Developmental imaging studies show that cortical grey matter decreases in volume during childhood and adolescence. However, considerably less research has addressed the development of subcortical ...regions (caudate, putamen, pallidum, accumbens, thalamus, amygdala, hippocampus and the cerebellar cortex), in particular not in longitudinal designs. We used the automatic labeling procedure in FreeSurfer to estimate the developmental trajectories of the volume of these subcortical structures in 147 participants (age 7.0–24.3years old, 94 males; 53 females) of whom 53 participants were scanned twice or more. A total of 223 magnetic resonance imaging (MRI) scans (acquired at 1.5-T) were analyzed. Substantial diversity in the developmental trajectories was observed between the different subcortical gray matter structures: the volume of caudate, putamen and nucleus accumbens decreased with age, whereas the volume of hippocampus, amygdala, pallidum and cerebellum showed an inverted U-shaped developmental trajectory. The thalamus showed an initial small increase in volume followed by a slight decrease. All structures had a larger volume in males than females over the whole age range, except for the cerebellum that had a sexually dimorphic developmental trajectory. Thus, subcortical structures appear to not yet be fully developed in childhood, similar to the cerebral cortex, and continue to show maturational changes into adolescence. In addition, there is substantial heterogeneity between the developmental trajectories of these structures.
•Development of subcortical structures was examined in 150 typically developing children.•Similar to the cerebral cortex, subcortical structures are not yet fully developed in childhood.•There was substantial heterogeneity in developmental trajectories of subcortical structures.•All structures were larger in males than females over the whole age range.•The cerebellum was the only structure to show a sexually dimorphic trajectory.
Balance between excitation (E) and inhibition (I) is a key principle for neuronal network organization and information processing. Consistent with this notion, excitation-inhibition imbalances are ...considered a pathophysiological mechanism in many brain disorders including autism spectrum disorder (ASD). However, methods to measure E/I ratios in human brain networks are lacking. Here, we present a method to quantify a functional E/I ratio (fE/I) from neuronal oscillations, and validate it in healthy subjects and children with ASD. We define structural E/I ratio in an in silico neuronal network, investigate how it relates to power and long-range temporal correlations (LRTC) of the network's activity, and use these relationships to design the fE/I algorithm. Application of this algorithm to the EEGs of healthy adults showed that fE/I is balanced at the population level and is decreased through GABAergic enforcement. In children with ASD, we observed larger fE/I variability and stronger LRTC compared to typically developing children (TDC). Interestingly, visual grading for EEG abnormalities that are thought to reflect E/I imbalances revealed elevated fE/I and LRTC in ASD children with normal EEG compared to TDC or ASD with abnormal EEG. We speculate that our approach will help understand physiological heterogeneity also in other brain disorders.
Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 ...individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen's d = -0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.
Recent trials have indicated positive effects of bumetanide in autism spectrum disorder (ASD). We tested efficacy of bumetanide on core symptom domains using a single center, parallel-group, ...participant-randomized, double-blind, placebo-controlled phase-2 superiority trial in a tertiary hospital in the Netherlands.
Unmedicated children aged 7 to 15 years with ASD and IQ ≥55 were block-randomized 1:1 to oral-solution bumetanide versus placebo, titrated to a maximum of 1.0 mg twice daily for 91 days (D91), followed by a 28-day wash-out period. The primary outcome was difference in Social Responsiveness Scale−2 (SRS-2) total score at D91, analyzed by modified intention-to-treat with linear mixed models.
A total of 92 participants (mean age 10.5 SD 2.4 years) enrolled between June 2016 and December 2018. In all, 47 children were allocated to bumetanide and 45 to placebo. Two participants dropped out per treatment arm. After 91 days, bumetanide was not superior to placebo on the primary outcome, the SRS-2 (mean difference −3.16, 95% CI = −9.68 to 3.37, p = .338). A superior effect was found on one of the secondary outcomes, the Repetitive Behavior Scale−Revised (mean difference −4.16, 95% CI = −8.06 to −0.25, p = .0375), but not on the Sensory Profile (mean difference 5.64, 95% CI = −11.30 to 22.57, p = .508) or the Aberrant Behavior Checklist Irritability Subscale (mean difference −0.65, 95% CI = −2.83 to 1.52, p = .552). No significant wash-out effect was observed. Significant adverse effects were predominantly diuretic effects (orthostatic hypotension (17 36% versus 5 11%, p = .007); hypokalemia (24 51% versus 0 0%, p < .0001), the occurrence of which did not statistically influence treatment outcome.
The trial outcome was negative in terms of no superior effect on the primary outcome. The secondary outcomes suggest efficacy on repetitive behavior symptoms for a subset of patients.
Bumetanide in Autism Medication and Biomarker Study (BAMBI); https://www.clinicaltrialsregister.eu/; 2014-001560-35.
Schizophrenia is a complex brain disease involving several neurotransmitter systems, including aberrant noradrenergic activity, which might underlie cognitive deficits. Clonidine is an α
-agonist and ...previous research has demonstrated that single dosages of clonidine normalize sensori(motor) gating in schizophrenia. Currently, we investigated whether clonidine is able to normalize mismatch negativity (MMN) and P3a amplitude deficits in this same group of patients. This is important, since reports have shown that MMN amplitude is associated with cognitive functioning and daily life functions in schizophrenia. Twenty chronically ill, male schizophrenia patients were tested with the MMN paradigm from the Copenhagen Psychophysiological Test Battery (CPTB) on 5 occasions, separated by a week. Patients received randomized, yet balanced, either a placebo or a single dose (25, 50, 75 or 150 μg) of clonidine (each dose only once) on top of their usual medication on each occasion. Patients were matched on age and gender with 20 healthy controls (HC) who did not receive any treatment. We found decreased MMN and P3a amplitudes in our patients compared to HC. Although clonidine did neither significantly increase MMN nor P3a amplitude in our patients, it did increase certain levels of MMN and P3a amplitude such that these were not significantly different anymore from the healthy controls. Together with our previous reports indicating normalized sensori(motor) gating in the same patients following administration of clonidine, our results could be of potential high clinical relevance in treating schizophrenia. Future studies should focus on longer trial periods to investigate if clonidine also improves cognitive functioning in schizophrenia.
Autism spectrum disorders (ASD) have been associated with atypical cortical gray and subcortical white matter development. Neurodevelopmental theories postulate that a relation between cortical ...maturation and structural brain connectivity may exist. We therefore investigated the development of gyrification and white matter connectivity and their relationship in individuals with ASD and their typically developing peers.
T1- and diffusion-weighted images were acquired from a representative sample of 30 children and adolescents with ASD (aged 8-18 years), and 29 typically developing children matched for age, sex, hand preference, and socioeconomic status. The FreeSurfer suite was used to calculate cortical volume, surface area, and gyrification index. Measures of structural connectivity were estimated using probabilistic tractography and tract-based spatial statistics (TBSS).
Left prefrontal and parietal cortex showed a relative, age-dependent decrease in gyrification index in children and adolescents with ASD compared to typically developing controls. This result was replicated in an age-and IQ-matched sample provided by the Autism Brain Imaging Data Exchange (ABIDE) initiative. Furthermore, tractography and TBSS showed a complementary pattern in which left prefrontal gyrification was negatively related to radial diffusivity in the forceps minor in participants with ASD.
The present study builds on earlier findings of abnormal gyrification and structural connectivity in the prefrontal cortex in ASD. It provides a more comprehensive neurodevelopmental characterization of ASD, involving interdependent changes in microstructural white and cortical gray matter. The findings of related abnormal patterns of gyrification and white matter connectivity support the notion of the intertwined development of 2 major morphometric domains in ASD.
The reproducibility of machine-learning analyses in computational psychiatry is a growing concern. In a multimodal neuropsychiatric dataset of antipsychotic-naïve, first-episode schizophrenia ...patients, we discuss a workflow aimed at reducing bias and overfitting by invoking simulated data in the design process and analysis in two independent machine-learning approaches, one based on a single algorithm and the other incorporating an ensemble of algorithms. We aimed to (1) classify patients from controls to establish the framework, (2) predict short- and long-term treatment response, and (3) validate the methodological framework. We included 138 antipsychotic-naïve, first-episode schizophrenia patients with data on psychopathology, cognition, electrophysiology, and structural magnetic resonance imaging (MRI). Perinatal data and long-term outcome measures were obtained from Danish registers. Short-term treatment response was defined as change in Positive And Negative Syndrome Score (PANSS) after the initial antipsychotic treatment period. Baseline diagnostic classification algorithms also included data from 151 matched controls. Both approaches significantly classified patients from healthy controls with a balanced accuracy of 63.8% and 64.2%, respectively. Post-hoc analyses showed that the classification primarily was driven by the cognitive data. Neither approach predicted short- nor long-term treatment response. Validation of the framework showed that choice of algorithm and parameter settings in the real data was successfully guided by results from the simulated data. In conclusion, this novel approach holds promise as an important step to minimize bias and obtain reliable results with modest sample sizes when independent replication samples are not available.
Numerous studies have demonstrated impaired sensory gating in schizophrenia and this impairment has been proposed as a candidate biomarker for the disorder. The typical age of onset for schizophrenia ...is early adulthood, however a sizable group of patients present with psychotic symptoms before the age of 18, commonly referred to as early-onset psychosis (EOP). How an earlier onset influences sensory gating is currently unknown. Impaired sensory gating may not be specific to psychosis, but rather a shared disturbance of neurodevelopmental disorders, such as attention deficit/hyperactivity disorder (ADHD). Therefore, the current study investigated P50 suppression in young adolescents (12-17 years old) with either EOP (N = 55) or ADHD (N = 28) and age and gender matched healthy controls (HC) (N = 71). In addition to P50 suppression, N100 and P200 suppression data were also analyzed. No significant group differences in either raw mean P50 amplitude or mean P50 gating ratios were observed between EOP, ADHD, and HC. Additionally, we observed no P50 suppression deficit in those EOP patients diagnosed with schizophrenia (N = 39). Similarly, we observed no differences in N100 or P200 between the three groups. Healthy levels of P50 suppression were found in both patient groups. The results are in line with some previous studies showing healthy levels of P50 suppression in the early phases of schizophrenia. Our findings do not support P50 sensory gating as a valid biomarker for EOP or ADHD.
Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including ...autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of γ-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC.
Participants were treated with bumetanide (2dd 0.5-1.0 mg) for 13 weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91 days of treatment and after a 28-day wash-out period.
Fifteen patients (8-21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p = .001, d = .773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p = .002, d = .549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p = .003, d = .686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency.
The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures.
Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.
PDF
