfluent aphasia (PNFA) and progressive supranuclear palsy (PSP) and the intersection of these two entities. Here, we undertook a detailed prospective clinical, neuropsychological, and neuroimaging analysis of 14 consecutive patients presenting with PNFA to identify cases meeting clinical criteria for PSP. These patients had further detailed assessment of extrapyramidal and oculomotor functions. All patients had high-resolution MR brain volumetry and a cortical thickness analysis was undertaken on the brain images. Four patients presenting with PNFA subsequently developed features of a PSP syndrome, including a typical oculomotor palsy. The neuropsychological profile in these cases was similar to other patients with PNFA, however, with more marked reduction in propositional speech, fewer speech errors, less marked impairment of literacy skills but more severe associated deficits of episodic memory and praxis. These PSP-PNFA cases had less prominent midbrain atrophy but more marked prefrontal atrophy than a comparison group of five patients with pathologically confirmed PSP without PNFA and more prominent midbrain atrophy but less marked perisylvian atrophy than other PNFA cases. In summary, although the PSP-PNFA syndrome overlaps with PNFA without PSP, certain neuropsychological and neuroanatomical differences may help predict the development of a PSP syndrome.

Extrapyramidal signs predict the development of overt hepatic encephalopathy in patients with liver cirrhosis.

BACKGROUND/AIMS: The long-term evolution of cirrhotic patients with extrapyramidal signs has not yet been studied. We have investigated the influence of extrapyramidal signs on the prognosis, evolution, and quality of life of patients with liver cirrhosis. METHODS: Forty-six patients with cirrhosis were followed up and 18 of them were reevaluated, a mean of 45 months later. Cognitive impairment was measured with psychometric tests (Trail-Making Test part A, Grooved-Pegboard, Block-Design, Oral Symbol Digit and Stroop Test). Extrapyramidal signs were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Health-related quality of life was measured using the SF-36 scale and the Chronic Liver Disease Questionnaire. RESULTS: Eleven of the 46 patients who were followed up developed overt hepatic encephalopathy (HE) during the follow-up. The presence of extrapyramidal signs was the unique factor that predicted overt HE and patients with basal higher score in the part 3 of the UPDRS developed overt HE more frequently [hazard ratio=1.29; 95% confidence interval (1.04-1.60) P=0.023]. In the 18 reevaluated patients, there was an increase in the score of the UPDRS part 3 after follow-up. There was a worsening in the score values of the block design and the Number Connection Test. In health-related quality of life scales, patients scored better in the area of mental health of the SF-36 scale. Patients with extrapyramidal signs persisted with worse scores in several items of the SF-36 scale and the Chronic Liver Disease Questionnaire. CONCLUSION: The presence of extrapyramidal signs in patients with liver cirrhosis predicts the development of overt HE. These signs increased along the follow-up, and remain a bad influence on quality of life.

Effect of cervical dorsolateral funiculotomy on reach-to-grasp function in the rat.

Cervical spinal cord injury (SCI) can severely impair reaching and grasping ability, and several descending systems, including the rubrospinal tract and corticospinal tract, have been implicated in the control of reach-to-grasp movements. The primary aim of this study was to characterize further the forelimb deficits associated with a cervical dorsolateral funiculotomy, which ablates the rubrospinal tract but spares the dorsal and ventral corticospinal tract in the rat. Adult female rats that preferred to use their right forelimb to reach for single pellets received a lesion to the right cervical dorsolateral funiculus between the C3-4 dorsal roots. Gross forelimb motor function was assessed by measuring spontaneous forelimb usage during exploration in a cylinder, and fine motor function was assessed using staircase and single pellet reaching tests. Single pellet reaching was further evaluated by qualitative and quantitative kinematic scoring of the movement components. Histological analysis included the quantification of spared white matter. Cervical dorsolateral funiculotomy produced marked deficits in reaching performance on both the single pellet and staircase reaching tests, with transient deficits in gross forelimb usage in the cylinder. Quantitative kinematics also revealed a reduction in digit abduction during the reach, which persisted throughout the 8-week post-SCI period. Tests of reach-to-grasp function, therefore, were more sensitive than a test of gross forelimb usage after cervical dorsolateral funiculotomy and did not show recovery over the 8-week survival period. We suggest that the staircase test is a useful screening tool for intervention studies because of its ease of implementation, and that the single pellet test is valuable for examining reaching accuracy and detailed kinematics.

Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long-term antipsychotic treatment.

DRD(1) and DRD(2) receptor gene variants have been associated with clinical aspects of schizophrenia; however only specific features were analyzed in different samples. To assess the complex interaction between genetic and clinical factors, we studied the possible cross-interactions between DRD1 and DRD2 dopamine receptor gene polymorphisms, symptomatology of schizophrenia and schizoaffective disorders, and the occurrence of treatment induced side effects taking into consideration possible clinical confounding variables. One hundred thirty one outpatients in stable remission meeting the DSMIV criteria for schizophrenia spectrum disorders and receiving long-term maintenance therapy with haloperidol, fluphenazine, zuclopenthixole, or risperidone were genotyped for DRD1 A-48G, DRD2 Ins-141CDel, and DRD2 Ser311Cys polymorphisms. Psychopathological symptoms were assessed with the positive and negative syndrome scale for schizophrenia (PANSS). Extrapyramidal side effects were assessed with the Simpson-Angus extrapyramidal side effects scale (EPS), the Barnes Akathisia scale (BARS), and the abnormal involuntary movement scale (AIMS). Drug dosage was included as covariant because it was associated with the severity of symptomatology, akathisia, and parkinsonism. No association was observed for DRD1 and DRD2 polymorphisms and extrapyramidal side effects, or with the other clinical variables considered. Our study suggests that DRD1 and DRD2 variants are not liability factors for tardive dyskinesia.

Deterioration of hemiparesis after recurrent stroke in the unaffected hemisphere: Three further cases with possible interpretation.

BACKGROUND: The concept of neural reorganization after brain damage is already well established, and many previous studies have successfully reported the translocation of the neural activation in the motor-related cortices during motor tasks using functional imaging modalities. Several primate and human studies have suggested the formation of newly reorganized tracts in the ipsilesional or contralesional hemisphere, but the mechanism for the formation of these tracts is still largely unknown. METHODS: Three acute stroke patients who presented with abrupt deterioration of their right-sided hemiparesis due to the infarcts following a recurrent stroke in the originally unaffected hemisphere were studied using magnetic resonance imaging (MRI), MR angiography and single-photon emission CT. The relationship between the neurological symptom on admission and the precise location of the new infarct was carefully investigated from the perspective of reorganization. RESULTS: Diffusion-weighted MRI showed a new subcortical infarct in the right hemisphere contralateral to the initial stroke in all patients. These new lesions involved the thalamus, globus pallidus or corona radiata, sparing the area of the internal capsule. T2-weighed MRI on admission showed an old infarct in the left middle cerebral artery territory, which had caused the original right-sided hemiparesis. CONCLUSION: It is proposed that the 'extrapyramidal' motor pathway in the unaffected hemisphere is associated with poststroke neural reorganization.

Joubert syndrome surviving to adulthood associated with a progressive movement disorder.

A 48-year-old man presented with a progressive gait disorder. He had longstanding ataxia, oculomotor apraxia, motor delay, and cognitive impairment, diagnosed as cerebral palsy. Physical examination revealed ataxia, oculomotor apraxia, extrapyramidal signs, and a wide-based, shuffling gait. Magnetic resonance imaging showed vermian aplasia, consistent with Joubert syndrome. Positron emission tomography scan revealed normal fluorodopa uptake, but elevated raclopride binding, compatible with dopamine deficiency. This case demonstrates that a patient with Joubert syndrome may survive into adulthood and present as a chronic neurologic disorder with subacute extrapyramidal signs.