The visual perception of natural motion: abnormal task-related neural activity in DYT1 dystonia.

Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of 'natural' versus 'unnatural' motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of 'natural' and 'unnatural' motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to 'natural' versus 'unnatural' motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P < 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P < 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P < 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways.

Thalamocortical Connectivity Correlates with Phenotypic Variability in Dystonia.

Dystonia is a brain disorder characterized by abnormal involuntary movements without defining neuropathological changes. The disease is often inherited as an autosomal-dominant trait with incomplete penetrance. Individuals with dystonia, whether inherited or sporadic, exhibit striking phenotypic variability, with marked differences in the somatic distribution and severity of clinical manifestations. In the current study, we used magnetic resonance diffusion tensor imaging to identify microstructural changes associated with specific limb manifestations. Functional MRI was used to localize specific limb regions within the somatosensory cortex. Microstructural integrity was preserved when assessed in subrolandic white matter regions somatotopically related to the clinically involved limbs, but was reduced in regions linked to clinically uninvolved (asymptomatic) body areas. Clinical manifestations were greatest in subjects with relatively intact microstructure in somatotopically relevant white matter regions. Tractography revealed significant phenotype-related differences in the visualized thalamocortical tracts while corticostriatal and corticospinal pathways did not differ between groups. Cerebellothalamic microstructural abnormalities were also seen in the dystonia subjects, but these changes were associated with genotype, rather than with phenotypic variation. The findings suggest that the thalamocortical motor system is a major determinant of dystonia phenotype. This pathway may represent a novel therapeutic target for individuals with refractory limb dystonia.

Emerging drugs for schizophrenia: an update.

INTRODUCTION: Schizophrenia is one of the most serious mental disorders. Its treatment remains challenging, as existing antipsychotic antidopaminergic medications improve only/predominantly positive symptoms, agitation and aggression but have limited/insignificant efficacy for negative and cognitive symptoms, which strongly affect functional outcome. Therefore, new therapeutic agents are urgently needed that treat aspects of the spectrum of schizophrenia symptomatology and improve functional outcome. AREAS COVERED: The authors review the mechanisms of action and key clinical results of drug development targets currently in Phase II and III clinical testing for schizophrenia. They further discuss potential barriers to the successful development of these targets and summarize the drug development status of emerging treatments for various aspects of schizophrenia. EXPERT OPINION: Although modifications and variations of antidopaminergic mechanisms are expected to be successful, the added benefits will likely remain small, at least regarding enhanced efficacy for negative symptoms, cognition and functional outcomes. Greater innovation will likely come from further and deeper exploration of extra-dopaminergic mechanisms. Investment is needed to develop clinically meaningful animal paradigms probing the different symptom domains, to discover more efficient in vivo screening methods for novel drug targets, to optimize clinical trial design and trial conduct, and to parse the heterogeneous groups of schizophrenias into biologically more homogeneous subgroups.

Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia.

Since currently available antipsychotic medications predominantly treat hallucinations, delusions, disorganized thoughts and behavior, and related agitation/aggression, attention has traditionally been focused on managing positive symptoms. However, prominent negative symptoms and clinically relevant cognitive impairment affect approximately 40% and 80% of people with schizophrenia, respectively. Moreover, negative and cognitive symptoms are closely related to functional outcomes, and contribute substantially to the overall illness burden. Therefore, approaches to describe, measure, and manage these symptom domains are relevant. This article summarizes the phenomenology, prevalence, assessment, and treatment of negative and cognitive symptoms in patients with schizophrenia, including pharmacologic and nonpharmacologic management strategies that can be used in clinical care now, as well as pharmacologic approaches that are being tested. Currently, no approved treatments targeting negative or cognitive symptomatology in schizophrenia are available. It is hoped that progress in the understanding of the neurobiology of these important symptom domains of schizophrenia will help develop effective treatment strategies in the future. However, until this goal is achieved, clinicians should avoid therapeutic nihilism. Rather, the severity and impact of negative and cognitive symptoms should be determined, quantified, and monitored. Further, psychosocial treatments have shown therapeutic benefits. Thus, cognitive behavioral therapy, cognitive remediation, social skills training, and computer-assisted training programs should be offered in conjunction with antipsychotic treatment. Several non-antipsychotic augmentation strategies can be tried off-label. Treatment plans that incorporate currently available management options for negative and cognitive symptomatology in patients with schizophrenia should be adapted over time and based on the individual's needs, with the aim to enhance overall outcomes.

Impaired sequence learning in dystonia mutation carriers: a genotypic effect.

Abnormalities in motor sequence learning have been observed in non-manifesting carriers of the DYT1 dystonia mutation. Indeed, motor sequence learning deficits in these subjects have been associated with increased cerebellar activation during task performance. In the current study, we determined whether similar changes are also present in clinically manifesting DYT1 carriers as well as in carriers of other primary dystonia mutations such as DYT6. Additionally, we determined whether sequence learning performance and associated brain activation in these subjects correlate with previously described genotype-related abnormalities of cerebellar pathway integrity and striatal D2 dopamine receptor binding. Nineteen DYT1 carriers (10 non-manifesting DYT1: 51.5±15.1 years; nine manifesting DYT1: 46.1±15.1 years) and 12 healthy control subjects (42.8±15.3 years) were scanned with H2(15)O positron emission tomography while performing controlled sequence learning and reference tasks. Eleven DYT6 carriers (four non-manifesting DYT6: 38.0±22.1; seven manifesting DYT6: 35.3±14.2 years) were evaluated during task performance without concurrent imaging. DYT1 and DYT6 carriers also underwent diffusion tensor magnetic resonance imaging for the assessment of tract integrity and 11C-raclopride positron emission tomography to measure caudate/putamen D2 receptor binding. These imaging measures were correlated with sequence learning performance and associated activation responses. Sequence learning deficits of similar magnitude were observed in manifesting and non-manifesting DYT1 carriers. In contrast, learning deficits were not detected in DYT6 carriers, irrespective of clinical penetrance. Affected DYT1 carriers exhibited significant increases in sequence learning-related activation in the left lateral cerebellar cortex and in the right premotor and inferior parietal regions. Increases in premotor cortical activation observed in the mutation carriers correlated with reductions in cerebellar pathway integrity measured using magnetic resonance diffusion tensor imaging and probabilistic tractography. Additionally, the cerebellar tract changes correlated with reductions in dentate nucleus activation recorded during task performance. Sequence learning performance and task-related activation responses did not correlate with striatal D2 receptor binding. In summary, we found that sequence learning deficits and concomitant increases in cerebellar activation are specific features of the DYT1 genotype. The close relationship between reduced cerebellar pathway integrity and increased learning-related activation of the premotor cortex is compatible with the view of DYT1 dystonia as a neurodevelopmental circuit disorder.

Hereditary dystonia as a neurodevelopmental circuit disorder: Evidence from neuroimaging.

Primary dystonia has traditionally been viewed as a basal ganglia disorder, but recent studies suggest that the cerebellum plays a crucial role in the disease. Primary dystonia is associated with several genotypes. Among those, DYT1 and DYT6 are inherited in autosomal dominant fashion with reduced penetrance. Extensive structural and functional imaging studies have been performed on manifesting and non-manifesting carriers of these mutations. The results suggest that primary dystonia can be viewed as a neurodevelopmental circuit disorder, involving the cortico-striato-pallido-thalamo-cortical and cerebello-thalamo-cortical pathways. Anatomical disruption of the cerebellar outflow is found in non-manifesting and manifesting mutation carriers, and a second downstream disruption in thalamo-cortical projections appears clinically protective in non-manifesting carriers. The microstructural deficits in cerebellar outflow are linked to an abnormally elevated sensorimotor network (NMRP) in dystonia patients. Abnormal expression of this network is reduced by successful treatment with deep brain stimulation. This article is part of a Special Issue entitled "Advances in dystonia".

Increased sensorimotor network activity in DYT1 dystonia: a functional imaging study.

Neurophysiological studies have provided evidence of primary motor cortex hyperexcitability in primary dystonia, but several functional imaging studies suggest otherwise. To address this issue, we measured sensorimotor activation at both the regional and network levels in carriers of the DYT1 dystonia mutation and in control subjects. We used (15)Oxygen-labelled water and positron emission tomography to scan nine manifesting DYT1 carriers, 10 non-manifesting DYT1 carriers and 12 age-matched controls while they performed a kinematically controlled motor task; they were also scanned in a non-motor audio-visual control condition. Within- and between-group contrasts were analysed with statistical parametric mapping. For network analysis, we first identified a normal motor-related activation pattern in a set of 39 motor and audio-visual scans acquired in an independent cohort of 18 healthy volunteer subjects. The expression of this pattern was prospectively quantified in the motor and control scans acquired in each of the gene carriers and controls. Network values for the three groups were compared with ANOVA and post hoc contrasts. Voxel-wise comparison of DYT1 carriers and controls revealed abnormally increased motor activation responses in the former group (P < 0.05, corrected; statistical parametric mapping), localized to the sensorimotor cortex, dorsal premotor cortex, supplementary motor area and the inferior parietal cortex. Network analysis of the normative derivation cohort revealed a significant normal motor-related activation pattern topography (P < 0.0001) characterized by covarying neural activity in the sensorimotor cortex, dorsal premotor cortex, supplementary motor area and cerebellum. In the study cohort, normal motor-related activation pattern expression measured during movement was abnormally elevated in the manifesting gene carriers (P < 0.001) but not in their non-manifesting counterparts. In contrast, in the non-motor control condition, abnormal increases in network activity were present in both groups of gene carriers (P < 0.001). In this condition, normal motor-related activation pattern expression in non-manifesting carriers was greater than in controls, but lower than in affected carriers. In the latter group, measures of normal motor-related activation pattern expression in the audio-visual condition correlated with independent dystonia clinical ratings (r = 0.70, P = 0.04). These findings confirm that overexcitability of the sensorimotor system is a robust feature of dystonia. The presence of elevated normal motor-related activation pattern expression in the non-motor condition suggests that abnormal integration of audio-visual input with sensorimotor network activity is an important trait feature of this disorder. Lastly, quantification of normal motor-related activation pattern expression in individual cases may have utility as an objective descriptor of therapeutic response in trials of new treatments for dystonia and related disorders.

Cerebellothalamocortical connectivity regulates penetrance in dystonia.

Dystonia is a brain disorder characterized by sustained involuntary muscle contractions. It is typically inherited as an autosomal dominant trait with incomplete penetrance. While lacking clear degenerative neuropathology, primary dystonia is thought to involve microstructural and functional changes in neuronal circuitry. In the current study, we used magnetic resonance diffusion tensor imaging and probabilistic tractography to identify the specific circuit abnormalities that underlie clinical penetrance in carriers of genetic mutations for this disorder. This approach revealed reduced integrity of cerebellothalamocortical fiber tracts, likely developmental in origin, in both manifesting and clinically nonmanifesting dystonia mutation carriers. In these subjects, reductions in cerebellothalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Nonmanifesting mutation carriers were distinguished by an additional area of fiber tract disruption situated distally along the thalamocortical segment of the pathway, in tandem with the proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Overall, these findings point to a novel mechanism to explain differences in clinical expression in carriers of genes for brain disease.

Early Parkinson's disease: longitudinal changes in brain activity during sequence learning.

Impairment of sequence learning is common in Parkinson's disease (PD), but the time course of this cognitive abnormality is not known. We assessed longitudinal changes in sequence learning performance and associated task-related cerebral blood flow in 13 early stage PD patients who underwent H(2)(15)O PET at baseline and again 2 years later. Ten healthy volunteer subjects served as controls. A trend toward decline in learning performance (p=0.08) was evident over the 2 years of follow-up. During this interval, significant declines in learning-related activation were detected in parietal and temporo-occipital association areas and in the right dorsolateral prefrontal cortex. Learning-related activation in these regions was normal at baseline, but declined to subnormal levels (p<0.01) at 2 years. Significant hippocampal activation (p<0.005) was present in the subjects with high learning performance over time. The findings are consistent with a decline in learning-related neural activity in cortical areas with prominent Lewy body formation.

DSM-5 Attenuated Psychosis Syndrome in Adolescents Hospitalized With Non-psychotic Psychiatric Disorders.

Introduction: Although attenuated psychotic symptoms often occur for the first time during adolescence, studies focusing on adolescents are scarce. Attenuated psychotic symptoms form the criteria to identify individuals at increased clinical risk of developing psychosis. The study of individuals with these symptoms has led to the release of the DSM-5 diagnosis of Attenuated Psychosis Syndrome (APS) as a condition for further research. We aimed to characterize and compare hospitalized adolescents with DSM-5-APS diagnosis vs. hospitalized adolescents without a DSM-5-APS diagnosis. Methods: Interviewing help-seeking, hospitalized adolescents (aged 12-18 years) and their caregivers independently with established research instruments, we (1) evaluated the presence of APS among non-psychotic adolescents, (2) characterized and compared APS and non-APS individuals regarding sociodemographic, illness and intervention characteristics, (3) correlated psychopathology with levels of functioning and severity of illness and (4) investigated the influence of individual clinical, functional and comorbidity variables on the likelihood of participants to be diagnosed with APS. Results: Among 248 consecutively recruited adolescents (age=15.4 ± 1.5 years, females = 69.6%) with non-psychotic psychiatric disorders, 65 (26.2%) fulfilled APS criteria and 183 (73.8%) did not fulfill them. Adolescents with APS had higher number of psychiatric disorders than non-APS adolescents (3.5 vs. 2.4, p < 0.001; Cohen's d = 0.77), particularly, disruptive behavior disorders (Cramer's V = 0.16), personality disorder traits (Cramer's V = 0.26), anxiety disorders (Cramer's V = 0.15), and eating disorders (Cramer's V = 0.16). Adolescents with APS scored higher on positive (Cohen's d = 1.5), negative (Cohen's d = 0.55), disorganized (Cohen's d = 0.51), and general symptoms (Cohen's d = 0.84), and were more severely ill (Cohen's d = 1.0) and functionally impaired (Cohen's d = 0.31). Negative symptoms were associated with lower functional levels (Pearson ρ = -0.17 to -0.20; p = 0.014 to 0.031). Global illness severity was associated with higher positive, negative, and general symptoms (Pearson ρ = 0.22 to 0.46; p = 0.04 to p < 0.001). APS status was independently associated with perceptual abnormalities (OR = 2.0; 95% CI = 1.6-2.5, p < 0.001), number of psychiatric diagnoses (OR = 1.5; 95% CI = 1.2-2.0, p = 0.002), and impaired stress tolerance (OR = 1.4; 95% CI = 1.1-1.7, p = 0.002) (r 2 = 0.315, p < 0.001). Conclusions: A considerable number of adolescents hospitalized with non-psychotic psychiatric disorders meet DSM-5-APS criteria. These help-seeking adolescents have more comorbid disorders and more severe symptoms, functional impairment, and severity of illness than non-APS adolescents. Thus, they warrant high intensity clinical care.

Demographic and Clinical Characteristics, Including Subsyndromal Symptoms Across Bipolar-Spectrum Disorders in Adolescents.

Objectives: Bipolar disorder (BD) is a debilitating illness that often starts at an early age. Prevention of first and subsequent mood episodes, which are usually preceded by a period characterized by subthreshold symptoms is important. We compared demographic and clinical characteristics including severity and duration of subsyndromal symptoms across adolescents with three different bipolar-spectrum disorders. Methods: Syndromal and subsyndromal psychopathology were assessed in adolescent inpatients (age = 12-18 years) with a clinical mood disorder diagnosis. Assessments included the validated Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P). We compared phenomenology across patients with a research consensus conference-confirmed DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnoses of BD-I, BD-not otherwise specified (NOS), or mood disorder (MD) NOS. Results: Seventy-six adolescents (age = 15.6 ± 1.4 years, females = 59.2%) were included (BD-I = 24; BD-NOS = 29; MD-NOS = 23) in this study. Median baseline global assessment of functioning scale score was 21 (interquartile range = 17-40; between-group p = 0.31). Comorbidity was frequent, and similar across groups, including disruptive behavior disorders (55.5%, p = 0.27), anxiety disorders (40.8%, p = 0.98), and personality disorder traits (25.0%, p = 0.21). Mania symptoms (most frequent: irritability = 93.4%, p = 0.82) and depressive symptoms (most frequent: depressed mood = 81.6%, p = 0.14) were common in all three BD-spectrum groups. Manic and depressive symptoms were more severe in both BD-I and BD-NOS versus MD-NOS (p < 0.0001). Median duration of subthreshold manic symptoms was shorter in MD-NOS versus BD-NOS (11.7 vs. 20.4 weeks, p = 0.002) and substantial in both groups. The most used psychotropics upon discharge were antipsychotics (65.8%; BD-I = 79.2%; BD-NOS = 62.1%; MD-NOS = 56.5%, p = 0.227), followed by mood stabilizers (43.4%; BD-I = 66.7%; BD-NOS = 31.0%; MD-NOS = 34.8%, p = 0.02) and antidepressants (19.7%; BD-I = 20.8%; BD-NOS = 10.3%; MD-NOS = 30.4%). Conclusions: Youth with BD-I, BD-NOS, and MD-NOS experience considerable symptomatology and are functionally impaired, with few differences observed in psychiatric comorbidity and clinical severity. Moreover, youth with BD-NOS and MD-NOS undergo a period with subthreshold manic symptoms, enabling identification and, possibly, preventive intervention of those at risk for developing BD or other affective episodes requiring hospitalization.

Dopaminergic suppression of brain deactivation responses during sequence learning.

Cognitive processing is associated with deactivation of the default mode network. The presence of dopaminoceptive neurons in proximity to the medial prefrontal node of this network suggests that this neurotransmitter may modulate deactivation in this region. We therefore used positron emission tomography to measure cerebral blood flow in 15 Parkinson's disease (PD) patients while they performed a motor sequence learning task and a simple movement task. Scanning was conducted before and during intravenous levodopa infusion; the pace and extent of movement was controlled across tasks and treatment conditions. In normal and unmedicated PD patients, learning-related deactivation was present in the ventromedial prefrontal cortex (p < 0.001). This response was absent in the treated condition. Treatment-mediated changes in deactivation correlated with baseline performance (p < 0.002) and with the val(158)met catechol-O-methyltransferase genotype. Our findings suggest that dopamine can influence prefrontal deactivation during learning, and that these changes are linked to baseline performance and genotype.

Dissociation of metabolic and neurovascular responses to levodopa in the treatment of Parkinson's disease.

We compared the metabolic and neurovascular effects of levodopa (LD) therapy for Parkinson's disease (PD). Eleven PD patients were scanned with both [15O]-H2O and [18F]-fluorodeoxyglucose positron emission tomography in the unmedicated state and during intravenous LD infusion. Images were used to quantify LD-mediated changes in the expression of motor- and cognition-related PD covariance patterns in scans of cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR). These changes in network activity were compared with those occurring during subthalamic nucleus (STN) deep brain stimulation (DBS), and those observed in a test-retest PD control group. Separate voxel-based searches were conducted to identify individual regions with dissociated treatment-mediated changes in local cerebral blood flow and metabolism. We found a significant dissociation between CBF and CMR in the modulation of the PD motor-related network by LD treatment (p < 0.001). This dissociation was characterized by reductions in network activity in the CMR scans (p < 0.003) occurring concurrently with increases in the CBF scans (p < 0.01). Flow-metabolism dissociation was also evident at the regional level, with LD-mediated reductions in CMR and increases in CBF in the putamen/globus pallidus, dorsal midbrain/pons, STN, and ventral thalamus. CBF responses to LD in the putamen and pons were relatively greater in patients exhibiting drug-induced dyskinesia. In contrast, flow-metabolism dissociation was not present in the STN DBS treatment group or in the PD control group. These findings suggest that flow-metabolism dissociation is a distinctive feature of LD treatment. This phenomenon may be especially pronounced in patients with LD-induced dyskinesia.

Increased cerebellar activation during sequence learning in DYT1 carriers: an equiperformance study.

We have found that motor sequence learning and related brain activation is impaired in non-manifesting (nm) carriers of the DYT1 deletion for dystonia. In the present study we used a trial-and-error sequence-learning task in conjunction with an equiperformance study design to identify the neural substrates that support sequence learning in nmDYT1 mutation carriers. Six nmDYT1 mutation carriers and six control subjects were scanned with H215O PET during the performance of a trial-and-error guided, kinematically controlled motor sequence learning task and a matched motor execution task. Controls were matched for age and performance. PET data analysis was performed using statistical parametric mapping (SPM99). Although performing at matched levels, nmDYT1 mutation carriers overactivated the lateral cerebellum and the right inferotemporal cortex relative to age-matched controls (P < 0.001). In contrast, they showed relative activation deficits in the dorsolateral prefrontal cortex bilaterally, as well as in the left anterior cingulate and the dorsal premotor cortex (P < 0.001). Prominent compensatory involvement of the cerebellum during target learning is consistent with our prior sequence-learning experiments in nmDYT1 mutation carriers. Contrasting to mutation carriers, normals used bilateral cerebellar activation in conjunction with a prominent prefrontal bilateralization only when confronted with a much higher task difficulty. nmDYT1 mutation carriers lack recruitment of these prefrontal regions that depend on modulation within the cortico-striato-pallido-thalamocortical (CSPTC) loops. Instead, they compensate solely using cerebellar activation. This observation is in keeping with recent evidence of impaired structure/function relationships within CSPTC networks in dystonia perhaps occurring on a neurodevelopmental basis. The inability to recruit the appropriate set of neocortical areas because of altered fronto-striatal connectivity may have led to the shift to cerebellar processing.

Metabolic correlates of subthalamic nucleus activity in Parkinson's disease.

Overactivity of subthalamic nucleus (STN) neurons is a consistent feature of Parkinson's disease (PD) and is a target of therapy for this disorder. However, the relationship of STN firing rate to regional brain function is not known. We scanned 17 PD patients with (18)F-fluorodeoxyglucose (FDG) PET to measure resting glucose metabolism before the implantation of STN deep brain stimulation electrodes. Spontaneous STN firing rates were recorded during surgery and correlated with preoperative regional glucose metabolism on a voxel-by-voxel basis. We also examined the relationship between firing rate and the activity of metabolic brain networks associated with the motor and cognitive manifestations of the disease. Mean firing rates were 47.2 +/- 6.1 and 48.7 +/- 8.5 Hz for the left and right hemispheres, respectively. These measures correlated (P < 0.007) with glucose metabolism in the putamen and globus pallidus, which receive projections from this structure. Significant correlations (P < 0.0005) were also evident in the primary motor (BA4) and dorsolateral prefrontal (BA46/10) cortical areas. The activity of both the motor (P < 0.0001) and the cognitive (P < 0.006) PD-related metabolic networks was elevated in these patients. STN firing rates correlated with the activity of the former (P < 0.007) but not the latter network (P = 0.39). The findings suggest that the functional pathways associated with motor disability in PD are linked to the STN firing rate. These pathways are likely to mediate the clinical benefit that is seen following targeted STN interventions for this disease.

Bipolar Prodrome Symptom Scale - Abbreviated Screen for Patients: Description and validation.

OBJECTIVE: There is no standard method for assessing symptoms of the prodrome to bipolar disorder (BD), which has limited progress toward early identification and intervention. We aimed to validate the Bipolar Prodrome Symptom Scale-Abbreviated Screen for Patients (BPSS-AS-P), a brief self-report derived from the validated, clinician-rated Bipolar Prodrome Symptom Interview and Scale-Full Prospective (BPSS-FP), as a means to screen and identify people for whom further evaluation is indicated. METHOD: Altogether, 134 participants (aged 12-18 years) were drawn from a study of the pre-syndromal stage of mood and psychotic disorders. All participants had chart diagnoses of a mood- or psychosis-spectrum disorder. Participants were interviewed with the BPSS-FP and completed measures of mania and non-mood psychopathology. Prior to being interviewed, patients completed the BPSS-AS-P. Scores on the BPSS-AS-P were determined by summing the severity and frequency ratings for each item. RESULTS: BPSS-AS-P scores were highly reliable (Cronbach's alpha = 0.94) and correlated with the interview-based BPSS-FP Mania Symptom Index (r = 0.55, p < .0001). BPSS-AS-P scores had good convergent validity, correlating with the General Behavior Inventory-10M (r = 0.65, p < .0001) and Young Mania Rating Scale; r = 0.48, p < .0001). The BPSS-AS-P had good discriminant validity, not being correlated with scales measuring positive and negative symptoms of psychotic disorders (p-values = 0.072-0.667). LIMITATIONS: Findings are limited by the cross-sectional nature of the study by the fact that the participants were all treatment-seeking. Future studies need to evaluate the predictive validity of the BPSS-AS-P for identifying those who develop BD in a community sample. CONCLUSION: BPSS-AS-P has promise as a screening tool for people at risk for BD. Adopting the BPSS-AS-P would support the goal of characterizing the prodrome systematically in order to facilitate research and clinical care.

Microstructural white matter changes in primary torsion dystonia.

Primary torsion dystonia (PTD) has been conceptualized as a disorder of the basal ganglia. However, recent data suggest a widespread pathology involving motor control pathways. In this report, we explored whether PTD is associated with abnormal anatomical connectivity within motor control pathways. We used diffusion tensor magnetic resonance imaging (DT-MRI) to assess the microstructure of white matter. We found that fractional anisotropy, a measure of axonal integrity and coherence, was significantly reduced in PTD patients in the pontine brainstem in the vicinity of the left superior cerebellar peduncle and bilaterally in the white matter of the sensorimotor region. Our data thus support the possibility of a disturbance in cerebello-thalamo-cortical pathways as a cause of the clinical manifestations of PTD.

Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis.

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second-generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first-generation antipsychotics, FGAs). As some reports questioned this notion, we meta-analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head-to-head RCTs, including 32 FGA and 86 SGA arms, were meta-analyzed, yielding 32 FGA-SGA pairs and 35 SGA-SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3-7.8%) vs. 2.6% (95% CI: 2.0-3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39-0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28-0.45, p<0.0001, number-needed-to-treat, NNT=20). Meta-regression showed no FGA dose effect on FGA-SGA comparisons (Z=-1.03, p=0.30). FGA-SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non-clozapine SGAs in exploratory pairwise comparisons. SGA-SGA comparisons confirmed the olanzapine advantage vs. non-clozapine SGAs (RaR=0.66, 95% CI: 0.49-0.88, p=0.006, k=17, NNT=100). This meta-analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.

Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism.

Parkinson's disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group x time interaction, P<0.001). On FDG PET, the GAD animals exhibited an increase in glucose utilization in the right motor cortex relative to GFP controls (P<0.001). Metabolism in this region correlated with clinical ratings at end point (P<0.01). Histology confirmed GAD expression in treated animals. These findings suggest that STN AAV-GAD is well tolerated and potentially effective in a primate model of PD. The changes in motor cortical glucose utilization observed after gene therapy are consistent with the modulation of metabolic brain networks associated with this disorder.

Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis.

OBJECTIVE: Comparison of tardive dyskinesia (TD) prevalence during contemporaneous treatment with first-generation antipsychotics (FGAs) and/or second-generation antipsychotics (SGAs). DATA SOURCES: PubMed/MEDLINE/Google Scholar search (January 1, 2000-September 30, 2015) without language restriction using (tardive dyskinesia OR tardive) AND (antipsychotic*) plus specific names of SGAs. STUDY SELECTION: Of 8,895 hits, we screened 203 full-text articles for cross-sectional, rating scale-based TD rates during SGA, FGA, or FGA+SGA treatment. Forty-one studies were used for random effects meta-analysis and meta-regression. DATA EXTRACTION: Two authors independently extracted data on overall and antipsychotic class-wise TD rates and on TD moderators. RESULTS: The global mean TD prevalence was 25.3% (95% CI = 22.7%-28.1%) across all 41 studies (N = 11,493, mean age = 42.8 years, male = 66.4%, schizophrenia-spectrum disorders = 77.1%). TD prevalence varied greatly: Rates were lower with current SGA treatment (20.7%; 95% CI = 16.6%-25.4%, N = 5,103) vs current FGA treatment (30.0%; 95% CI = 26.4%-33.8%, N = 5,062; Q = 9.17, P = .002). This difference remained significant after controlling for moderators: higher age (Z = 2.85, P = .004; number of studies = 39 ) and region (39 studies; Asia vs Europe, Z = 1.55, P = .12; Asia lower than United States, Z = 2.6, P = .009; Asia lower than other regions, Z = 2.42, P = .015). Additional moderators of TD prevalence included longer illness duration (R² = 0.15; P = .03; 21 studies) and frequency of parkinsonism (R² = 0.23, P = .017; number of studies = 19). Particularly low TD prevalence (7.2%; number of studies = 4) was found in the treatment arms with FGA-naive subjects relative to SGA-treated cohorts with likely prior FGA exposure (23.4%; P < .001; 28 studies). Lower TD prevalence of SGA relative to FGA was also confirmed in the subgroup of studies reporting on ≥ 2 antipsychotic classes/combinations; this was found for both SGAs vs FGAs (risk ratio = 0.80; 95% CI = 0.67-0.95, Z = -2.55, P = .011) and FGA + SGA vs FGAs (risk ratio = 0.80, 95% CI = 0.71-0.90, Z = -3.56, P < .001). Reports on TD severity, provided by 10 studies, were of insufficient quality for meta-analysis. CONCLUSIONS: Rating scale-based TD remains highly prevalent, with higher rates during FGA than during SGA treatment. However, TD severity was insufficiently reported to allow for interpretation of the clinical impact of identified TD cases with SGAs and FGAs. Reasons for high geographical variation warrant future research.