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

Early adult mental health, functional and neuropsychological outcomes of young people who have reported psychotic experiences: a 10-year longitudinal study

Background: Psychotic experiences (PE) are highly prevalent in childhood and are known to be associated with co-morbid mental health disorders and functional difficulties in adolescence. However, little is known about the long-term outcomes of young people who report PE.Methods: As part of the Adolescent Brain Development Study, 211 young people were recruited in childhood (mean age 11.7 years) and underwent detailed clinical interviews, with 25% reporting PE. A 10 year follow-up study was completed and 103 participants returned (mean age 20.9 years). Structured clinical interviews for DSM-5 (SCID-5) and interviewer-rated assessments of functioning were conducted. A detailed neuropsychological battery was also administered. Analyses investigated group differences between those who had ever reported PE and controls in early adulthood.Results: The PE group was at a significantly higher risk of meeting DSM-5 criteria for a current (OR 4.08, CI 1.16-14.29, p = 0.03) and lifetime psychiatric disorder (OR 3.27, CI 1.43-7.47, p = 0.005). They were also at a significantly higher risk of multi-morbid lifetime psychiatric disorders. Significantly lower scores on current social and global functioning measures were observed for the PE group. Overall, there were no differences in neuropsychological performance between groups apart from significantly lower scores on the Stroop Word task and the Purdue Pegboard task for the PE group.Conclusions: Our findings suggest that reports of PE are associated with poorer mental health and functional outcomes in early adulthood, with some persisting cognitive and motor deficits. Young people who report such symptoms could be considered a target group for interventions to aid functional outcomes.</p

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

Childhood trauma, the HPA axis and psychiatric illnesses: a targeted literature synthesis

Studies of early life stress (ELS) demonstrate the long-lasting effects of acute and chronic stress on developmental trajectories. Such experiences can become biologically consolidated, creating individual vulnerability to psychological and psychiatric issues later in life. The hippocampus, amygdala, and the medial prefrontal cortex are all important limbic structures involved in the processes that undermine mental health. Hyperarousal of the sympathetic nervous system with sustained allostatic load along the Hypothalamic Pituitary Adrenal (HPA) axis and its connections has been theorized as the basis for adult psychopathology following early childhood trauma. In this review we synthesize current understandings and hypotheses concerning the neurobiological link between childhood trauma, the HPA axis, and adult psychiatric illness. We examine the mechanisms at play in the brain of the developing child and discuss how adverse environmental stimuli may become biologically incorporated into the structure and function of the adult brain via a discussion of the neurosequential model of development, sensitive periods and plasticity. The HPA connections and brain areas implicated in ELS and psychopathology are also explored. In a targeted review of HPA activation in mood and psychotic disorders, cortisol is generally elevated across mood and psychotic disorders. However, in bipolar disorder and psychosis patients with previous early life stress, blunted cortisol responses are found to awakening, psychological stressors and physiological manipulation compared to patients without previous early life stress. These attenuated responses occur in bipolar and psychosis patients on a background of increased cortisol turnover. Although cortisol measures are generally raised in depression, the evidence for a different HPA activation profile in those with early life stress is inconclusive. Further research is needed to explore the stress responses commonalities between bipolar disorder and psychosis in those patients with early life stress. </p