Translational Psychiatry
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Distinct contributions of GluA1-containing AMPA receptors of different hippocampal subfields to salience processing, memory and impulse control Abstract Schizophrenia is associated with a broad range of severe and currently pharmacoresistant cognitive deficits. Prior evidence suggests that hypofunction of AMPA-type glutamate receptors (AMPARs) containing the subunit GLUA1, encoded by GRIA1 , might be causally related to impairments of selective attention and memory in this disorder, at least in some patients. In order to clarify the roles of GluA1 in distinct cell populations, we investigated behavioural consequences of selective Gria1- knockout in excitatory neurons of subdivisions of the prefrontal cortex and the hippocampus, assessing sustained attention, impulsivity, cognitive flexibility, anxiety, sociability, hyperactivity, and various forms of short-term memory in mice. We found that virally induced reduction of GluA1 across multiple hippocampal subfields impaired spatial working memory. Transgene-mediated ablation of GluA1 from excitatory cells of CA2 impaired short-term memory for conspecifics and objects. Gria1 knockout in CA3 pyramidal cells caused mild impairments of object-related and spatial short-term memory, but appeared to partially increase social interaction and sustained attention and to reduce motor impulsivity. Our data suggest that reduced hippocampal GluA1 expression—as seen in some patients with schizophrenia—may be a central cause particularly for several short-term memory deficits. However, as impulse control and sustained attention actually appeared to improve with GluA1 ablation in CA3, strategies of enhancement of AMPAR signalling likely require a fine balance to be therapeutically effective across the broad symptom spectrum of schizophrenia.
Translational Psychiatry - Tập 12 Số 1
Hypervigilance for fear after basolateral amygdala damage in humans
Translational Psychiatry - Tập 2 Số 5 - Trang e115-e115
Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment
Translational Psychiatry - Tập 3 Số 1 - Trang e218-e218
Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening
Translational Psychiatry - Tập 3 Số 8 - Trang e294-e294
Psychobiological factors of resilience and depression in late life Abstract In contrast to traditional perspectives of resilience as a stable, trait-like characteristic, resilience is now recognized as a multidimentional, dynamic capacity influenced by life-long interactions between internal and environmental resources. We review psychosocial and neurobiological factors associated with resilience to late-life depression (LLD). Recent research has identified both psychosocial characteristics associated with elevated LLD risk (e.g., insecure attachment, neuroticism) and psychosocial processes that may be useful intervention targets (e.g., self-efficacy, sense of purpose, coping behaviors, social support). Psychobiological factors include a variety of endocrine, genetic, inflammatory, metabolic, neural, and cardiovascular processes that bidirectionally interact to affect risk for LLD onset and course of illness. Several resilience-enhancing intervention modalities show promise for the prevention and treatment of LLD, including cognitive/psychological or mind–body (positive psychology; psychotherapy; heart rate variability biofeedback; meditation), movement-based (aerobic exercise; yoga; tai chi), and biological approaches (pharmacotherapy, electroconvulsive therapy). Additional research is needed to further elucidate psychosocial and biological factors that affect risk and course of LLD. In addition, research to identify psychobiological factors predicting differential treatment response to various interventions will be essential to the development of more individualized and effective approaches to the prevention and treatment of LLD.
Translational Psychiatry - Tập 9 Số 1
Examining overlap and homogeneity in ASD, ADHD, and OCD: a data-driven, diagnosis-agnostic approach Abstract The validity of diagnostic labels of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD) is an open question given the mounting evidence that these categories may not correspond to conditions with distinct etiologies, biologies, or phenotypes. The objective of this study was to determine the agreement between existing diagnostic labels and groups discovered based on a data-driven, diagnosis-agnostic approach integrating cortical neuroanatomy and core-domain phenotype features. A machine learning pipeline, called bagged-multiview clustering, was designed to discover homogeneous subgroups by integrating cortical thickness data and measures of core-domain phenotypic features of ASD, ADHD, and OCD. This study was conducted using data from the Province of Ontario Neurodevelopmental Disorders (POND) Network, a multi-center study in Ontario, Canada. Participants (n = 226) included children between the ages of 6 and 18 with a diagnosis of ASD (n = 112, median [IQR] age = 11.7[4.8], 21% female), ADHD (n = 58, median [IQR] age = 10.2[3.3], 14% female), or OCD (n = 34, median [IQR] age = 12.1[4.2], 38% female), as well as typically developing controls (n = 22, median [IQR] age = 11.0[3.8], 55% female). The diagnosis-agnostic groups were significantly different than each other in phenotypic characteristics (SCQ: χ2 (9) = 111.21, p < 0.0001; SWAN: χ2 (9) = 142.44, p < 0.0001) as well as cortical thickness in 75 regions of the brain. The analyses revealed disagreement between existing diagnostic labels and the diagnosis-agnostic homogeneous groups (normalized mutual information < 0.20). Our results did not support the validity of existing diagnostic labels of ASD, ADHD, and OCD as distinct entities with respect to phenotype and cortical morphology.
Translational Psychiatry - Tập 9 Số 1
Dynamical properties of elemental metabolism distinguish attention deficit hyperactivity disorder from autism spectrum disorder Abstract Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions of overlapping etiologies and phenotypes. For ASD, we recently reported altered elemental metabolic patterns in the form of short and irregular zinc and copper cycles. Here, we extend the application of these biomarkers of prenatal and early postnatal elemental metabolism to distinguish between individuals diagnosed with ADHD and/or ASD and neurotypical controls. We recruited twins discordant for ADHD, ASD and other neurodevelopmental diagnoses from national twin studies in Sweden (N = 74) diagnosed according to DSM-5 clinical consensus and standardized psychiatric instruments. Detailed temporal profiles of exposure to 10 metals over the prenatal and early childhood periods were measured using tooth biomarkers. We used recurrence quantification analysis (RQA) to characterize properties of cyclical metabolic patterns of these metals. Regularity (determinism) and complexity (entropy) of elemental cycles was consistently reduced in ADHD for cobalt, lead, and vanadium (determinism: cobalt, β = −0.03, P = 0.017; lead, β = −0.03, P = 0.016; and vanadium, β = −0.03, P = 0.01. Entropy: cobalt, β = −0.13, P = 0.017; lead, β = −0.18, P = 0.016; and vanadium, β = −0.15, P = 0.008). Further, we found elemental pathways and dynamical features specific to ADHD vs ASD, and unique characteristics associated with ADHD/ASD combined presentation. Dysregulation of cyclical processes in elemental metabolism during prenatal and early postnatal development not only encompasses pathways shared by ADHD and ASD, but also comprise features specific to either condition.
Translational Psychiatry - Tập 9 Số 1
Shared endo-phenotypes of default mode dysfunction in attention deficit/hyperactivity disorder and autism spectrum disorder Abstract Categorical diagnoses from the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) manuals are increasingly found to be incongruent with emerging neuroscientific evidence that points towards shared neurobiological dysfunction underlying attention deficit/hyperactivity disorder and autism spectrum disorder. Using resting-state functional magnetic resonance imaging data, functional connectivity of the default mode network, the dorsal attention and salience network was studied in 1305 typically developing and diagnosed participants. A transdiagnostic hierarchical Bayesian modeling framework combining Indian Buffet Processes and Latent Dirichlet Allocation was proposed to address the urgent need for objective brain-derived measures that can acknowledge shared brain network dysfunction in both disorders. We identified three main variation factors characterized by distinct coupling patterns of the temporoparietal cortices in the default mode network with the dorsal attention and salience network. The brain-derived factors were demonstrated to effectively capture the underlying neural dysfunction shared in both disorders more accurately, and to enable more reliable diagnoses of neurobiological dysfunction. The brain-derived phenotypes alone allowed for a classification accuracy reflecting an underlying neuropathology of 67.33% (+/−3.07) in new individuals, which significantly outperformed the 46.73% (+/−3.97) accuracy of categorical diagnoses. Our results provide initial evidence that shared neural dysfunction in ADHD and ASD can be derived from conventional brain recordings in a data-led fashion. Our work is encouraging to pursue a translational endeavor to find and further study brain-derived phenotypes, which could potentially be used to improve clinical decision-making and optimize treatment in the future.
Translational Psychiatry - Tập 8 Số 1
Meta-analysis of reward processing in major depressive disorder reveals distinct abnormalities within the reward circuit
Translational Psychiatry - Tập 9 Số 1 - Trang 1-10
Many neuroimaging studies have investigated reward processing dysfunction in major depressive disorder. These studies have led to the common idea that major depressive disorder is associated with blunted responses within the reward circuit, particularly in the ventral striatum. Yet, the link between major depressive disorder and reward-related responses in other regions remains inconclusive, thus limiting our understanding of the pathophysiology of major depressive disorder. To address this issue, we performed a coordinate-based meta-analysis of 41 whole-brain neuroimaging studies encompassing reward-related responses from a total of 794 patients with major depressive disorder and 803 healthy controls. Our findings argue against the common idea that major depressive disorder is primarily linked to deficits within the reward system. Instead, our results demonstrate that major depressive disorder is associated with opposing abnormalities in the reward circuit: hypo-responses in the ventral striatum and hyper-responses in the orbitofrontal cortex. The current findings suggest that dysregulated corticostriatal connectivity may underlie reward-processing abnormalities in major depressive disorder, providing an empirical foundation for a more refined understanding of abnormalities in the reward circuitry in major depressive disorder.
Paying attention to attention in depression Abstract Attention is the gate through which sensory information enters our conscious experiences. Oftentimes, patients with major depressive disorder (MDD) complain of concentration difficulties that negatively impact their day-to-day function, and these attention problems are not alleviated by current first-line treatments. In spite of attention’s influence on many aspects of cognitive and emotional functioning, and the inclusion of concentration difficulties in the diagnostic criteria for MDD, the focus of depression as a disease is typically on mood features, with attentional features considered less of an imperative for investigation. Here, we summarize the breadth and depth of findings from the cognitive neurosciences regarding the neural mechanisms supporting goal-directed attention in order to better understand how these might go awry in depression. First, we characterize behavioral impairments in selective, sustained, and divided attention in depressed individuals. We then discuss interactions between goal-directed attention and other aspects of cognition (cognitive control, perception, and decision-making) and emotional functioning (negative biases, internally-focused attention, and interactions of mood and attention). We then review evidence for neurobiological mechanisms supporting attention, including the organization of large-scale neural networks and electrophysiological synchrony. Finally, we discuss the failure of current first-line treatments to alleviate attention impairments in MDD and review evidence for more targeted pharmacological, brain stimulation, and behavioral interventions. By synthesizing findings across disciplines and delineating avenues for future research, we aim to provide a clearer outline of how attention impairments may arise in the context of MDD and how, mechanistically, they may negatively impact daily functioning across various domains.
Translational Psychiatry - Tập 9 Số 1
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