Spatiotemporal dynamics of hippocampal-cortical networks underlying the unique phenomenological properties of trauma-related intrusive memories.

Trauma-related intrusive memories (TR-IMs) possess unique phenomenological properties that contribute to adverse post-traumatic outcomes, positioning them as critical intervention targets. However, transdiagnostic treatments for TR-IMs are scarce, as their underlying mechanisms have been investigated separate from their unique phenomenological properties. Extant models of more general episodic memory highlight dynamic hippocampal-cortical interactions that vary along the anterior-posterior axis of the hippocampus (HPC) to support different cognitive-affective and sensory-perceptual features of memory. Extending this work into the unique properties of TR-IMs, we conducted a study of eighty-four trauma-exposed adults who completed daily ecological momentary assessments of TR-IM properties followed by resting-state functional magnetic resonance imaging (rs-fMRI). Spatiotemporal dynamics of anterior and posterior hippocampal (a/pHPC)-cortical networks were assessed using co-activation pattern analysis to investigate their associations with different properties of TR-IMs. Emotional intensity of TR-IMs was inversely associated with the frequency and persistence of an aHPC-default mode network co-activation pattern. Conversely, sensory features of TR-IMs were associated with more frequent co-activation of the HPC with sensory cortices and the ventral attention network, and the reliving of TR-IMs in the "here-and-now" was associated with more persistent co-activation of the pHPC and the visual cortex. Notably, no associations were found between HPC-cortical network dynamics and conventional symptom measures, including TR-IM frequency or retrospective recall, underscoring the utility of ecological assessments of memory properties in identifying their neural substrates. These findings provide novel insights into the neural correlates of the unique features of TR-IMs that are critical for the development of individualized, transdiagnostic treatments for this pervasive, difficult-to-treat symptom.

Trauma-related intrusive memories and anterior hippocampus structural covariance: an ecological momentary assessment study in posttraumatic stress disorder.

Trauma-related intrusive memories (TR-IMs) are hallmark symptoms of posttraumatic stress disorder (PTSD), but their neural correlates remain partly unknown. Given its role in autobiographical memory, the hippocampus may play a critical role in TR-IM neurophysiology. The anterior and posterior hippocampi are known to have partially distinct functions, including during retrieval of autobiographical memories. This study aimed to investigate the relationship between TR-IM frequency and the anterior and posterior hippocampi morphology in PTSD. Ninety-three trauma-exposed adults completed daily ecological momentary assessments for fourteen days to capture their TR-IM frequency. Participants then underwent anatomical magnetic resonance imaging to obtain measures of anterior and posterior hippocampal volumes. Partial least squares analysis was applied to identify a structural covariance network that differentiated the anterior and posterior hippocampi. Poisson regression models examined the relationship of TR-IM frequency with anterior and posterior hippocampal volumes and the resulting structural covariance network. Results revealed no significant relationship of TR-IM frequency with hippocampal volumes. However, TR-IM frequency was significantly negatively correlated with the expression of a structural covariance pattern specifically associated with the anterior hippocampus volume. This association remained significant after accounting for the severity of PTSD symptoms other than intrusion symptoms. The network included the bilateral inferior temporal gyri, superior frontal gyri, precuneus, and fusiform gyri. These novel findings indicate that higher TR-IM frequency in individuals with PTSD is associated with lower structural covariance between the anterior hippocampus and other brain regions involved in autobiographical memory, shedding light on the neural correlates underlying this core symptom of PTSD.

Transcranial stimulation of alpha oscillations modulates brain state dynamics in sustained attention.

The brain operates an advanced complex system to support mental activities. Cognition is thought to emerge from dynamic states of the complex brain system, which are organized spatially through large-scale neural networks and temporally via neural synchrony. However, specific mechanisms underlying these processes remain obscure. Applying high-definition alpha-frequency transcranial alternating-current stimulation (HD α-tACS) in a continuous performance task (CPT) during functional resonance imaging (fMRI), we causally elucidate these major organizational architectures in a key cognitive operation-sustained attention. We demonstrated that α-tACS enhanced both electroencephalogram (EEG) alpha power and sustained attention, in a correlated fashion. Akin to temporal fluctuations inherent in sustained attention, our hidden Markov modeling (HMM) of fMRI timeseries uncovered several recurrent, dynamic brain states, which were organized through a few major neural networks and regulated by the alpha oscillation. Specifically, during sustain attention, α-tACS regulated the temporal dynamics of the brain states by suppressing a Task-Negative state (characterized by activation of the default mode network/DMN) and Distraction state (with activation of the ventral attention and visual networks). These findings thus linked dynamic states of major neural networks and alpha oscillations, providing important insights into systems-level mechanisms of attention. They also highlight the efficacy of non-invasive oscillatory neuromodulation in probing the functioning of the complex brain system and encourage future clinical applications to improve neural systems health and cognitive performance.

Circulating PACAP levels are associated with increased amygdala-default mode network resting-state connectivity in posttraumatic stress disorder.

The pituitary adenylate cyclase-activating polypeptide (PACAP) system is implicated in posttraumatic stress disorder (PTSD) and related amygdala-mediated arousal and threat reactivity. PTSD is characterized by increased amygdala reactivity to threat and, more recently, aberrant intrinsic connectivity of the amygdala with large-scale resting state networks, specifically the default mode network (DMN). While the influence of PACAP on amygdala reactivity has been described, its association with intrinsic amygdala connectivity remains unknown. To fill this gap, we examined functional connectivity of resting-state functional magnetic resonance imaging (fMRI) in eighty-nine trauma-exposed adults (69 female) screened for PTSD symptoms to examine the association between blood-borne (circulating) PACAP levels and amygdala-DMN connectivity. Higher circulating PACAP levels were associated with increased amygdala connectivity with posterior DMN regions, including the posterior cingulate cortex/precuneus (PCC/Precun) and left angular gyrus (lANG). Consistent with prior work, this effect was seen in female, but not male, participants and the centromedial, but not basolateral, subregions of the amygdala. Clinical association analyses linked amygdala-PCC/Precun connectivity to anxious arousal symptoms, specifically exaggerated startle response. Taken together, our findings converge with previously demonstrated effects of PACAP on amygdala activity in PTSD-related processes and offer novel evidence for an association between PACAP and intrinsic amygdala connectivity patterns in PTSD. Moreover, these data provide preliminary evidence to motivate future work ascertaining the sex- and subregion-specificity of these effects. Such findings may enable novel mechanistic insights into neural circuit dysfunction in PTSD and how the PACAP system confers risk through a disruption of intrinsic resting-state network dynamics.

Pattern differentiation and tuning shift in human sensory cortex underlie long-term threat memory.

The amygdala-prefrontal-cortex circuit has long occupied the center of the threat system,1 but new evidence has rapidly amassed to implicate threat processing outside this canonical circuit.2-4 Through nonhuman research, the sensory cortex has emerged as a critical substrate for long-term threat memory,5-9 underpinned by sensory cortical pattern separation/completion10,11 and tuning shift.12,13 In humans, research has begun to associate the human sensory cortex with long-term threat memory,14,15 but the lack of mechanistic insights obscures a direct linkage. Toward that end, we assessed human olfactory threat conditioning and long-term (9 days) threat memory, combining affective appraisal, olfactory psychophysics, and functional magnetic resonance imaging (fMRI) over a linear odor-morphing continuum (five levels of binary mixtures of the conditioned stimuli/CS+ and CS- odors). Affective ratings and olfactory perceptual discrimination confirmed (explicit) affective and perceptual learning and memory via conditioning. fMRI representational similarity analysis (RSA) and voxel-based tuning analysis further revealed associative plasticity in the human olfactory (piriform) cortex, including immediate and lasting pattern differentiation between CS and neighboring non-CS and a late onset, lasting tuning shift toward the CS. The two plastic processes were especially salient and lasting in anxious individuals, among whom they were further correlated. These findings thus support an evolutionarily conserved sensory cortical system of long-term threat representation, which can underpin threat perception and memory. Importantly, hyperfunctioning of this sensory mnemonic system of threat in anxiety further implicates a hitherto underappreciated sensory mechanism of anxiety.

A narrative review of treatment interventions to improve cognitive performance in schizophrenia, with an emphasis on at-risk and early course stages.

Cognitive dysfunction is a core feature of schizophrenia (SCZ), which unfavorably affects SCZ patients' daily functioning and overall clinical outcome. An increasing body of evidence has shown that cognitive deficits are present not only at the beginning of the illness but also several years before the onset of psychosis. Nonetheless, the majority of treatment interventions targeting cognitive dysfunction in SCZ, using both pharmacological and nonpharmacological approaches, have focused on chronic patients rather than individuals at high risk or in the early stages of the disease. In this article, we provide a narrative review of cognitive interventions in SCZ patients, with a particular focus on pre-emptive interventions in at-risk/early course individuals when available. Furthermore, we discuss current challenges for these pre-emptive treatment interventions and provide some suggestions on how future work may ameliorate cognitive dysfunction in these individuals.

An investigation into the bidirectional relationship between post-traumatic stress disorder and suicidal ideation: A nine year study.

Suicide is the second leading cause of death in adolescents; a frequent precursor of suicide is suicidal ideation (SI). Literature indicates that Post-Traumatic Stress Disorder (PTSD) and SI are robust cross-sectional correlates of one another, with PTSD often being conceptualized as a risk factor (i.e., conferring risk) for SI. Indeed, PTSD is a well-established risk factor for SI; however, SI is an understudied risk factor for PTSD. It is possible that, yet unknown if, PTSD and SI promote each other over time in a bidirectional fashion. We investigated the bidirectional longitudinal associations between PTSD and SI in a large, diverse sample, who at baseline were adolescents. Participants were interviewed between 1995 and 1998 and again between 2004 and 2008. We hypothesized that PTSD and SI would be cross-sectionally, longitudinally, and bidirectionally related and that the number of traumas endorsed at baseline would be positively associated with PTSD and SI at baseline and follow-up. Indeed, PTSD and SI were cross-sectionally correlated at baseline, but not follow-up. PTSD predicted SI over nine years; however, SI during adolescence did not predict PTSD in adulthood. Finally, poly-trauma endorsed at baseline was associated with increased risk of SI, but not PTSD, over nine years.

Transcranial stimulation of alpha oscillations up-regulates the default mode network.

The default mode network (DMN) is the most-prominent intrinsic connectivity network, serving as a key architecture of the brain's functional organization. Conversely, dysregulated DMN is characteristic of major neuropsychiatric disorders. However, the field still lacks mechanistic insights into the regulation of the DMN and effective interventions for DMN dysregulation. The current study approached this problem by manipulating neural synchrony, particularly alpha (8 to 12 Hz) oscillations, a dominant intrinsic oscillatory activity that has been increasingly associated with the DMN in both function and physiology. Using high-definition alpha-frequency transcranial alternating current stimulation (α-tACS) to stimulate the cortical source of alpha oscillations, in combination with simultaneous electroencephalography and functional MRI (EEG-fMRI), we demonstrated that α-tACS (versus Sham control) not only augmented EEG alpha oscillations but also strengthened fMRI and (source-level) alpha connectivity within the core of the DMN. Importantly, increase in alpha oscillations mediated the DMN connectivity enhancement. These findings thus identify a mechanistic link between alpha oscillations and DMN functioning. That transcranial alpha modulation can up-regulate the DMN further highlights an effective noninvasive intervention to normalize DMN functioning in various disorders.

Synthetic biology open language visual (SBOL Visual) version 2.3.

People who are engineering biological organisms often find it useful to communicate in diagrams, both about the structure of the nucleic acid sequences that they are engineering and about the functional relationships between sequence features and other molecular species. Some typical practices and conventions have begun to emerge for such diagrams. The Synthetic Biology Open Language Visual (SBOL Visual) has been developed as a standard for organizing and systematizing such conventions in order to produce a coherent language for expressing the structure and function of genetic designs. This document details version 2.3 of SBOL Visual, which builds on the prior SBOL Visual 2.2 in several ways. First, the specification now includes higher-level "interactions with interactions," such as an inducer molecule stimulating a repression interaction. Second, binding with a nucleic acid backbone can be shown by overlapping glyphs, as with other molecular complexes. Finally, a new "unspecified interaction" glyph is added for visualizing interactions whose nature is unknown, the "insulator" glyph is deprecated in favor of a new "inert DNA spacer" glyph, and the polypeptide region glyph is recommended for showing 2A sequences.

Posttraumatic Stress Disorder Is Associated with α Dysrhythmia across the Visual Cortex and the Default Mode Network.

Anomalies in default mode network (DMN) activity and α (8-12 Hz) oscillations have been independently observed in posttraumatic stress disorder (PTSD). Recent spatiotemporal analyses suggest that α oscillations support DMN functioning via interregional synchronization and sensory cortical inhibition. Therefore, we examined a unifying pathology of α deficits in the visual-cortex-DMN system in PTSD. Human patients with PTSD (N = 25) and two control groups, patients with generalized anxiety disorder (GAD; N = 24) and healthy controls (HCs; N = 20), underwent a standard eyes-open resting state (S-RS) and a modified resting state (M-RS) of passively viewing salient images (known to deactivate the DMN). High-density electroencephalogram (hdEEG) were recorded, from which intracortical α activity (power and connectivity/Granger causality) was extracted using the exact low-resolution electromagnetic tomography (eLORETA). Patients with PTSD (vs GAD/HC) demonstrated attenuated α power in the visual cortex (VC) and key hubs of the DMN [posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC)] at both states, the severity of which further correlated with hypervigilance symptoms. With increased visual input (at M-RS vs S-RS), patients with PTSD further demonstrated reduced α-frequency directed connectivity within the DMN (PCC→mPFC) and, importantly, from the VC to both DMN hubs (VC→PCC and VC→mPFC), linking α deficits in the two systems. These interrelated α deficits align with DMN hypoactivity/hypoconnectivity, sensory disinhibition, and hypervigilance in PTSD, representing a unifying neural underpinning of these anomalies. The identification of visual-cortex-DMN α dysrhythmia in PTSD further presents a novel therapeutic target, promoting network-based intervention of neural oscillations.

Synthetic biology open language visual (SBOL visual) version 2.2.

People who are engineering biological organisms often find it useful to communicate in diagrams, both about the structure of the nucleic acid sequences that they are engineering and about the functional relationships between sequence features and other molecular species. Some typical practices and conventions have begun to emerge for such diagrams. The Synthetic Biology Open Language Visual (SBOL Visual) has been developed as a standard for organizing and systematizing such conventions in order to produce a coherent language for expressing the structure and function of genetic designs. This document details version 2.2 of SBOL Visual, which builds on the prior SBOL Visual 2.1 in several ways. First, the grounding of molecular species glyphs is changed from BioPAX to SBO, aligning with the use of SBO terms for interaction glyphs. Second, new glyphs are added for proteins, introns, and polypeptide regions (e. g., protein domains), the prior recommended macromolecule glyph is deprecated in favor of its alternative, and small polygons are introduced as alternative glyphs for simple chemicals.

Building mental health and resilience: regional and global perspectives from the inaugural Syrian American Medical Society Mental Health Mission Trip (July 2 to July 7, 2019).

The Syrian conflict has resulted in the most significant refugee crisis since World War II. Current estimates suggest there are over 13.5 million Syrians in need of comprehensive humanitarian assistance as a direct result of the conflict. These humanitarian needs include mental health services to address the elevated rates of psychiatric disorders in this population. Towards this end, the Syrian American Medical Society conducted its inaugural mental health mission trip to Lebanon and Jordan from June to July 2019 to advance the state of mental health care for displaced Syrians. Following two weeks of trainings by international experts in trauma psychology, the mission concluded with a two-day scientific symposium, identifying two key elements for the advancement of humanitarian mental health care: 1) the need for community-based mental health services, and 2) the importance of transitioning from a crisis-response model in humanitarian mental health towards a model of resilience and post-traumatic growth.

Intrinsic sensory disinhibition contributes to intrusive re-experiencing in combat veterans.

Intrusive re-experiencing of traumatic events is a hallmark symptom of posttraumatic stress disorder, characterized by rich and vivid sensory details as reported in "flashbacks". While prevailing models of trauma intrusions focus on dysregulated emotional processes, we hypothesize that a deficiency in intrinsic sensory inhibition could drive overactivation of sensory representations of trauma memories, precipitating sensory-rich intrusions. In a sample of combat veterans, we examined resting-state alpha (8-12 Hz) oscillatory activity (in both power and posterior→frontal connectivity), given its role in sensory cortical inhibition, in association with intrusive re-experiencing symptoms. Veterans further participated in an odor task (including both combat and non-combat odors) to assess olfactory trauma memory and emotional response. We observed an association between intrusive re-experiencing symptoms and attenuated resting-state posterior→frontal alpha connectivity, which were both correlated with olfactory trauma memory. Importantly, olfactory trauma memory was identified as a mediator of the relationship between alpha connectivity and intrusive re-experiencing, suggesting that deficits in intrinsic sensory inhibition contributed to intrusive re-experiencing of trauma via heightened trauma memory. Therefore, by permitting unfiltered sensory cues to enter information processing and activate sensory representations of trauma, sensory disinhibition can constitute a sensory mechanism of intrusive re-experiencing in trauma-exposed individuals.

Impaired early visual categorization of fear in social anxiety.

Social anxiety is associated with biased social perception, especially of ambiguous cues. While aberrations in high-level processes (e.g., cognitive appraisal and interpretation) have been implicated in such biases, contributions of early, low-level stimulus processing remain unclear. Categorical perception represents an efficient process to resolve signal ambiguity, and categorical emotion perception can swiftly classify sensory input, "tagging" biologically important stimuli at early stages of processing to facilitate ecological response. However, early threat categorization could be disrupted by exaggerated (or disinhibited) threat processing in anxiety, resulting in biased perception of ambiguous signals. We tested this hypothesis among individuals with low and high trait social anxiety (LSA/HSA; defined relative to the current sample), who performed a two-alternative forced-choice (fear or neutral) task on facial expressions parametrically varied along a neutral-fear continuum. The groups diverged in the reaction time (RT) profile along the neutral-fear continuum, which was characteristic of categorical perception in the LSA (vs. HSA) group with drastically increased RT from neutral to intermediate (boundary) fear intensities, contrasting monotonic, nonsignificant RT changes in the HSA group. Neurometric analysis along the continuum identified an early neutral-fear categorization operation (arising in the P1, an early visual ERP at 100 ms), which was nonetheless impaired in the HSA group (due to disinhibited response at the neutral-fear boundary). Absent group differences in higher-level cognitive operations (identified by later ERPs), current findings highlight a dispositional cognitive vulnerability in early visual categorization of social threat, which could precipitate further cognitive aberrations and, eventually, the onset of social anxiety disorder.

Communicating Structure and Function in Synthetic Biology Diagrams.

Biological engineers often find it useful to communicate using diagrams. These diagrams can include information both about the structure of the nucleic acid sequences they are engineering and about the functional relationships between features of these sequences and/or other molecular species. A number of conventions and practices have begun to emerge within synthetic biology for creating such diagrams, and the Synthetic Biology Open Language Visual (SBOL Visual) has been developed as a standard to organize, systematize, and extend such conventions in order to produce a coherent visual language. Here, we describe SBOL Visual version 2, which expands previous diagram standards to include new functional interactions, categories of molecular species, support for families of glyph variants, and the ability to indicate modular structure and mappings between elements of a system. SBOL Visual 2 also clarifies a number of requirements and best practices, significantly expands the collection of glyphs available to describe genetic features, and can be readily applied using a wide variety of software tools, both general and bespoke.

Synthetic Biology Open Language Visual (SBOL Visual) Version 2.1.

People who are engineering biological organisms often find it useful to communicate in diagrams, both about the structure of the nucleic acid sequences that they are engineering and about the functional relationships between sequence features and other molecular species . Some typical practices and conventions have begun to emerge for such diagrams. The Synthetic Biology Open Language Visual (SBOL Visual) has been developed as a standard for organizing and systematizing such conventions in order to produce a coherent language for expressing the structure and function of genetic designs. This document details version 2.1 of SBOL Visual, which builds on the prior SBOL Visual 2.0 standard by expanding diagram syntax to include methods for showing modular structure and mappings between elements of a system, interactions arrows that can split or join (with the glyph at the split or join indicating either superposition or a chemical process), and adding new glyphs for indicating genomic context (e.g., integration into a plasmid or genome) and for stop codons.

Synthetic Biology Open Language (SBOL) Version 2.3.

Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems is to improve the exchange of information about designed systems between laboratories. The synthetic biology open language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.3.0 of SBOL, which builds upon version 2.2.0 published in last year's JIB Standards in Systems Biology special issue. In particular, SBOL 2.3.0 includes means of succinctly representing sequence modifications, such as insertion, deletion, and replacement, an extension to support organization and attachment of experimental data derived from designs, and an extension for describing numerical parameters of design elements. The new version also includes specifying types of synthetic biology activities, unambiguous locations for sequences with multiple encodings, refinement of a number of validation rules, improved figures and examples, and clarification on a number of issues related to the use of external ontology terms.

Lasting connectivity increase and anxiety reduction via transcranial alternating current stimulation.

Growing evidence of transcranial alternating current stimulation (tACS) modulating intrinsic neural oscillations has spawned interest in applying tACS to treat psychiatric disorders associated with aberrant neural oscillations. The alpha rhythmic activity is known to dominate neural oscillations at the awake, restful state, while attenuated resting-state alpha activity has been implicated in anxious mood. Administering repeated alpha-frequency tACS (α-tACS; at individual peak alpha frequency; 8-12 Hz) over four consecutive days (in the experiment group, sham stimulation in the control group), we demonstrated immediate and lasting (>24 h) increases in resting-state posterior ➔frontal connectivity in the alpha frequency, quantified by Granger causality. Critically, this connectivity enhancement was accompanied by sustained reductions in both anxious arousal and negative perception of sensory stimuli. Resting-state alpha power also increased, albeit only transiently, reversing to the baseline level within 24 h after tACS. Therefore, the lasting enhancement of long-range alpha connectivity due to α-tACS differs from local alpha activity that is nonetheless conserved, highlighting the adaptability of alpha oscillatory networks. In light of increasing recognition of large-scale network dysfunctions as a transdiagnostic pathophysiology of psychiatric disorders, this enduring connectivity plasticity, along with the behavioral improvements, paves the way for tACS applications in clinical interventions of psychiatric 'oscillopathies'.

Synthetic Biology Open Language (SBOL) Version 2.2.0.

Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The synthetic biology open language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.2.0 of SBOL that builds upon version 2.1.0 published in last year's JIB special issue. In particular, SBOL 2.2.0 includes improved description and validation rules for genetic design provenance, an extension to support combinatorial genetic designs, a new class to add non-SBOL data as attachments, a new class for genetic design implementations, and a description of a methodology to describe the entire design-build-test-learn cycle within the SBOL data model.

Synthetic Biology Open Language Visual (SBOL Visual) Version 2.0.

People who are engineering biological organisms often find it useful to communicate in diagrams, both about the structure of the nucleic acid sequences that they are engineering and about the functional relationships between sequence features and other molecular species. Some typical practices and conventions have begun to emerge for such diagrams. The Synthetic Biology Open Language Visual (SBOL Visual) has been developed as a standard for organizing and systematizing such conventions in order to produce a coherent language for expressing the structure and function of genetic designs. This document details version 2.0 of SBOL Visual, which builds on the prior SBOL Visual 1.0 standard by expanding diagram syntax to include functional interactions and molecular species, making the relationship between diagrams and the SBOL data model explicit, supporting families of symbol variants, clarifying a number of requirements and best practices, and significantly expanding the collection of diagram glyphs.