The relationship between performance in a theory of mind task and intrinsic functional connectivity in youth with early onset psychosis

Psychotic disorders are characterized by theory of mind (ToM) impairment. Although ToM undergoes maturational changes throughout adolescence, there is a lack of studies examining ToM performance and its brain functional correlates in individuals with an early onset of psychosis (EOP; onset prior to age 18), and its relationship with age. Twenty-seven individuals with EOP were compared with 41 healthy volunteers using the "Reading-the-Mind-in-the-Eyes" Test, as a measure of ToM performance. A resting-state functional MRI scan was also acquired, in which the default mode network was used to identify areas relevant to ToM processing employing independent component analysis. Group effects revealed worse ToM performance and less intrinsic functional connectivity in the medial prefrontal cortex in EOP relative to healthy volunteers. Group by age interaction revealed age-positive associations in ToM task performance and in intrinsic connectivity in the medial prefrontal cortex in healthy volunteers, which were not present in EOP. Differences in ToM performance were partially mediated by intrinsic functional connectivity in the medial prefrontal cortex. Poorer ToM performance in EOP, coupled with less medial prefrontal cortex connectivity, could be associated with the impact of psychosis during a critical period of development of the social brain, limiting normative age-related maturation

Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation

Brain structural trajectories in youth at familial risk for schizophrenia or bipolar disorder according to development of psychosis spectrum symptoms

Background: The evaluation of child and adolescent offspring of patients with schizophrenia (SzO) or bipolar disorder (BpO) may help understand changes taking place in the brain in individuals at heightened risk for disease during a key developmental period. Methods: One hundred twenty-eight individuals (33 SzO and 46 BpO, considered jointly as 'Familial High Risk' (FHR), and 49 controls) aged 6-17 years underwent clinical, cognitive and neuroimaging assessment at baseline, 2- and 4-year follow-up. Twenty FHR participants (11 SzO and 9 BpO) developed psychotic spectrum symptoms during follow-up, while 59 FHR participants did not. Magnetic resonance imaging was performed on a 3Tesla scanner; cortical surface reconstruction was applied to measure cortical thickness, surface area and grey matter volume. Results: FHR participants who developed psychotic spectrum symptoms over time showed greater time-related mean cortical thinning than those who did not and than controls. By subgroups, this effect was present in both BpO and SzO in the occipital cortex. At baseline, FHR participants who developed psychotic spectrum symptoms over time had smaller total surface area and grey matter volume than those who did not and than controls. Over time, all FHR participants showed less longitudinal decrease in surface area than controls. In those who developed psychotic spectrum symptoms over time, this effect was driven by BpO, while in those who did not, this was due to SzO, who also showed less grey matter volume reduction. Conclusion: The emergence of psychotic spectrum symptoms in FHR was indexed by smaller cross-sectional surface area and progressive cortical thinning. Relative preservation of surface area over time may signal different processes according to familial risk. These findings lay the foundation for future studies aimed at stratification of FHR youth

Cognitive reserve and its correlates in child and adolescent offspring of patients diagnosed with schizophrenia or bipolar disorder

Aim: To analyze cognitive reserve (CR) in child and adolescent offspring of patients diagnosed with schizophrenia (SZ-off) or bipolar disorder (BD-off) and compare them with a group of community controls (CC-off). We also aimed to investigate whether there was an association between CR and clinical and neuropsychological variables according to group. Methods: The study included 46 SZ-off, 105 BD-off and 102 CC-off. All participants completed assessments regarding CR and clinical, neuropsychological and psychosocial functioning. CR was measured with a proxy based on premorbid intelligence, parental occupational level, educational attainment, developmental milestones and sociability. The clinical assessment included the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime, the Semi-structured Interview for Prodromal Syndromes, and the Global Assessment Functioning scale. The neuropsychological assessment included measures of executive functioning, attention, verbal memory, working memory and processing speed. Results: SZ-off showed a lower level of CR compared to BD-off and CC-off, while BD-off showed an intermediate level of CR between SZ-off and CC-off. Moreover, an association between higher CR and less lifetime psychopathology, fewer prodromal psychotic symptoms, higher psychosocial functioning, and a higher working memory score was observed in all groups, but it was stronger in SZ-off. Conclusions: CR seemed to be associated with psychopathology, clinical symptoms, psychosocial functioning, and some cognitive functions. SZ-off appeared to benefit more from a higher CR, therefore it could be considered a protective factor against the development of clinical symptomatology and cognitive impairment

Executive functioning and emotion recognition in youth with oppositional defiant disorder and/or conduct disorder

Objectives: Executive functioning and emotion recognition may be impaired in disruptive youth, yet findings in oppositional defiant disorder (ODD) and conduct disorder (CD) are inconsistent. We examined these functions related to ODD and CD, accounting for comorbid attention-deficit/hyperactivity disorder (ADHD) and internalising symptoms.Methods: We compared executive functioning (visual working memory, visual attention, inhibitory control) and emotion recognition between youth (8-18 years old, 123 boys, 55 girls) with ODD (n = 44) or CD (with/without ODD, n = 48), and healthy controls (n = 86). We also related ODD, CD, and ADHD symptom counts and internalising symptomatology to all outcome measures, as well as executive functioning to emotion recognition.Results: Visual working memory and inhibitory control were impaired in the ODD and CD groups versus healthy controls. Anger, disgust, fear, happiness, and sadness recognition were impaired in the CD group; only anger recognition was impaired in the ODD group. Deficits were not explained by comorbid ADHD or internalising symptoms. Visual working memory was associated with recognition of all basic emotions.Conclusions: Our findings challenge the view that neuropsychological impairments in youth with ODD/CD are driven by comorbid ADHD and suggest possible distinct neurocognitive mechanisms in CD versus ODD

Specific cortical and subcortical alterations for reactive and proactive aggression in children and adolescents with disruptive behavior.

Maladaptive aggression, as present in conduct disorder (CD) and, to a lesser extent, oppositional defiant disorder (ODD), has been associated with structural alterations in various brain regions, such as ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, insula and ventral striatum. Although aggression can be subdivided into reactive and proactive subtypes, no neuroimaging studies have yet investigated if any structural brain alterations are associated with either of the subtypes specifically. Here we investigated associations between aggression subtypes, CU traits and ADHD symptoms in predefined regions of interest. T1-weighted magnetic resonance images were acquired from 158 children and adolescents with disruptive behavior (ODD/CD) and 96 controls in a multi-center study (aged 8-18). Aggression subtypes were assessed by questionnaires filled in by participants and their parents. Cortical volume and subcortical volumes and shape were determined using Freesurfer and the FMRIB integrated registration and segmentation tool. Associations between volumes and continuous measures of aggression were established using multilevel linear mixed effects models. Proactive aggression was negatively associated with amygdala volume (b = -10.7, p = 0.02), while reactive aggression was negatively associated with insula volume (b = -21.7, p = 0.01). No associations were found with CU traits or ADHD symptomatology. Classical group comparison showed that children and adolescents with disruptive behavior had smaller volumes than controls in (bilateral) vmPFC (p = 0.003) with modest effect size and a reduced shape in the anterior part of the left ventral striatum (p = 0.005). Our study showed negative associations between reactive aggression and volumes in a region involved in threat responsivity and between proactive aggression and a region linked to empathy. This provides evidence for aggression subtype-specific alterations in brain structure which may provide useful insights for clinical practice

Aggression subtypes relate to distinct resting state functional connectivity in children and adolescents with disruptive behavior

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control

Característiques clíniques i neuropsicològiques en nens i adolescents amb trastorn de l’espectre autista d’alt funcionament i en els seus germans

[cat] El trastorn de l’espectre autista (TEA) ha sigut inclòs recentment dins el grup de trastorns del neurodesenvolupament que engloba trastorns que tenen un inici en el període de desenvolupament i cursen amb disfunció cognitiva i amb interferència en el funcionament personal, social, acadèmic o laboral. Aquests trastorns també comparteixen una elevada heretabilitat, el solapament de símptomes entre ells i la tendència a coexistir en la mateixa persona. Els estudis previs en població TEA suggereixen una alta comorbiditat amb el trastorn per dèficit d’atenció i hiperactivitat (TDAH) i trastorns d’ansietat, així com múltiples dèficits cognitius. A més, hi ha estudis que han relacionat aquests dèficits cognitius amb més gravetat dels símptomes i pitjor funcionament adaptatiu a la vida diària. Per una altra banda, molts pocs estudis han avaluat les característiques clíniques i psicopatològiques dels germans no afectats pel trastorn, tot hi que estudis preliminars han suggerit més presència de TEA i altres trastorns com el TDAH així com la presència de dèficits lleus en el funcionament cognitiu. Però fins a la data, no tenim dades concloents ja que existeix una alta variabilitat entre els estudis. Aquesta heterogeneïtat entre els resultats pot deure’s a diferències metodològiques o factors sociodemogràfics no controlats, como ara el quocient intel·lectual (QI). L’objectiu d’aquesta tesi va ser revisar la comorbiditat i els dèficits cognitius que presentaven un grup de nens i adolescents amb TEA d’alt funcionament (TEA-AF) i comparar-los amb la població general. Donat l’alta heretabilitat d’aquest trastorn, es va voler avaluar un grup de germans d’aquests pacients amb TEA-AF a nivell clínic i neuropsicològic. A més, es va observar una falta de proves validades a l’espanyol per avaluar cognició social avançada en població TEA- AF, per lo que es va traduir i validar l’escala “Stories from everyday life” (SEL) del Dr. Nils Kaland. Els resultats van mostrar un alta comorbiditat amb TDAH i trastorns d’ansietat en el nostre grup de nens i adolescents amb TEA-AF, que va ser superior a la trobada en la població general. El major risc de patir psicopatologia comòrbida es va relacionar amb un QI i un nivell socioeconòmic (NSE) més baix en la nostra mostra. A nivell neuropsicològic, es van observar múltiples dèficits cognitius en la planificació, la flexibilitat cognitiva, la memòria verbal i de treball, el processament visual local-global i el reconeixement d’emocions. Alguns d’aquests dèficits eren independents del QI i estaven relacionats amb més gravetat dels símptomes i pitjor funcionament adaptatiu. En quant als germans es va trobar més presència de TDAH en comparació a la població general, i es va relacionar el QI baix amb major risc de desenvolupar psicopatologia. A nivell neuropsicològic no es van trobar dèficits cognitius comparat amb la població general però es va observar un perfil intermedi en algunes àrees. Per últim, la validació espanyola de l’escala SEL va mostrar bones propietats psicomètriques i es va desenvolupar un manual per millorar la seva administració. El grup amb TEA-AF va mostrar un pitjor rendiment en tasques on se’ls demanava fer tant inferències físiques com mentals en contextos socials, però al controlar pel QI verbal (i no verbal) només les inferències mentals s’erigien com el dèficit principal d’aquesta població. L’avaluació de comorbiditats psiquiàtriques i del dèficits cognitius en la població TEA-AF es de gran importància per tal d’individualitzar el procés de diagnòstic. S’hauria d’establir un pla de tractament que tingui en compte totes les comorbiditats així com obrir les portes a la rehabilitació cognitiva com una alternativa a incloure al tractament convencional. S’hauria de tenir més en compte els seus germans al ser una població d’alt risc.[eng] Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder (NDD) that presents with cognitive dysfunction and personal, social and/or academic impairment. NDD share a high heritability and tend to co-occur. Previous studies on ASD population suggest a high comorbidity with attention deficit and hyperactivity disorder (ADHD) and anxiety disorders. Cognitive deficits in multiple areas have been reported. In addition, there are studies that have linked these cognitive deficits with more severe symptoms and worse adaptive functioning. Only few studies have evaluated the clinical and psychopathological characteristics of ASD siblings not affected by the disorder. Preliminary studies have suggested greater presence of ASD and other disorders such as ADHD and the presence of mild cognitive deficits. The main aim of this thesis was to review comorbidity and cognitive deficits in a group of children with high functioning ASD (HF-ASD) and compare them with general population. Given the high heritability of this disorder, we also evaluated a group of HF-ASD unaffected siblings at clinical and neuropsychological level. In addition, noticing the lack of Spanish validated tests to assess HF-ASD population in social cognition, a new instrument was validated (“Stories from everyday life" - SEL). Our results showed that HF-ASD children and adolescents presented a high comorbidity with ADHD and anxiety disorders. IQ and socioeconomic status would have a relationship with this increased risk of psychopathology. They also have multiple IQ-independent cognitive deficits that were related to more severe symptoms and worse adaptive functioning. HF-ASD siblings also had greater presence of ADHD compared to general population, showing a relationship with lower IQ; and show an intermediate cognitive profile between their siblings with HF-ASD and general population. The Spanish version of the SEL scale stands as a good tool for assessing advanced social cognition in people with HF-ASD. The evaluation of psychiatric comorbidities and cognitive deficits in HF-ASD population is important to individualize diagnostic process. It should help to establish a treatment plan that includes all comorbid symptoms and opens the door to cognitive rehabilitation as an alternative to the conventional treatment. More attention should be paid to HF-ASD unaffected siblings, as a high-risk population

Age-related brain deviations and aggression

BACKGROUND: Disruptive behavior disorders (DBD) are heterogeneous at the clinical and the biological level. Therefore, the aims were to dissect the heterogeneous neurodevelopmental deviations of the affective brain circuitry and provide an integration of these differences across modalities.METHODS: We combined two novel approaches. First, normative modeling to map deviations from the typical age-related pattern at the level of the individual of (i) activity during emotion matching and (ii) of anatomical images derived from DBD cases (n = 77) and controls (n = 52) aged 8-18 years from the EU-funded Aggressotype and MATRICS consortia. Second, linked independent component analysis to integrate subject-specific deviations from both modalities.RESULTS: While cases exhibited on average a higher activity than would be expected for their age during face processing in regions such as the amygdala when compared to controls these positive deviations were widespread at the individual level. A multimodal integration of all functional and anatomical deviations explained 23% of the variance in the clinical DBD phenotype. Most notably, the top marker, encompassing the default mode network (DMN) and subcortical regions such as the amygdala and the striatum, was related to aggression across the whole sample.CONCLUSIONS: Overall increased age-related deviations in the amygdala in DBD suggest a maturational delay, which has to be further validated in future studies. Further, the integration of individual deviation patterns from multiple imaging modalities allowed to dissect some of the heterogeneity of DBD and identified the DMN, the striatum and the amygdala as neural signatures that were associated with aggression.</p

Subgrouping children and adolescents with disruptive behaviors: symptom profiles and the role of callous-unemotional traits

Disruptive behavior during childhood and adolescence is heterogeneous and associated with several psychiatric disorders. The identification of more homogeneous subgroups might help identify different underlying pathways and tailor treatment strategies. Children and adolescents (aged 8-18) with disruptive behaviors (N = 121) and healthy controls (N = 100) were included in a European multi-center cognition and brain imaging study. They were assessed via a battery of standardized semi-structured interviews and questionnaires. K-means cluster-model analysis was carried out to identify subgroups within the group with disruptive behaviors, based on clinical symptom profiles, callous-unemotional (CU) traits, and proactive and reactive aggression. The resulting subgroups were then compared to healthy controls with regard to these clinical variables. Three distinct subgroups were found within the group with disruptive behaviors. The High CU Traits subgroup presented elevated scores for CU traits, proactive aggression and conduct disorder (CD) symptoms, as well as a higher proportion of comorbidities (CD + oppositional defiant disorder + attention deficit hyperactivity disorder (ADHD). The ADHD and Affective Dysregulation subgroup showed elevated scores for internalizing and ADHD symptoms, as well as a higher proportion of females. The Low Severity subgroup had relatively low levels of psychopathology and aggressive behavior compared to the other two subgroups. The High CU Traits subgroup displayed more antisocial behaviors than the Low Severity subgroup, but did not differ when compared to the ADHD and Affective Dysregulation subgroup. All three subgroups differed significantly from the healthy controls in all the variables analyzed. The present study extends previous findings on subgrouping children and adolescents with disruptive behaviors using a multidimensional approach and describes levels of anxiety, affective problems, ADHD, proactive aggression and CU traits as key factors that differentiate conclusively between subgroups