Abstract The patient reported here presented with first symptoms at the age of 10 showing an abnormal gait, calf hypertrophy and winged scapulae. She was diagnosed with eosinophilic myositis after ...muscle biopsy. A second muscle biopsy at the age of 20 and subsequent genetic testing, however, revealed the underlying condition of a primary γ-sarcoglycanopathy, or LGMD2C. To our knowledge, this is the first LGMD2C patient reported who initially presented with eosinophilic myositis. Eosinophilia has been reported previously in patients with Calpainopathy and Becker Muscular Dystrophy and might be an early, but transient feature of a wider range of muscular dystrophies.
Impaired social cognition is one of the core characteristics of autism spectrum disorders (ASD). Appropriate measures of social cognition for high-functioning adolescents with ASD are, however, ...lacking. The Movie for the Assessment of Social Cognition (MASC) uses dynamic social stimuli, ensuring ecological validity, and has proven to be a sensitive measure in adulthood. In the current study, 33 adolescents with ASD and 23 controls were administered the MASC, while concurrent eye tracking was used to relate gaze behavior to performance levels. The ASD group exhibited reduced MASC scores, with social cognition performance being explained by shorter fixation duration on eyes and decreased pupil dilation. These potential diagnostic markers are discussed as indicators of different processing of social information in ASD.
The objective of this study was to analyse the mutations of the acetylcholine receptor (AChR) delta subunit gene (CHRND) in a patient with sporadic congenital myasthenic syndrome (CMS). Mutations in ...various genes encoding proteins expressed at the neuromuscular junction may cause CMS. Mutations of AChR subunit genes lead to end-plate AChR deficiency or to altered kinetic properties of the receptor. Mutations in the alpha, beta and delta subunits of the AChR are less frequent than mutations of the epsilon subunit; mutations in these subunits leading to AChR deficiency are often associated with a severe phenotype. A sporadic patient from Germany was studied, who presented with an early onset CMS associated with feeding difficulties, ptosis, a moderate general weakness responsive to anticholinesterase treatment and recurrent episodes of respiratory insufficiency provoked by infections. The CHRND gene was screened for mutations by RFLP, long-range PCR and sequence analysis. Subsequently, we conducted functional studies of AChR mutants co-transfected with rapsyn in HEK 293 cells. Heterozygously to a 2.2 kb microdeletion disrupting the CHRND gene, we identified a novel point mutation in the long cytoplasmic loop, CHRND E381K. The cytoplasmic loop of the AChR subunits is known to be essential for AChR–rapsyn co-clustering. We therefore studied the interaction of AChR containing the CHRND E381K mutation with rapsyn by evaluating expression and co-localization of rapsyn and mutated AChR subunits in co-transfected HEK 293 cells. Interestingly, the mutated receptor showed severely reduced cluster formation compared with the wild-type receptor. In contrast, the corresponding amino acid substitution in the cytoplasmic loop of the AChR epsilon (CHRNE E376K) as well as a recently reported CMS mutation affecting this domain (CHRNE N436del) had no impact on cluster formation. CHRND mutations are a rare cause for CMS but should be considered in patients with a severe, early onset disease form, clinically resembling a rapsyn phenotype with recurrent episodic apnoeas. Our results suggest that impairment of AChR–rapsyn co-clustering—a well-known molecular mechanism for rapsyn mutations—could also result from mutations in the delta subunit. Introduction of the same mutation in the epsilon subunit had no effect on AChR clustering indicating a special role of the delta subunit in AChR–rapsyn interactions.
Abstract Effective planning of clinical trials requires an appropriate number of patients who fulfil given inclusion criteria. In the case of so called “orphan” diseases, such as Duchenne and Becker ...muscular dystrophy (DMD/BMD), the number of suitable patients within one country is usually limited. We developed a detailed registry of Czech and Slovak DMD/BMD patients which may contribute to cooperation on the European level. The registry uses internet and database technologies with a multilevel architecture. Patients may view their own data. As of May 2008, 163 patients have been registered in the database. The registry provides a detailed phenotypic and genotypic description of patients. The main purpose of such a registry is the time-effective recruitment of eligible patients for a clinical trial or therapy and may allow the anticipation of possible future effects of appropriate therapy on individual patients. The importance of the DMD/BMD patient registries has recently also been rising with new clinical trials focused on mutation-specific approaches. Other outputs include assessment of epidemiology, phenotype and genotype relationships, or standards of care.
Abstract
The relationship between transdiagnostic, dimensional, and categorical approaches to psychiatric nosology is under intense debate. To inform this discussion, we studied neural systems linked ...to reward anticipation across a range of disorders and behavioral dimensions. We assessed brain responses to reward expectancy in a large sample of 221 participants, including patients with schizophrenia (SZ; n = 27), bipolar disorder (BP; n = 28), major depressive disorder (MD; n = 31), autism spectrum disorder (ASD; n = 25), and healthy controls (n = 110). We also characterized all subjects with an extensive test battery from which a cognitive, affective, and social functioning factor was constructed. These factors were subsequently related to functional responses in the ventral striatum (vST) and neural networks linked to it. We found that blunted vST responses were present in SZ, BP, and ASD but not in MD. Activation within the vST predicted individual differences in affective, cognitive, and social functioning across diagnostic boundaries. Network alterations extended beyond the reward network to include regions implicated in executive control. We further confirmed the robustness of our results in various control analyses. Our findings suggest that altered brain responses during reward anticipation show transdiagnostic alterations that can be mapped onto dimensional measures of functioning. They also highlight the role of executive control of reward and salience signaling in the disorders we study and show the power of systems-level neuroscience to account for clinically relevant behaviors.
Adolescents with increased callous unemotional traits (CU traits) in the context of disruptive behavior disorder (DBD) show a persistent pattern of antisocial behavior with shallow affect and a lack ...of empathy or remorse. The amygdala and insula as regions commonly associated with emotion processing, empathy and arousal are implicated in DBD with high CU traits. While behavioral therapies for DBD provide significant but small effects, individualized treatments targeting the implicated brain regions are missing.
In this explorative randomized controlled trial we randomly assigned twenty-seven adolescents with DBD to individualized real-time functional magnetic resonance neurofeedback (rtfMRI-NF) or behavioral treatment as usual (TAU). Visual feedback of either amygdala or insula activity was provided during rtfMRI-NF by gauges and included a simple and concurrent video run plus a transfer run. A linear mixed model (LMM) was applied to determine improvement of self-regulation. Specificity was assessed by correlating individual self-regulation improvement with clinical outcomes.
The rtfMRI-NF (n = 11) and TAU (n = 10) completers showed comparable and significant clinical improvement indicating neither superiority nor inferiority of rtfMRI-NF. The exploratory LMM revealed successful learning of self-regulation along the course of training for participants who received feedback from the amygdala. A significant exploratory correlation between individual target region activity in the simple run and clinical improvement was found for one dimension of DBD.
This exploratory study demonstrated feasibility and suggests clinical efficacy of individualized rtfMRI-NF comparable to active TAU for adolescents with DBD and increased CU traits. Further studies are needed to confirm efficacy, specificity and to clarify underlying learning mechanisms.
•Feasibility of individualized real-time fMRI neurofeedback in a sample of adolescents with disruptive behavior disorder•Significant clinical improvement comparable to treatment as usual with behavioral therapy•Increased brain activation over time in group with amygdala feedback compared to insula feedback
The modulation of brain circuits of emotion is a promising pathway to treat borderline personality disorder (BPD). Precise and scalable approaches have yet to be established. Two studies ...investigating the amygdala-related electrical fingerprint (Amyg-EFP) in BPD are presented: one study addressing the deep-brain correlates of Amyg-EFP, and a second study investigating neurofeedback (NF) as a means to improve brain self-regulation.
Study 1 combined electroencephalography (EEG) and simultaneous functional magnetic resonance imaging to investigate the replicability of Amyg-EFP-related brain activation found in the reference dataset (
= 24 healthy subjects, 8 female; re-analysis of published data) in the replication dataset (
= 16 female individuals with BPD). In the replication dataset, we additionally explored how the Amyg-EFP would map to neural circuits defined by the research domain criteria. Study 2 investigated a 10-session Amyg-EFP NF training in parallel to a 12-weeks residential dialectical behavior therapy (DBT) program. Fifteen patients with BPD completed the training,
= 15 matched patients served as DBT-only controls.
Study 1 replicated previous findings and showed significant amygdala blood oxygenation level dependent activation in a whole-brain regression analysis with the Amyg-EFP. Neurocircuitry activation (negative affect, salience, and cognitive control) was correlated with the Amyg-EFP signal. Study 2 showed Amyg-EFP modulation with NF training, but patients received reversed feedback for technical reasons, which limited interpretation of results.
Recorded via scalp EEG, the Amyg-EFP picks up brain activation of high relevance for emotion. Administering Amyg-EFP NF in addition to standardized BPD treatment was shown to be feasible. Clinical utility remains to be investigated.
Brain imaging studies have shown altered amygdala activity during emotion processing in children and adolescents with oppositional defiant disorder (ODD) and conduct disorder (CD) compared to ...typically developing children and adolescents (TD). Here we aimed to assess whether aggression-related subtypes (reactive and proactive aggression) and callous-unemotional (CU) traits predicted variation in amygdala activity and skin conductance (SC) response during emotion processing.
We included 177 participants (n = 108 cases with disruptive behaviour and/or ODD/CD and n = 69 TD), aged 8-18 years, across nine sites in Europe, as part of the EU Aggressotype and MATRICS projects. All participants performed an emotional face-matching functional magnetic resonance imaging task.
Differences between cases and TD in affective processing, as well as specificity of activation patterns for aggression subtypes and CU traits, were assessed. Simultaneous SC recordings were acquired in a subsample (n = 63). Cases compared to TDs showed higher amygdala activity in response to negative faces (fearful and angry) v. shapes. Subtyping cases according to aggression-related subtypes did not significantly influence on amygdala activity; while stratification based on CU traits was more sensitive and revealed decreased amygdala activity in the high CU group. SC responses were significantly lower in cases and negatively correlated with CU traits, reactive and proactive aggression.
Our results showed differences in amygdala activity and SC responses to emotional faces between cases with ODD/CD and TD, while CU traits moderate both central (amygdala) and peripheral (SC) responses. Our insights regarding subtypes and trait-specific aggression could be used for improved diagnostics and personalized treatment.
Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed ...to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA-VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOA× CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders.
The cerebellum contains more than 50% of the brain neurons and is involved in social cognition. Cerebellar anatomical atypicalities have repeatedly been reported in individuals with autism. However, ...studies have yielded inconsistent findings, likely because of a lack of statistical power, and did not capture the clinical and neuroanatomical diversity of autism. Our aim was to better understand cerebellar anatomy and its diversity in autism.
We studied the cerebellar grey matter morphology in 274 individuals with autism and 219 controls of a multicenter European cohort (EU-AIMS LEAP). To ensure the robustness of our results, we conducted lobular parcellation of the cerebellum with two different pipelines in addition to voxel-based morphometry. We performed statistical analyses with linear, multivariate - including normative modeling - and a meta-analytic approach to capture the diversity of cerebellar anatomy in individuals with autism and controls. Last, we performed a dimensional analysis of cerebellar anatomy in an independent cohort of 352 individuals with autism-related symptoms.
We did not find any significant difference in the cerebellum when comparing individuals with autism and controls using linear models. In addition, there were no significant deviations in our normative models in the cerebellum in individuals with autism. Finally, we found no evidence of cerebellar atypicalities related either to age, IQ, sex or social functioning in individuals with autism.
Despite positive results published in the last decade from relatively small samples, our results suggest that there is no striking difference in cerebellar anatomy of individuals with autism.
PDF
