Longitudinal Gray Matter Development Associated With Psychotic Experiences in Young People

Background: Grey matter abnormalities are observed across the psychosis spectrum. The trajectory of these abnormalities in healthy adolescents reporting sub-threshold psychotic experiences (PE) may provide insight into the neural mechanisms underlying psychotic symptoms. The risk of psychosis and additional psychopathology is even higher amongst these individuals who also report childhood adversity/DSM5 diagnoses. Thus, the aims of this longitudinal study are to investigate PE related volumetric changes in young people, noting any effects of childhood adversity/DSM5 diagnosis. Methods: 211 young people aged 11-13 participated in the initial Adolescent Brain Development study. PE classification was determined by expert consensus at each timepoint. Participants underwent neuroimaging at 3 timepoints, over 6 years. 76 participants with at least one scan were included in the final sample; 34 who met criteria for PE at least once across all the timepoints (PE group), and 42 controls. Data from 20 bilateral regions of interest were extracted for Linear Mixed Effects analyses. Results: Right hippocampal volume increased over time in the control group, with no increase in the PE group (p = 0.00352). DSM5 diagnosis and childhood adversity were not significantly associated with right hippocampal volume. There was no significant effect of group or interaction in any other region. Conclusions: These findings further implicate right hippocampal volumetric abnormalities in the pathophysiology underlying psychotic experiences. Furthermore, as suggested by previous studies in those at clinical high risk for psychosis and those with first episode psychosis, it is possible that these deficits may be a marker for later clinical outcomes.</p

Longitudinal hippocampal subfield development associated with psychotic experiences in young people

Hippocampal volumetric reductions are observed across the psychosis spectrum, with interest in the localisation of these reductions within the hippocampal subfields increasing. Deficits of the CA1 subfield in particular have been implicated in the neuropathophysiology of psychotic disorders. Investigating the trajectory of these abnormalities in healthy adolescents reporting sub-threshold psychotic experiences (PE) can provide insight into the neural mechanisms underlying psychotic symptoms without the potentially confounding effects of a formal disorder, or antipsychotic medication. In this novel investigation, a sample of 211 young people aged 11-13 participated initially in the Adolescent Brain Development study. PE classification was determined by expert consensus at each timepoint. Participants underwent neuroimaging at 3 timepoints, over 6 years. 78 participants with at least one scan were included in the final sample; 33 who met criteria for a definite PE at least once across all the timepoints (PE group), and 45 controls. Data from bilateral subfields of interest (CA1, CA2/3, CA4/DG, presubiculum and subiculum) were extracted for Linear Mixed Effects analyses. Before correction, subfield volumes were found to increase in the control group and decrease in the PE group for the right CA2 and CA2/3 subfields, with moderate to large effect sizes (d = -0.61, and d = -0.79, respectively). Before correction, right subiculum and left presubiculum volumes were reduced in the PE group compared to controls, regardless of time, with moderate effect sizes (d = -0.52, and d = -0.59, respectively). However, none of these effects survived correction. Severity of symptoms were not associated with any of the noted subfields. These findings provide novel insight to the discussion of the role of hippocampal subfield abnormalities in the pathophysiology underlying psychotic experiences. </p

The limbic system in children and adolescents with attention-deficit/hyperactivity disorder: a longitudinal structural magnetic resonance imaging analysis

BACKGROUND: During childhood and adolescence, attention-deficit/hyperactivity disorder (ADHD) is associated with changes in symptoms and brain structures, but the link between brain structure and function remains unclear. The limbic system, often termed the “emotional network,” plays an important role in a number of neurodevelopmental disorders, yet this brain network remains largely unexplored in ADHD. Investigating the developmental trajectories of key limbic system structures during childhood and adolescence will provide novel insights into the neurobiological underpinnings of ADHD. METHODS: Structural magnetic resonance imaging data (380 scans), emotional regulation (Affective Reactivity In-dex), and ADHD symptom severity (Conners 3 ADHD Index) were measured at up to 3 time points between 9 and 14 years of age in a sample of children and adolescents with ADHD (n = 57) and control children (n = 109). RESULTS: Compared with the control group, the ADHD group had lower volume of the amygdala (left: b standardized [b_std] = 20.38; right: b_std = 20.34), hippocampus (left: b_std = 20.44; right: b_std = 20.34), cingulate gyrus (left: b_std = 20.42; right: b_std = 20.32), and orbitofrontal cortex (right: b_std = 20.33) across development (9–14 years). There were no significant group-by-age interactions in any of the limbic system structures. Exploratory analysis found a significant Conners 3 ADHD Index-by-age interaction effect on the volume of the left mammillary body (b_std = 0.17) in the ADHD group across the 3 study time points. CONCLUSIONS: Children and adolescents with ADHD displayed lower volume and atypical development in limbic system structures. Furthermore, atypical limbic system development was associated with increased symptom severity, highlighting a potential neurobiological correlate of ADHD severity </p

The limbic system in children and adolescents with attention-deficit/hyperactivity disorder: a longitudinal structural magnetic resonance imaging analysis

BACKGROUND: During childhood and adolescence, attention-deficit/hyperactivity disorder (ADHD) is associated with changes in symptoms and brain structures, but the link between brain structure and function remains unclear. The limbic system, often termed the “emotional network,” plays an important role in a number of neurodevelopmental disorders, yet this brain network remains largely unexplored in ADHD. Investigating the developmental trajectories of key limbic system structures during childhood and adolescence will provide novel insights into the neurobiological underpinnings of ADHD. METHODS: Structural magnetic resonance imaging data (380 scans), emotional regulation (Affective Reactivity In-dex), and ADHD symptom severity (Conners 3 ADHD Index) were measured at up to 3 time points between 9 and 14 years of age in a sample of children and adolescents with ADHD (n = 57) and control children (n = 109). RESULTS: Compared with the control group, the ADHD group had lower volume of the amygdala (left: b standardized [b_std] = 20.38; right: b_std = 20.34), hippocampus (left: b_std = 20.44; right: b_std = 20.34), cingulate gyrus (left: b_std = 20.42; right: b_std = 20.32), and orbitofrontal cortex (right: b_std = 20.33) across development (9–14 years). There were no significant group-by-age interactions in any of the limbic system structures. Exploratory analysis found a significant Conners 3 ADHD Index-by-age interaction effect on the volume of the left mammillary body (b_std = 0.17) in the ADHD group across the 3 study time points. CONCLUSIONS: Children and adolescents with ADHD displayed lower volume and atypical development in limbic system structures. Furthermore, atypical limbic system development was associated with increased symptom severity, highlighting a potential neurobiological correlate of ADHD severity </p

Multiple Network Dysconnectivity in Adolescents with Psychotic Experiences: a longitudinal population-based study

Background: Functional dysconnectivity amongst neural networks is well established in psychosis, and has been implicated in the psychopathology associated with the disorder. However, little is known about functional connectivity (FC) in individuals, particularly adolescents, who experience sub-threshold psychotic experiences (PE), and their trajectory over time. Thus, the aim of this study was to investigate large and small-scale network FC in adolescents with PE.Methods: A population-based case-control study of 24 adolescents (mean age 13.58) who met criteria for PE were drawn from a sample of 211 young people recruited for a neuroimaging study, followed up 2 years later (n=18, mean age = 15.78), and compared to matched controls drawn from the same sample. Functional seed networks included the default mode (DMN), salience (SN), central executive (CEN), motor (MN), and auditory networks (AN). Whole-brain FC analyses were performed using the CONN functional connectivity toolbox.Results: At both timepoints, the PE group generally displayed significant hypoconnectivity, with specific instances of hyperconnectivity, compared to controls. At baseline, FC in the PE group was decreased between regions in the MN and DMN, and the AN and visual regions. At follow up, FC in the PE group was decreased between regions in the SN and DMN, the AN and visual regions, and also within the MN.Conclusions: Significant hypoconnectivity across multiple networks reflects findings in established psychosis, supporting a prominent role for the default mode network in the dysfunctional information processing and integration thought to underlie psychotic experiences.</div

Psychotic experiences in childhood are associated with increased structural integrity of the left arcuate fasciculus – a population-based case-control study

Around 1 in 5 children under 13 years old experience sub-clinical psychotic experiences (PEs) like hallucinations and delusions. While PEs in childhood are a significant risk factor for adult psychotic disorders, the majority of those experiencing childhood PEs do not develop a psychotic disorder. Individual differences in regional brain maturation rates may be responsible for this age-related and often transient emergence of PEs. Fronto-temporal association tracts undergo extensive maturation and myelination throughout childhood and adolescence, thus we focus on individual differences in one such tract, the arcuate fasciculus. A normative population-based sample of children (aged 11–13) attended a clinical interview and MRI (n = 100), 25 of whom were identified as reporting strong PEs. This group had reduced mean and radial diffusivity in the arcuate fasciculus compared with a group of matched controls (n = 25) who reported no PEs. The group difference was greater in the left hemisphere than the right. Mediation analyses showed that this group difference was driven predominantly by perceptual disturbances and an along-tract analysis showed that the group difference was greatest approximately halfway between the frontal and temporal termination points of the tract (adjacent to the left lateral ventricle). This study is the first to investigate links between arcuate fasciculus diffusivity and psychotic experiences in a population sample of children

Microstructural changes along the cingulum in young adolescents with psychotic experiences: an along-tract analysis

Psychotic experiences (PEs) such as hallucinations and delusions are common among young people without psychiatric diagnoses and are associated with connectivity and white matter abnormalities, particularly in the limbic system. Using diffusion magnetic resonance imaging (MRI) in adolescents with reported PEs and matched controls, we examined the cingulum white matter tract along its length rather than as the usually reported single indivisible structure. Complex regional differences in diffusion metrics were found along the bundle at key loci following Bonferroni significance adjustment (p < .00013) with moderate to large effect sizes (.11-.76) throughout all significant subsegments. In this prospective community-based cohort of school-age children, these findings suggest that white matter alterations in the limbic system may be more common in the general non-clinical adolescent population than previously thought. Such white matter alternations may only be uncovered using a similar more granular along-tract analysis of white matter tracts. </p

A pilot study of adolescents with psychotic experiences: potential cerebellar circuitry disruption early along the psychosis spectrum

Aberrant connectivity in the cerebellum has been found in psychotic conditions such as schizophrenia corresponding with cognitive and motor deficits found in these conditions. Diffusion differences in the superior cerebellar peduncles, the white matter connecting the cerebellar circuitry to the rest of the brain, have also been found in schizophrenia and high-risk states. However, white matter diffusivity in the peduncles in individuals with sub-threshold psychotic experiences (PEs) but not reaching the threshold for a definitive diagnosis remains unstudied. This study investigates the cerebellar peduncles in adolescents with PEs but no formal psychiatric diagnosis.Sixteen adolescents with PEs and 17 age-matched controls recruited from schools underwent High-Angular-Resolution-Diffusion neuroimaging. Following constrained spherical deconvolution whole-brain tractography, the superior, inferior and middle peduncles were isolated and virtually dissected out using ExploreDTI. Differences for macroscopic and microscopic tract metrics were calculated using one-way between-group analyses of covariance controlling for age, sex and estimated Total Intracranial Volume (eTIV). Multiple comparisons were corrected using Bonferroni correction.A decrease in fractional anisotropy was identified in the right (p = 0.045) and left (p = 0.058) superior cerebellar peduncle; however, this did not survive strict Bonferroni multiple comparison correction. There were no differences in volumes or other diffusion metrics in either the middle or inferior peduncles.Our trend level changes in the superior cerebellar peduncle in a non-clinical sample exhibiting psychotic experiences complement similar but more profound changes previously found in ultra-high-risk individuals and those with psychotic disorders. This suggests that superior cerebellar peduncle circuitry perturbations may occur early along in the psychosis spectrum. </p