Psychiatry - Research Publications
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ItemNo Preview AvailableCannabidiol for Treatment-Resistant Anxiety Disorders in Young People: An Open-Label Trial(PHYSICIANS POSTGRADUATE PRESS, 2022-08-03)Background: Treatment resistance is a significant problem among young people experiencing moderate-to-severe anxiety, affecting nearly half of all patients. This study investigated the safety and efficacy of cannabidiol (CBD), a non-intoxicating component of Cannabis sativa, for anxiety disorders in young people who previously failed to respond to standard treatment. Methods: In this open-label trial, 31 young people aged 12-25 years with a DSM-5 anxiety disorder and no clinical improvement despite treatment with cognitive-behavioral therapy and/or antidepressant medication were enrolled between May 16, 2018, and June 28, 2019. All participants received add-on CBD for 12 weeks on a fixed-flexible schedule titrated up to 800 mg/d. The primary outcome was improvement in anxiety severity, measured with the Overall Anxiety Severity and Impairment Scale (OASIS), at week 12. Secondary outcomes included comorbid depressive symptoms, Clinical Global Impressions scale (CGI) score, and social and occupational functioning. Results: Mean (SD) OASIS scores decreased from 10.8 (3.8) at baseline to 6.3 (4.5) at week 12, corresponding to a -42.6% reduction (P < .0001). Depressive symptoms (P < .0001), CGI-Severity scale scores (P = .0008), and functioning (P = .04) improved significantly. Adverse events were reported in 25 (80.6%) of 31 participants and included fatigue, low mood, and hot flushes or cold chills. There were no serious and/or unexpected adverse events. Conclusions: These findings suggest that CBD can reduce anxiety severity and has an adequate safety profile in young people with treatment-resistant anxiety disorders. Randomized controlled trials are needed to confirm the efficacy and longer-term safety of this compound. Trial Registration: New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12617000825358.
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ItemNo Preview AvailableCortico-Striatal Activity Characterizes Human Safety Learning via Pavlovian Conditioned Inhibition(SOC NEUROSCIENCE, 2022-06-22)Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (PFDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of "stimulus-safety" associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.SIGNIFICANCE STATEMENT Identifying safety is critical for maintaining adaptive levels of anxiety, but the neural mechanisms of human safety learning remain unclear. Using 7 Tesla fMRI, we compared learning-related brain activity for a conditioned inhibitor, which actively predicted threat omission, and a standard safety signal (CS-), which was passively unpaired with threat. The inhibitor engaged an extended circuitry primarily featuring the dorsal striatum, along with thalamic, midbrain, and premotor/PFC regions. The CS- exclusively involved cortical safety-related regions observed in basic safety conditioning, such as the vmPFC. These findings extend current models to include learning-specific mechanisms for encoding stimulus-safety associations, which might be distinguished from expression-related cortical mechanisms. These insights may suggest novel avenues for targeting dysfunctional safety learning in psychopathology.
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ItemNo Preview AvailableAssessing Suicidal Ideation in Young People With Depression: Factor Structure of the Suicidal Ideation Questionnaire(SAGE PUBLICATIONS INC, 2022-09-06)Evaluating suicidal ideation in young people seeking mental health treatment is an important component of clinical assessment and treatment planning. To reduce the burden of youth suicide, we need to improve our understanding of suicidal ideation, its underlying constructs, and how ideation translates into suicidal behaviour. Using exploratory factor analysis, we investigated the dimensionality of the Suicidal Ideation Questionnaire (SIQ) among 273 participants aged 15-25 with Major Depressive Disorder. Area under the receiver operating characteristic curve (AUROC) analysis was used to explore associations between latent factors and actual suicidal behaviour. Findings suggested that the SIQ assesses multiple factors underlying suicidal ideation. AUROC analyses demonstrated that latent factors relating to both active and passive suicidal ideation predicted past-month suicidal behaviour and suicide attempt. These findings contribute to an improved understanding of the complexities of suicidal ideation and relationships with suicidal behaviour in young people with depression.
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ItemNo Preview AvailableThe specific phenotype of depression in recent onset schizophrenia spectrum disorders: A symptom profile and network comparison to recent onset major depressive disorder without psychotic features(ELSEVIER, 2022-02)The specific phenotype of depression in recent-onset schizophrenia spectrum disorders (SSD) and its relation to non-psychotic depression is unknown. Symptom profile and network analysis are complementary statistical techniques that may provide important insights into the presentation and relative importance of individual symptoms that give rise to depression. The aim of the current study was to characterise the profile and network of depressive symptoms in SSD and compare it to individuals with major depressive disorder (MDD) without psychotic features. This study involved analysis of baseline data pertaining to 109 individuals with comorbid SSD and depression and 283 with MDD without psychotic features. Study cohorts were the Psychosis Recent Onset GRoningen Survey (PROGR-S) and Youth Depression Alleviation (YoDA) trials, respectively. Profile and network analyses revealed that SSD and MDD differed in the profile and relative importance of individual depressive symptoms. While reported sadness was the primary hallmark of depression in both SSD and MDD, individuals with depression in SSD were more likely to sleep more, and have lower lassitude and pessimism. While sadness had great importance in MDD and SSD, in SSD but not MDD lassitude, sleep, appetite, concentration difficulties, and inability to feel were important in the network of depressive symptoms. The specific phenotype of depression might be different in SSD compared to MDD. Symptom inequivalence or underlying functional mechanisms in SSD might result in depression in SSD that is similar to MDD with atypical features.
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ItemNo Preview AvailableThe neurobiology of Pavlovian safety learning: Towards an acquisition-expression framework(PERGAMON-ELSEVIER SCIENCE LTD, 2022-11)Safety learning creates associations between conditional stimuli and the absence of threat. Studies of human fear conditioning have accumulated evidence for the neural signatures of safety over various paradigms, aligning on several common brain systems. While these systems are often interpreted as underlying safety learning in a generic sense, they may instead reflect the expression of learned safety, pertaining to processes of fear inhibition, positive affect, and memory. Animal models strongly suggest these can be separable from neural circuits implicated in the conditioning process itself (or safety acquisition). While acquisition-expression distinctions are ubiquitous in behavioural science, this lens has not been applied to safety learning, which remains a novel area in the field. In this mini-review, we overview findings from prevalent safety paradigms in humans, and synthesise these with insights from animal models to propose that the neurobiology of safety learning be conceptualised along an acquisition-expression model, with the aim of stimulating richer brain-based characterisations of this important process.
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ItemNo Preview AvailableVirtual Ontogeny of Cortical Growth Preceding Mental Illness(ELSEVIER SCIENCE INC, 2022-08-15)BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
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ItemStructural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium(SPRINGERNATURE, 2022-11)Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.
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ItemNo Preview AvailableInfluence of negative mood states on moral decision-making(Elsevier BV, 2022-06-01)
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ItemNo Preview AvailableModulation of the brain's core-self network by self-appraisal processes(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2022-05-01)The 'core' regions of the default mode network (DMN) - the medial prefrontal cortex (MPFC), the posterior cingulate cortex (PCC), and inferior parietal lobules (IPL) - show consistent engagement across mental states that involve self-oriented processing. Precisely how these regions interact in support of such processes remains an important unanswered question. In the current functional magnetic resonance imaging (fMRI) study, we examined dynamic interactions of the 'core-self' DMN regions during two forms of self-referential cognition: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about oneself from a third-person perspective). One-hundred and eleven participants completed our dual self-appraisal task during fMRI, and general linear models were used to characterize common and distinct neural responses to these conditions. Informed by these results, we then applied dynamic causal modelling to examine causal interactions among the 'core-self' regions, and how they were specifically modulated under the influence of direct and reflected self-appraisal. As a primary observation, this network modelling revealed a distinct inhibitory influence of the left IPL on the PCC during reflected compared to direct self-appraisal, which was accompanied by evidence of greater activation in both regions during the reflected self-appraisal condition. We suggest that the greater engagement of posterior DMN regions during reflected self-appraisal is a function of the higher-order processing needed for this form of self-appraisal, with the left IPL supporting abstract self-related processes including episodic memory retrieval and shifts of perspective. Overall, we show that core DMN regions interact in functionally unique ways in support of self-referential processes, even when these processes are inter-related. Further characterization of DMN functional interactions across self-related mental states is likely to inform a deeper understanding of how this brain network orchestrates the self.
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ItemNo Preview AvailableBrain Correlates of Suicide Attempt in 18,925 Participants Across 18 International Cohorts(ELSEVIER SCIENCE INC, 2021-08-15)BACKGROUND: Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD Working Group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior. METHODS: Here, we pooled data from 18 international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide). We compared regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes between suicide attempters, clinical control subjects (nonattempters with depression), and healthy control subjects. RESULTS: We identified 25 regions of interest with statistically significant (false discovery rate < .05) differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe. CONCLUSIONS: This study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt and further demonstrates the need for well-powered samples and collaborative efforts. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. Future functional and connectivity studies of suicidal behaviors may focus on understanding how these regions relate to the neurobiological mechanisms of suicide attempt risk.