Search

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.

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.

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

To assess activating and tranquilizing effects of second-generation antipsychotics (SGAs) in youth.As part of the naturalistic inception cohort study, "Second-generation Antipsychotic Treatment Indication, Effectiveness and Tolerability in Youth (SATIETY)," subjective ratings of activating and tranquilizing symptoms were obtained monthly for 3 months from antipsychotic-naïve youth initiating SGAs using the Treatment Emergent Symptoms Scale (TESS). Discontinuation rates, and TESS-reported symptom rates, and severity were related to clinical and treatment parameters. Two compound measures of TESS were defined: presence of any daytime activating (ACTIVATION+) and sedating symptoms (SEDATION+).In 327 antipsychotic-naïve youth originally initiating the four studied SGAs, discontinuation due to sedation was marginally highest with quetiapine (13.0%) followed by olanzapine (7.3%), risperidone (4.2%), and aripiprazole (2.0%) (p = 0.056). Two hundred fifty-seven antipsychotic-naïve youth (13.8 ± 3.6 years, male = 57.8%) initiated aripiprazole (n = 40), olanzapine (n = 45), quetiapine (n = 36), or risperidone (n = 135) and completed ≥1 postbaseline follow-up visit. Baseline prevalence of ACTIVATION+ (39.9%) or SEDATION+ (54.1%) did not differ between SGAs. Rates of both compound measures changed significantly over time (decrease for ACTIVATION+, p = 0.0002; increase for SEDATION+, p 0.0001) with slight differences between SGAs, explained by lower rates of ACTIVATION+ with olanzapine (p = 0.002) and slightly higher rates of ACTIVATION+ with aripiprazole (p = 0.018) during follow-up, and lower rates of SEDATION+ with aripiprazole (p = 0.018). All four SGAs reduced insomnia (p = 0.001) and increased hypersomnia (p 0.001). Postbaseline prevalence of drowsiness, the most frequent, but mild TESS complaint was 85%, without SGA differences. Younger age was associated with activating symptoms, higher age with sedating symptoms, and lower baseline functioning increased both. Psychomotor retardation rates were high in subjects with schizophrenia-spectrum disorders, whereas stimulant comedication was associated with psychomotor activation, regardless of diagnosis.Although small SGA-specific differences in activating/sedating compound side effect measures were noted, independent predictors of single TESS ratings included clinical parameters, rather than specific SGAs, suggesting a need for carefully individualized treatment strategies.

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

OBJECTIVES: DSM-5 conceptualized attenuated psychosis syndrome (APS) as self-contained rather than as a risk syndrome, including it under "Conditions for Further Study," but also as a codable/billable condition in the main section. Since many major mental disorders emerge during adolescence, we assessed the frequency and characteristics of APS in adolescent psychiatric inpatients. METHODS: Consecutively recruited adolescents hospitalized for nonpsychotic disorders (September 2009-May 2013) were divided into APS youth versus non-APS youth, based on the Structured Interview of Prodromal Syndromes (SIPS) and according to DSM-5 criteria, and compared across multiple characteristics. RESULTS: Of 89 adolescents (mean ± SD age = 15.1 ± 1.6 years), 21 (23.6%) had APS. Compared to non-APS, APS was associated with more comorbid disorders (2.7 ± 1.0 vs 2.2 ± 1.3), major depressive disorder (61.9% vs 27.9%), oppositional defiant disorder/conduct disorder (52.4% vs 25.0%), and personality disorder traits (57.1% vs 7.4%, the only diagnostic category surviving Bonferroni correction). APS youth were more severely ill, having higher SIPS total positive, negative, and general symptoms; Brief Psychiatric Rating Scale total and positive scores; depression and global illness ratings; and lower Global Assessment of Functioning (GAF). Conversely, Young Mania Rating Scale scores, suicidal behavior, prescribed psychotropic medications, and mental disorder awareness were similar between APS and non-APS groups. In multivariable analysis, lowest GAF score in the past year (odds ratio [OR] = 51.15; 95% confidence interval [CI], 2.46-2,439.0) and social isolation (OR = 27.52; 95% CI, 3.36-313.87) were independently associated with APS (r(2) = 0.302, P < .0001). Although psychotic disorders were excluded, 65.2% (APS = 57.1%, non-APS = 67.7%, P = .38) received antipsychotics. CONCLUSION: One in 4 nonpsychotic adolescent inpatients met DSM-5 criteria for APS. APS youth were more impaired, showing a complex entanglement with a broad range of psychiatric symptoms and disorders, including depression, impulse-control, and, especially, emerging personality disorders. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01383915.

OBJECTIVES: The purpose of this study was to assess differences in the outcomes of youth with schizophrenia-spectrum disorders (SCZ-S) and psychotic disorder not otherwise specified (PsyNOS) during early antipsychotic treatment.METHODS: The study was a prospective, naturalistic, inception cohort study of youth ≤19 years old with SCZ-S (schizophrenia, schizoaffective disorder, schizophreniform disorder) or PsyNOS (PsyNOS, brief psychotic disorder) and ≤24 months of lifetime antipsychotic treatment receiving clinician's choice antipsychotic treatment. Baseline demographic, illness and treatment variables, and effectiveness outcomes were compared at 12 weeks last-observation-carried-forward across SCZ-S and PsyNOS patients, adjusting for significantly different baseline variables.RESULTS: Altogether, 130 youth with SCZ-S (n=42) or PsyNOS (n=88), mostly antipsychotic naïve (76.9%), were prescribed risperidone (47.7%), olanzapine (19.2%), aripiprazole (14.6%), quetiapine (11.5%), or ziprasidone (6.9%). Compared with those with PsyNOS, SCZ-S youth were older (16.4±2.1 vs. 14.8±3.2, p=0.0040), and less likely to be Caucasian (19.1% vs. 42.5%, p=0.009). At baseline, SCZ-S patients had significantly higher Clinical Global Impressions-Severity (CGI-S) scores (6.0±0.9 vs. 5.5±0.8, p=0.0018) and lower Children's Global Assessment Scale (CGAS) scores (29.6±9.2 vs. 36.1±8.9, p=0.0002) and were more likely to be in the severely ill CGAS group (i.e., CGAS≤40). SCZ-S and PsyNOS patients did not differ regarding all-cause discontinuation (40.5 vs. 40.3%. p=0.49), discontinuation because of adverse effects (12.2% vs. 12.4%, p=0.97), or nonadherence (29.3% vs. 30.9%, p=0.88), but somewhat more SCZ-S patients discontinued treatment for inefficacy (19.5% vs. 7.4%, p=0.063). CGI-S and CGAS scores improved significantly in both diagnostic groups (p=0.0001, each). Adjusting for baseline differences, PsyNOS patients experienced significantly better CGI-I improvement (CGI-I) scores (p=0.012) and more frequently reached higher categorical CGAS group status (p=0.021) than SCZ-S patients.CONCLUSIONS: Both youth with SCZ-S and those with PsyNOS experienced significant improvements with clinician's choice antipsychotic treatment. However, treatment discontinuation was common within 12 weeks, with greater inefficacy-related discontinuation in the SCZ-S group, whereas CGI-I and CGAS score-based improvements were greater in the PsyNOS group.

Background: Tardive dyskinesia (TD) rates with second-generation antipsychotic (SGA) treatment were estimated to be considerably lower than with first-generation antipsychotics (FGAs). As recent data have questioned this notion, we conducted a meta-analysis on contemporaneous TD prevalence.

Background: Tardive dyskinesia (TD) rates with second-generation antipsychotic (SGA) treatment were estimated to be considerably lower compared with first-generation antipsychotics (FGAs). As recent data have questioned this notion, we conducted a meta-analysis on TD incidence during randomized controlled studies.

The search for clinical outcome predictors for schizophrenia is as old as the field of psychiatry. However, despite a wealth of large, longitudinal studies into prognostic factors, only very few clinically useful outcome predictors have been identified. The goal of future treatment is to either affect modifiable risk factors, or use nonmodifiable factors to parse patients into therapeutically meaningful subgroups. Most clinical outcome predictors are nonspecific and/or nonmodifiable. Nonmodifiable predictors for poor odds of remission include male sex, younger age at disease onset, poor premorbid adjustment, and severe baseline psychopathology. Modifiable risk factors for poor therapeutic outcomes that clinicians can act upon include longer duration of untreated illness, nonadherence to antipsychotics, comorbidities (especially substance-use disorders), lack of early antipsychotic response, and lack of improvement with non-clozapine antipsychotics, predicting clozapine response. It is hoped that this limited capacity for prediction will improve as pathophysiological understanding increases and/or new treatments for specific aspects of schizophrenia become available.La búsqueda de predictores de resultado clínico en la esquizofrenia es tan antigua como la psíquiatría. Sin embargo, a pesar de una gran cantídad de estudios longitudinales sobre los factores pronóstico, solo se han identificado unos pocos predíctores de resultado con utilidad clínica. El objetivo de las terapias a futuro es influir sobre los factores de riesgo modíficables, o bien emplear los factores inmodíficables para analizar a los pacientes en subgrupos terapéuticamente signíficativos. La mayor parte de los predictores de resultado clínico son inespecíficos ylo inmodíficables. Cuando hay una baja probabílidad de remisión los predictores inmodíficables incluyen al sexo masculíno, la menor edad de aparición de la enfermedad, un pobre ajuste premórbido y una grave psicopatología basal. Cuando hay pobres resultados terapéuticos los factores de riesgo modíficables sobre los cuales pueden actuar los clínicos incluyen la mayor duración de la enfermedad sín tratamiento, la falta de adherencía a los antipsicóticos, la comorbilidad (especialmente el abuso de sustancias), la falta de respuesta ínicial a los antipsicóticos y la ausencia de mejoría con antipsicóticos distintos de la clozapina, lo que puede predecír una respuesta a esta última. Se espera que esta capacidad límitada de predíccíón aumente en la medída que sea mayor la comprensión fisiopatológica ylo se disponga de nuevos tratamientos para aspectos específicos de la esquizofrenia.La recherche de facteurs de prédiction des résultats cliniques dans la schizophrénie est aussi ancienne que la psychiatrie elle-meme. Néanmoins, malgré de nombreuses grandes études longitudinales sur les facteurs pronostiques, très peu de ces facteurs utiles cliniquement ont été identifiés. Le but d'un traitement futur est soit de changer les facteurs de risque modifiables ou d'utiliser des facteurs non modifiables pour regrouper les patients dans des sous-groupes déterminants sur le plan thérapeutique. La plupart des facteurs de prédiction des résultats cliniques sont non spécifiques et/ou non modifiables. Le sexe masculin, un plus jeune âge au début de la maladie, un mauvais ajustement prémorbide et une pathologie psychiatrique sévère dès le début font partie des facteurs de prédiction non modifiables pour des chances de rémission médiocres. Une durée plus longue de maladie non traitée, une absence d'observance des antipsychotiques, des comorbidités (surtout l'usage de substances illicites), une absence de réponse précoce aux antipsychotiques et l'absence d'amélioration avec les antipsychotiques non-clozapiniques prédisant la réponse à la clozapine font partie des facteurs de risque modifiables de résultats thérapeutiques médiocres sur lesquels les médecins peuvent agir. Il faut espérer que cette faible capacité prédictive s'améliorera avec une meilleure compréhension physiopathologique et/ou le développement de traitements visant des aspects spécifiques de la schizophrénie.

For economic reasons, the generic substitution of branded medications is common and welcome. These replacements are based on the concept of bioequivalence, which is considered equal to therapeutic equivalence. Regulatory standards for bioequivalence require the 90 % confidence intervals of group averages of pharmacokinetic measures of a generic and the original drug to overlap within ±20 %. However, therapeutic equivalence has been challenged for several psychotropic agents by retrospective studies and case reports. To evaluate the degree of bioequivalence and therapeutic equivalence of branded and generic psychotropic drugs, we performed an electronic search (from database inception until 24 May 2012 and without language restrictions) in PubMed/MEDLINE, Cochrane Library, and Web of Science. Search terms were “(generic) AND (psychotropic OR psychoactive OR antipsychotic OR antiepileptic OR antidepressant OR stimulant OR benzodiazepine)” or the respective individual substances. We included clinical studies, regardless of design, comparing branded with generic psychotropic drug formulations, identifying 35 such studies. We also included case reports/series reporting on outcomes after a switch between brand and generic psychotropics, identifying 145 clinical cases. Bioequivalence studies in healthy controls or animals, in-vitro studies, and health economics studies without medical information were excluded. An overview of the few randomized controlled studies supports that US FDA regulations assure clinically adequate drug delivery in the majority of patients switched from brand to generic. However, with a growing number of competing generic products for one substance, and growing economic pressure to substitute with the currently cheapest generic, frequent generic-generic switches, often unbeknownst to prescribing clinicians, raise concerns, particularly for antiepileptics/mood stabilizers. Generic-generic switches may vary by more than ±20 % from each other in individual patients since the pharmacokinetic properties of each generic may differ from the innovator drug in opposing directions. Ideally, therapeutic equivalence studies in addition to pharmacokinetic equivalence studies would be performed for each generic, reflecting the full variability of clinical responses due to changes of pharmacokinetic properties related to age, sex, ethnicity, genetic factors, and body mass index. This is particularly relevant, as bioequivalence studies are based on single-dose studies in healthy controls who are likely not representative of the patients who are prescribed the psychotropic medications. Additionally, individual case reports suggest potential clinical effects during brand-generic switches. Knowledge and consideration of intra-individual variations can help guide the clinical management during brand-generic or generic-generic switch periods. To optimize outcomes, clinicians need to consider that when using generic psychotropic medications, a change in the patient’s clinical status can be related to psychological, interactional, physiological, and pharmacological factors that may or may not be related to the change to a generic drug. In addition, throughout all treatment periods, clinicians need to be aware of the currently dispensed product (i.e., branded or exact generic formulation), particularly when evaluating clinical changes in efficacy, tolerability, and adherence. If clinical problems occur, the first response should be an assessment of adherence and a careful dose adjustments of the generic drug rather than an immediate switch back to the originator.

To identify brain regions with metabolic changes in DYT11 myoclonus-dystonia (DYT11-MD) relative to control subjects and to compare metabolic abnormalities in DYT11-MD with those found in other forms of hereditary dystonia and in posthypoxic myoclonus.[(18)F]-fluorodeoxyglucose PET was performed in 6 subjects with DYT11-MD (age 30.5 ± 10.1 years) and in 6 nonmanifesting DYT11 mutation carriers (NM-DYT11; age 59.1 ± 8.9 years) representing the parental generation of the affected individuals. These data were compared to scan data from age-matched healthy control subjects using voxel-based whole brain searches and group differences were considered significant at p0.05 (corrected, statistical parametric mapping). As a secondary analysis, overlapping abnormalities were identified by comparisons to hereditary dystonias (DYT1, DYT6, dopa-responsive dystonia) and to posthypoxic myoclonus.We found significant DYT11 genotype-specific metabolic increases in the inferior pons and in the posterior thalamus as well as reductions in the ventromedial prefrontal cortex. Significant phenotype-related increases were present in the parasagittal cerebellum. This latter abnormality was shared with posthypoxic myoclonus, but not with other forms of dystonia. By contrast, all dystonia cohorts exhibited significant metabolic increases in the superior parietal lobule.The findings are consistent with a subcortical myoclonus generator in DYT11-MD, likely involving the cerebellum. By contrast, subtle increases in the superior parietal cortex relate to the additional presence of dystonic symptoms. Although reduced penetrance in DYT11-MD has been attributed to the maternal imprinting epsilon-sarcoglycan mutations, NM-DYT11 carriers showed significant metabolic abnormalities that are not explained by this genetic model.

Although caregiver burden is relevant to the outcome for psychiatrically ill youth, most studies have focused on caregiver burden in the community or research settings. Therefore, we aimed at evaluating the subjective caregiver strain (SCS) at the time of presentation of youth to a pediatric psychiatric emergency room (PPER), assessing potential correlates to provide leads for improvements in formal support systems.In this retrospective cohort study, the internalized, externalized, and total SCS were assessed in caregivers of youth18 years of age consecutively evaluated at a PPER during a 1 year period using the Caregiver Strain Questionnaire. Sociodemographic and a broad range of clinical data were collected during the PPER visit using a 12-page semistructured institutional evaluation form. The Appropriateness of Pediatric Psychiatric Emergency Room Contact scale, incorporating acuity, severity and harm potential, was used to rate appropriateness of the visit.In caregivers of 444 youth, the internalized SCS was significantly higher than the externalized SCS (p 0.001). Multivariable analyses indicated that higher total and externalized SCS were associated with disruptive behavior or substance abuse/dependent disorder diagnosis, presenting complaint of aggression, and discharge plan to the police. Higher total and internalized SCS were associated with lower child functioning, whereas total and internalized SCS were lower in adopted children. In addition, higher externalized SCS was associated with investigator-rated inappropriateness of the emergency visit, presenting complaint of defiance, and a lack of prior psychiatric ER visits.High levels of CS in PPER highlight the necessity to adhere to existing guidelines regarding the inclusion of caregivers' perceptions into comprehensive psychiatric assessments. The particularly high strain in caregivers of children with externalizing disorders and in families with low-functioning youth may need to prompt PPER staff to provide efficient information on appropriate treatment options for these children and on support facilities for the parents.

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 H215O 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. * Abbreviations : CCW : motor execution task MSEQ : motor sequence learning VSEQ : visual sequence learning

dopamine, DYT1, DYT6, motor activation, positron emission tomography, primary torsion dystonia Received 3 August 2009 Accepted 5 March 2010 Background: Impaired cortical inhibiton and maladaptive cortical plasticity are functional hallmarks of sporadic focal dystonias. Whether or not these mechanisms translate to generalized dystonias and whether these features reflect state or trait characteristics are topics of research in hereditary dystonias. Methods: We present a series of studies using a multitracer approach with positron emission tomography (PET) and diffusion tensor MRI (DTI) in the DYT1 and the DYT6 genotype. Results: In these hereditary dystonias functional and microstructural abnormalities were found in cortico-striatal-pallido-thalamocortical (CSPTC) and cerebellar-thalamo-cortical circuits. Genotype-specific abnormalities were localized to the basal ganglia, SMA and cerebellum. Functional changes, as potential correlates of maladaptive sensorimotor plasticity were found throughout the sensorimotor system and were more pronounced in affected mutation carriers than in their non-manifesting counterparts. In both genotypes, striatal metabolic abnormalities were paralleled by genotype-specific reductions in D2 receptor availability. However, these reductions failed to show a clear association with clinical or functional markers of the disease. By contrast, microstructural changes of cerebellar pathways clearly related to penetrance and may thus represent the main intrinsic abnormality underlying cortical downstream effects, such as increased sensorimotor responsivity. Conclusions: These studies are consistent with the view of primary torsion dystonia as a neurodevelopmental circuit disorder involving CSPTC and related cerebellar pathways.

Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q21-22. Both forms are autosomal dominant with incomplete (approximately 30%) clinical penetrance. Extensive functional and microstructural imaging with positron emission tomography (PET) and diffusion tensor MRI (DTI) has been performed on manifesting and non-manifesting carriers of these mutations. The results are consistent with the view of PTD as a neurodevelopmental circuit disorder involving cortico-striatal-pallido-thalamocortical (CSPTC) and related cerebellar-thalamo-cortical pathways. Studies of resting regional metabolism have revealed consistent abnormalities in PTD involving multiple interconnected elements of these circuits. In gene carriers, changes in specific subsets of these regions have been found to relate to genotype, phenotype, or both. For instance, genotypic abnormalities in striatal metabolic activity parallel previously reported reductions in local D(2) receptor availability. Likewise, we have identified a unique penetrance-related metabolic network characterized by increases in the pre-supplementary motor area (SMA) and parietal association areas, associated with relative reductions in the cerebellum, brainstem, and ventral thalamus. Interestingly, metabolic activity in the hypermetabolic areas has recently been found to be modified by the penetrance regulating D216H polymorphism. The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment.

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 (MR) diffusion tensor imaging (DTI) 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 cerebello-thalamo-cortical (CbTC) fiber tracts, likely developmental in origin, in both manifesting and clinically non-manifesting dystonia mutation carriers. In these subjects, reductions in cerebello-thalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Non-manifesting mutation carriers were distinguished by an additional area of fiber tract disruption situated distally along the thalamo-cortical 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.

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.

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 (P0.007) with glucose metabolism in the putamen and globus pallidus, which receive projections from this structure. Significant correlations (P0.0005) were also evident in the primary motor (BA4) and dorsolateral prefrontal (BA46/10) cortical areas. The activity of both the motor (P0.0001) and the cognitive (P0.006) PD-related metabolic networks was elevated in these patients. STN firing rates correlated with the activity of the former (P0.007) 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.

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.

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.

Idiopathic torsion dystonia and Huntington’s disease represent autosomal dominant inherited hyperkinetic disorders that vary considerably with regard to pathologic mechanisms and clinical penetrance. To study these mechanisms, non-manifesting DYT1 mutation carriers (nmDYT1) and presymptomatic HD gene carriers (p-HD), as well as age-matched controls were scanned with (i) FDG PET in the resting state, and (ii) 15 O-labeled water PET while performing a motor sequence learning task and motor execution task. We used voxel-based principal components analysis (PCA) to isolate the effects of genotype on regional metabolism in the resting state and on patterns of activation during motor performance. We detected two specific genotype-related metabolic patterns in the resting state. The torsion dystonia-related pattern was characterized by hypermetabolism of the basal ganglia, cerebellum and the supplementary motor area (SMA). By contrast, the voxel-based HD-related pattern displayed reductions in caudate and putamen metabolic activity associated with relative increases in the thalamus, the calcarine cortex, and primary motor cortex. Both mutations were associated with sequence learning deficits compared to controls. Carriers of each genotype activated different networks while performing the sequence learning task. In nmDYT1, learning was associated with activation of a specific network involving the cerebellar hemispheres, the left pre-SMA and anterior cingulate region, as well as inferior prefrontal and occipital association cortices. In p-HD, the learning network involved activation of the orbitofrontal and occipital association regions bilaterally, the left mediodorsal thalamus, and the right cerebellar hemisphere. These topographies illustrate the utility of PCA in identifying functional abnormalities in fronto-striatal loops and related pathways. 2007 Association for research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved.

Second-generation antipsychotic (SGA) effects in youth were monitored to quantify extrapyramidal side effects (EPS) and to identify risk profiles for treatment-emergent EPS.Data were analyzed for the nonrandomized, prospective Second-generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) inception cohort study. EPS were assessed at baseline and 4, 8, and 12 weeks after naturalistic SGA initiation for schizophrenia, mood, disruptive behavior, and autism spectrum disorders using the Simpson-Angus Scale (SAS), Barnes Akathisia Scale, Abnormal Involuntary Movement Scale (AIMS), and Treatment Emergent Side Effect Scale. Drug-induced parkinsonism was defined by incident mean SAS score0.33, anticholinergic initiation, or increasing total SAS score ≥2 in patients with baseline EPS.In 342 youth aged 13.6 ± 3.5 years (male = 58.2%, antipsychotic-naive = 65.8%), 15.2% developed drug-induced parkinsonism. Raw SGA-grouped drug-induced parkinsonism rates were as follows: quetiapine = 1.5%, olanzapine = 13.8%, risperidone = 16.1%, ziprasidone = 20.0%, and aripiprazole = 27.3%. SGA type, dose, higher age, and lower baseline functioning were jointly associated with drug-induced parkinsonism (R(2) = 0.18; p.0001). Controlling for these factors, drug-induced parkinsonism rates were significantly lower only for quetiapine and olanzapine. Subjectively reported EPS (5%), EPS-related treatment discontinuation (3.3%), and anticholinergic initiation (3%) were infrequent. Anticholinergic initiation was most frequent with risperidone (10.2%; p = .0004). Treatment-emergent dyskinesia ranged from 4.5% (aripiprazole) to 15.5% (olanzapine). SGA type, younger age, white race/ethnicity, and baseline AIMS were jointly associated with treatment-emergent dyskinesia (R(2) = 0.31; p.0001). Controlling for these factors, treatment-emergent dyskinesia rates differed among SGA subgroups, with higher rates with olanzapine and ziprasidone. At baseline, psychostimulant use was associated with dyskinesia, and number of psychotropic comedications was associated with subjective EPS.In youth, SGA-related EPS rates did not generally exceed those reported in adults, with particularly low rates with quetiapine and olanzapine.

Sequence learning, a cognitive task linked to cortico-striatal function, is impaired in Parkinson's disease (PD). We chose this task as a behavioral paradigm to study the functional architecture of PD in treated and untreated conditions. In our studies, participants were scanned with H(2)(15)O while performing a kinematically controlled motor sequence learning task and a matching motor baseline task. Experiments revealed that a specific sequence learning network predicts learning in normal subjects, and in independent cohorts of early and advanced PD patients. The analysis of the relationship of network activity to learning performance revealed diverging influences of dopaminergic therapy and deep brain stimulation (DBS). DBS of the internal GP and of STN increased network activity and task performance, while levodopa decreased both measures. In separate studies, we investigated the role of dopaminergic modulation on brain activation during sequence learning. In healthy subjects dopamine transporter (DAT) binding correlated with learning-related brain activation in prefrontal, premotor and cingulate cortices, and in the thalamus. By contrast, in PD most of these regional relationships were lost. Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic input. In a final set of studies, we found a significant decline in learning performance in early stage PD patients followed over the course of 2 years. Longitudinal declines in learning-related activation were found in parietal areas, while concomitant increases were localized to the left hippocampus. These observations support hypotheses on disease-stage and task-specific effects within the different cortico-striato-pallido-thalamocortical loops and the mesocortical system in PD.

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 18F-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 × time interaction, P

Functional neuroimaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), provides a valuable technique for detecting regional changes in brain metabolic activity associated with human disease. These techniques have been applied in different dystonic disorders including primary generalized dystonia and dopa-responsive dystonia (DRD), as well as focal dystonic syndromes such as torticollis, writer's cramp, and blepharospasm. A common finding is abnormality of the basal ganglia and associated outflow pathways to sensorimotor cortex and other regions involved with motor performance. Other recent imaging research has utilized diffusion-based MRI techniques to localize distinct microstructural abnormalities in dystonia patients and gene carriers. This presentation will focus on an integrated approach to understanding the pathophysiology of this genetic and biochemically diverse disorder.

A clinical triad of movement, behavioral, and cognitive disorders characterizes Huntington's disease (HD).1–3 However, the neurodegenerative changes of HD precede the onset of clinical signs and may be associated with subclinical alterations in brain physiology. For example, careful neuropsychological testing can detect abnormalities in presymptomatic carriers of the HD gene mutation (p-HD).4–7 In this study, we applied functional imaging methods with atrophy correction to elucidate the mechanisms that may underlie preclinical cognitive changes in HD gene carriers. In earlier imaging studies conducted in the resting state, we used a network approach to demonstrate that HD is associated with an abnormal spatial covariance pattern in both presymptomatic and symptomatic phases of disease.8,9 This reproducible regional topography is characterized by caudate/putamen and temporal hypometabolism associated with occipital hypermetabolism. Other investigators have found widespread cortical involvement in the early stages of symptomatic HD, in addition to the well-known subcortical features of the disease.10–12 Given metabolic abnormalities in brain regions subserving both motor and cognitive functions, we now sought to determine whether p-HD subjects acquire sequential information abnormally. We also sought to understand whether p-HD subjects use the same brain regions as control subjects while performing motor learning tasks, and if not, how the early preclinical pathology of HD alters the neural circuitry of learning-related pathways.

It is assumed widely that the clinical expression of Parkinson's Disease (PD), both motor and cognitive, is subtended by topographically distributed brain networks. However, little is known about the functional neuroanatomy of executive dysfunction in PD. Our objective was to validate further in a PD group the use of network analysis to assess the relationship between executive processes and pathological disorganization of frontostriatal networks. We studied 15 patients with idiopathic PD, and 7 age-matched normal controls, using resting [18F]fluorodeoxyglucose (FDG) and high-resolution positron emission tomography (PET). We carried out network analysis on regional metabolic data to identify specific covariation patterns associated with motor and executive dysfunction. We detected two independent patterns relating respectively to the two clinical abnormalities. The first pattern (principal component 1) was topographically similar to that described previously in other PD populations. Subject scores for this pattern discriminated patients from controls and correlated significantly with bradykinesia ratings (P = 0.013, r = 0.655) in PD patients. The second pattern (principal component 2) was characterized by relative ventromedial frontal, hippocampal, and striatal hypometabolism, associated with mediodorsal thalamic hypermetabolism. In the PD group, scores from this pattern correlated with scores on the conditional associative learning (CAL; P = 0.01, r = 0.690) and the Brown Peterson paradigm (BPP; P = 0.017, r = −0.651) tests, respectively assessing strategy and planning, and working memory. According to these findings, the networks subserving bradykinesia and executive dysfunction in PD seems to be topographically distinct and to involve different aspects of subcortico-cortical processing. Hum. Brain Mapping 22:236–245, 2004. © 2004 Wiley-Liss, Inc.

Objective Injury currents are a hallmark of acute lesions in polarized cells. Our objective was to develop a non-invasive technique for monitoring human near-DC injury currents in vivo. Methods Using diagnostic muscle biopsy as controlled paradigm, injury-related magnetic DC-fields were mapped for 60 min postsurgery over leg muscle lesions of 9 subjects. A 49-channel magnetometer was used in combination with a mechanical horizontal modulation of the subject beneath the sensor array. Results Magnetic DC-field maps showed salient differences between biopsy and contralateral legs in 8/9 patients with a characteristic slowly decaying field in all biopsy legs. A variety of anomalous DC-field patterns was recorded over the biopsy sites, corresponding to theoretically predicted geometric variations of equivalent DC-current dipoles, i.e. wound surfaces, pointing into opposing muscle fibre ends. By contrast, all control measurements showed an elongated dipolar DC-field pattern. Additionally, mean global DC-field strengths were significantly higher over biopsy legs compared to the contralateral site. Conclusions Our pilot data illustrate that human injury currents can be detected using non-invasive magnetometry. Thus, DC-magnetometry may provide an essential new tool for clinical monitoring of injury currents, possibly also in brain tissue, e.g. in case of anoxic or peri-infarct depolarizations.

Background: The authors have previously used [18F]fluorodeoxyglucose (FDG) PET to identify a reproducible pattern of regional glucose metabolism that was expressed in both manifesting and nonmanifesting carriers of the DYT1 primary dystonia mutation.Objective: To identify specific regions that discriminated subjects according to clinical penetrance and genotype.Methods: FDG PET was used to scan 12 nonmanifesting and 11 manifesting DYT1 gene carriers, 6 nonmanifesting DYT6 gene carriers and 7 manifesting DYT6 gene carriers, as well as 11 control subjects. The data from all five groups were analyzed with statistical parametric mapping and analysis of variance with posthoc contrasts.Results: A dissociation of metabolic changes was found related to phenotype and genotype. Manifesting gene carriers of both genotypes exhibited bilateral hypermetabolism in the presupplementary motor area (Brodmann area [BA] 6) and parietal association cortices (BA 40/7) compared with the respective nonmanifesting counterparts. By contrast, genotype-specific increases in metabolism were found in the putamen, anterior cingulate (BA 24/32), and cerebellar hemispheres of DYT1 carriers. Genotype-specific changes in DYT6 involved hypometabolism of the putamen and hypermetabolism in the temporal cortex (BA 21).Conclusions: Dystonia may be associated with abnormal movement preparation caused by defective sensorimotor integration. Whereas clinical manifestations are related to cortical dysfunction, metabolic abnormalities in subcortical structures may represent trait features that are specific for individual dystonia genotypes.

In this study, we tested the hypotheses that (1) the acquisition of sequential information is related to the integrity of dopaminergic input to the caudate nucleus; and (2) the integrity of dopaminergic input to the caudate nucleus correlates significantly with brain activation during sequence acquisition. Twelve early stage Parkinson's disease (PD) patients and six age-matched healthy volunteers were scanned using a dual tracer PET imaging design. All subjects were scanned with [(18)F]fluoropropyl-betaCIT (FPCIT) to measure striatal dopamine transporter (DAT) binding and with [(15)O]water to assess activation during a sequence learning task where movements were made to a repeating sequence of eight targets. Caudate and putamen DAT binding in the PD cohort was reduced by 15% and 43%, respectively. In PD, caudate DAT binding correlated with target acquisition (R = 0.57, P < 0.05), while putamen DAT binding did not correlate with performance. In volunteers, caudate DAT binding correlated with learning-related activation (P < 0.05, corrected for multiple comparisons) in the left dorsolateral and ventral prefrontal cortices, the anterior cingulate and premotor regions, and the right cerebellum. A significant correlation with caudate DAT binding was additionally detected in the right anteromedial thalamus, extending into the rostral midbrain. By contrast, in the PD cohort, most of these regional relationships were lost: Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic tone. Our findings suggest that sequence learning is normally associated with tight coupling between dopaminergic input to the caudate and thalamo-cortical functional activity. Despite minimal reductions in nigro-caudate input, PD patients demonstrate a loss of this coupling early in the disease.

We tested the hypothesis that the DYT1 genotype is associated with a disorder of anatomical connectivity involving primarily the sensorimotor cortex. We used diffusion tensor magnetic resonance imaging (DTI) to assess the microstructure of white matter pathways in mutation carriers and control subjects. Fractional anisotropy (FA), a measure of axonal integrity and coherence, was reduced (p < 0.005) in the subgyral white matter of the sensorimotor cortex of DYT1 carriers. Abnormal anatomical connectivity of the supplementary motor area may contribute to the susceptibility of DYT1 carriers to develop clinical manifestations of dystonia.

Purpose of review Cognitive deficits that occur even early in the course of Parkinson's disease have received increasing attention in current imaging research. The exact physio-pathological processes mediating the deficits and the complex relationship of cognitive signs and antiparkinsonian treatment are not well understood. A clearer understanding of these mechanisms could potentially influence treatment choices, drug development and, ultimately, patient care. Recent findings Abnormal networks identified in studies of resting state metabolism in Parkinson's disease represent metabolic markers for remote effects of striato-nigral degeneration. These metabolic changes include subcortico-cortical networks, in particular cognitive cortico-striato-pallidal-thalamocortical loops. Recent brain studies focus on intervention-related brain changes. They illustrate different task-specific changes in brain activation with deep brain stimulation and with levodopa. Variable results of stimulation can be attributed to different effects on segregated cortico-striato-pallidal-thalamocortical loops during stimulation. By contrast, the heterogeneity observed in studies with levodopa possibly reflects the disease-stage and task-specific effects of levodopa. A decline in caudate dopamine modulated basal ganglia outflow appears to contribute to executive dysfunction and to brain activation changes in these loops at early Parkisnon's disease stages, while mesocortical degeneration mediated increases of inefficient dorsolateral prefrontal cortex activation may display a feature of more advanced disease stages only. Summary Despite evidence for the role of dopamine and cortico-striato-pallidal-thalamocortical loops in cognition, the specific contributions of mesocortical dopamine depletion and striatal dysfunction with downstream consequences on the loops remain to be separated. Additionally, more research is needed into the role of non-dopaminergic pathology in cognitive decline in Parkinson's disease.

The DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations.

This review focuses on recent investigations of alterations in behavior and functional brain organization induced by deep brain stimulation (DBS) for the treatment of Parkinson's disease. While the safety and ef®cacy of DBS in parkinsonism is well-established [1± 3], its mechanism of action is largely unknown [4±6]. Moreover, the effect of DBS on cognitive functioning remains controversial [7±9].

We used 15 O-labeled water and positron emission tomography to assess the effect of deep brain stimulation of the internal globus pallidus on motor sequence learning in Parkinson's disease. Seven right-handed patients were scanned on and off stimulation while they were performing a motor sequence learning task and a kinematically matched motor execution reference task. The scans were performed after a 12-hour medication washout. Stimulation parameters were adjusted for maximal motor improvement; experimental task parameters were held constant across stimulation conditions. Internal globus pallidus stimulation improved motor ratings by 37% (p < 0.01). During the sequence learning task, stimulation improved performance as measured by several correct anticipatory movements (p < 0.01) and by verbal report (p < 0.001). Concurrent positron emission tomography imaging during learning demonstrated significant (p < 0.01) increases in brain activation with stimulation in the left dorsolateral prefrontal cortex, bilaterally in premotor cortex, and in posterior parietal and occipital association areas. Stimulation did not affect the activity of these regions during the performance of the motor execution reference task. These findings suggest that internal globus pallidus deep brain stimulation can enhance the activity of prefrontal cortico-striato-pallidothalamic loops and related transcortical pathways. Improved sequence learning with stimulation may be directly related to these functional changes.

To develop a method to measure the dynamic response of the serotonin system in vivo, the effects of intravenously administered citalopram (the most selective of the serotonin reuptake inhibitors) on cerebral glucose metabolism were evaluated. Cerebral glucose metabolism was measured with positron emission tomography (PET) in 14 normal subjects scanned after administration of saline placebo and citalopram administered on 2 separate days. Citalopram administration resulted in a decrease in metabolism in the right anterior cingulate gyrus (BA 24/32), right superior (BA 9) and right middle frontal gyrus (BA 6), right parietal cortex (precuneus), right superior occipital gyrus, left thalamus, and right cerebellum. Increased metabolism was observed in the left superior temporal gyrus and left occipital cortex. Alterations in metabolism by acute citalopram administration involved the heteromodal association cortices that also show metabolic alterations in patients with geriatric depression and overlap with the regions affected by antidepressant treatment. Future studies will evaluate how the acute metabolic response to citalopram relates to the metabolic response after chronic treatment in patients with geriatric depression.

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.

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.

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.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.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.

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.

Self-paced hyperventilation (HV) induces slow cerebral magnetic field changes which were monitored and mapped continuously over 15 min using 49-channel DC-coupled ('direct current') magnetoencephalography (DC-MEG) based on a modulation technique. In nine/nine healthy subjects HV caused an increase (range: 1.1-6.2 pT) of the mean global DC-MEG field strength which slowly decayed after HV termination (mean time constant: 2 min). The complex HV-related field patterns were distinctly different from mainly dipolar somatosensory evoked field maps (N20m) in four/four subjects. Thus, current sources in the primary somatosensory cortex need not regularly dominate DC-field changes as had been previously considered. Rather, DC-MEG enabled the monitoring of a widely distributed HV-induced enhanced cortical excitability which may serve as model to study epileptic or post-anoxic cerebral hyperexcitability.

To determine whether reduced striatal D2 receptor binding reported in patients with idiopathic torsion dystonia is associated with the genotype, the authors used PET and [11C]-raclopride to assess non-manifesting carriers of the DYT1 mutation. D2 receptor binding was reduced by approximately 15% in caudate and putamen (p < 0.005). These results suggest that striatal D2 binding reductions are a trait feature of the DYT1 genotype.

Objective: The use of early response/nonresponse (ER/ENR) to antipsychotics as a predictor for ultimate response/nonresponse (UR/UNR) may help decrease inefficacious treatment continuation. However, data have been limited to adults, and ER/ENR has only been determined using time-consuming psychopathology rating scales. In the current study, we assessed if early improvement on the Clinical Global Impressions-Improvement (CGI-I) scale predicted UR/UNR in psychiatrically ill youth started on antipsychotic treatment. Methods: Seventy-nine youth aged 6–19 years, with schizophrenia spectrum disorders, treated naturalistically with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone and evaluated monthly, were divided into ER/ENR groups at week 4, using at least “minimally improved” on the CGI-I scale. Prediction using week 4 ER/ENR status for UR (CGI-I=at least “much improved”), effectiveness and adverse effect outcomes at 8–12 weeks were assessed. Results: At 4 weeks, 45.6% of subjects were ER and 54.4% were ENR without differences regarding baseline demographic, illness, and treatment variables, except for higher age (p=0.034) and maximum risperidone dose (p=0.0043) in ENR. ER/ENR status at 4 weeks predicted UR/UNR at week 12 significantly (p