Biology subjects

Steward, T.

Publications and source records attributed to Steward, T..

8 recordsLinked to original sources

bioRxiv2026

Mapping the neural circuitry of cognitive restructuring in depressive and anxiety disorders

BackgroundCognitive restructuring, the process of identifying and challenging negative thoughts, is a key technique for treating depressive and anxiety disorders. Although neuroimaging studies have characterised the brain systems supporting cognitive restructuring in healthy individuals, it remains unclear how these systems are altered in depression and anxiety, or whether each disorder is associated with distinct neural dysfunction. MethodsSeventy-three clinical participants with depressive or anxiety disorders and 70 healthy controls completed a cognitive restructuring paradigm during 7 Tesla functional magnetic resonance imaging (fMRI). The task required participants to either repeat a series of negative statements or challenge them using Socratic questioning. Group-level fMRI analyses examined the effects of depressive and anxiety symptom severity on brain activation, while dynamic causal modelling characterized the directional neural influences between implicated regions. ResultsDuring challenging compared to repeating statements, greater depressive symptoms were associated with reduced dorsolateral prefrontal cortex (dlPFC) activation. Conversely, greater anxiety symptoms were associated with greater dlPFC activation. Effective connectivity results revealed that depressive symptoms were associated with greater inhibition from the ventrolateral prefrontal cortex (vlPFC) to the ventromedial prefrontal cortex, whereas anxiety symptoms were associated with greater excitation from the dlPFC to amygdala and greater inhibition from the vlPFC to amygdala. ConclusionsWhile clinical participants modified negative beliefs as effectively as healthy controls, depressive and anxiety symptoms were associated with dissociable neural signatures during restructuring. This suggests that cognitive behavioral therapy may engage partially distinct mechanisms depending on symptom profile, a possibility that warrants longitudinal investigation of treatment response.

neuroscience↗

bioRxiv2025

Bivalent habenula modulation of human monoaminergic midbrain and cortical pathways

The habenula is implicated in signaling negative reward prediction errors (RPE), yet direct causal evidence demonstrating its influence on downstream human brain circuits is limited. Using ultra-high field (7T) fMRI and dynamic causal modelling across two negative RPE-inducing experimental tasks, we characterize habenula-directed connectivity with monoaminergic midbrain and cortical pathways in healthy adults. Negative feedback drove strong habenula inhibition of ventral tegmental area and dorsal raphe nucleus activity, while positive feedback had an excitatory effect. These core effects are replicated across reversal learning and perceptual decision uncertainty tasks, establishing a generalizable mechanism for behavioral adaptation. Task-specific modulatory effects emerged in pathways between the subcortical and cortical regions (ventral tegmental area[->]dorsal anterior cingulate cortex, dorsal raphe nucleus[->]medial prefrontal cortex, and dorsal anterior cingulate cortex[->]habenula), revealing context-dependent cortical elaboration of negative RPE-driven habenula signals. This provides the first evidence in humans for bivalent causal modulation of habenula function on monoaminergic midbrain and cortical pathways, demonstrating how the brain integrates negative and positive signals to guide adaptive behavior.

neuroscience↗

bioRxiv2025

The elusive neural signature of emotion regulation capabilities: evidence from a large-scale consortium

Cognitive reappraisal is a fundamental emotion regulation strategy for mental and physical well-being, but how its neural mechanisms relate to individual differences remains poorly understood. In a consortium effort analyzing 40 fMRI datasets (N=2,175), we examined the relationship between neural activation during reappraisal tasks and three core individual difference indices of reappraisal capabilities: (1) trait questionnaires, (2) task-based affective ratings, and (3) amygdala down-regulation. Strikingly, there was no shared overlap across these three common indices. Only a very weak correlation emerged between amygdala down-regulation and task-based affective ratings. Whole-brain analyses revealed no reliable neural associations with trait questionnaires, and associations with task-based affective ratings fell outside canonical emotion regulation networks (e.g., prefrontal circuitry). Moreover, amygdala down-regulation, often interpreted as a stable individual marker, was confounded by person-specific whole-brain responses -- a limitation extending to fMRI research beyond the emotion regulation domain. These findings challenge the assumption that an individuals prefrontal activity is a valid indicator of their reappraisal capabilities and suggest that common trait, behavioral, and neural measures might capture distinct facets of emotion regulation. More broadly, our results highlight concrete methodological challenges for fMRI research on individual differences, with implications extending beyond emotion regulation to the neuroscience of personality, psychopathology, and general well-being.

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bioRxiv2025

Effective connectivity reveals dual-route mechanism of visual prediction precision via insula and pulvinar

The brains ability to weight predictions by their precision is a central mechanism in predictive processing, enabling optimal integration of prior expectations with incoming sensory input. Despite its theoretical significance, the neural circuitry that implements precision-weighted prediction remains unclear. Using 7-Tesla fMRI and dynamic causal modelling (DCM), this study investigated how the brain encodes the precision of predictions during a visual cueing task with high- and low-precision conditions. We focused on the key regions implicated in predictive processing: the insular cortex, the pulvinar nucleus of the thalamus, and primary visual cortex (V1). Behaviourally, participants showed significantly greater accuracy in the high-precision condition (p < .001), confirming effective task manipulation. DCM analyses revealed that high-precision predictions elicited excitatory modulation of connectivity from the insula to V1 (Pp = .95), alongside inhibitory influences from the insula to the pulvinar (Pp = .99) and from the pulvinar to V1 (Pp = .89). Furthermore, leave-one-out cross validation revealed that individual differences in behavioural sensitivity to precision were positively predicted by pulvinar-to-insula connectivity (r = .36, p = .026) and negatively predicted by the connectivity between pulvinar and V1 (pulvinar to V1: r = .35, p = .033; V1 to pulvinar: r = .37, p = .026), highlighting the behavioural relevance of these pathways. Together, these findings suggest a dual-route mechanism whereby the insula directly enhances top-down predictions in V1 while indirectly dampening bottom-up sensory input via the pulvinar. This mechanism may facilitate Bayesian integration under uncertainty and offers new hypotheses into how precision weighting may be disrupted in neuropsychiatric conditions.

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bioRxiv2024

Altered basal forebrain regulation of intrinsic brain networks in depressive and anxiety disorders

Depressive and anxiety disorders are characterized by altered connectivity within and between the default mode (DMN) and salience networks. Basal forebrain subdivisions, critical for regulating network activity, remain understudied across these conditions. To address this gap, we analyzed 7-Tesla resting-state functional magnetic resonance imaging data from a transdiagnostic sample (n = 70), primarily with depressive and anxiety disorders, and healthy controls (n = 77). We used spectral dynamic causal modelling to assess effective connectivity between the medial septum/diagonal band (Ch1-3), nucleus basalis of Meynert (Ch4), ventral pallidum, and DMN and salience networks. Healthy participants showed excitatory connectivity from Ch1-3 to the DMN and from Ch4 to the anterior insula. In contrast, clinical participants exhibited greater inhibitory Ch4 to DMN connectivity and increased excitatory connectivity from Ch4 to the anterior insula. Wide-spread Ch4 connectivity dysfunction may implicate the cholinergic system as a mechanistic and therapeutic target for depressive and anxiety disorders.

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bioRxiv2021

Cortico-striatal activity characterizes human safety learning via Pavlovian conditioned inhibition

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviours. 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 (UHF) fMRI to examine the neural basis of inhibitory 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. The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular and dorsolateral prefrontal cortex compared to the standard safety signal, whereas the latter evoked greater activation of the ventromedial prefrontal cortex, 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 statementIdentifying safety is critical for maintaining adaptive levels of anxiety, but the neural mechanisms of human safety learning remain unclear. Using ultra-high field 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/prefrontal cortex 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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bioRxiv2021

Dynamic Subcortical Modulators of Human Default Mode Network Function

The brains default mode network (DMN) enables flexible switching between internally and externally focused cognition. Precisely how this modulation occurs is not well understood, although may involve key subcortical mechanisms, including hypothesized influences from the basal forebrain (BF) and mediodorsal thalamus (MD). Here, we used ultra-high field (7T) functional magnetic resonance imaging to examine the involvement of the BF and MD across states of task-induced DMN activity modulation. Specifically, we mapped DMN activity suppression ( deactivation) when participants transitioned between rest and externally focused task performance, as well as DMN activity engagement ( activation) when task performance was internally (i.e., self) focused. Consistent with recent rodent studies, the BF showed overall activity suppression with DMN cortical regions when comparing the rest to external task conditions. Further analyses, including dynamic causal modelling, confirmed that the BF drove changes in DMN cortical activity during these rest-to-task transitions. The MD, by comparison, was specifically engaged during internally focused cognition and demonstrated a broad excitatory influence on DMN cortical activation. These results provide the first direct evidence in humans of distinct basal forebrain and thalamic circuit influences on the control of DMN function and suggest novel mechanistic avenues for ongoing translational research.

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bioRxiv2021

A thalamo-centric neural signature for restructuring negative self-beliefs

Negative self-beliefs are a core feature of psychopathology. Despite this, we have a limited understanding of the brain mechanisms by which negative self-beliefs are cognitively restructured. Using a novel paradigm, we had participants use Socratic questioning techniques to restructure self-beliefs during ultra-high resolution 7-Tesla functional magnetic resonance imaging (UHF fMRI) scanning. Cognitive restructuring elicited prominent activation in a fronto-striato-thalamic circuit, including the mediodorsal thalamus (MD), a group of deep subcortical nuclei believed to synchronize and integrate prefrontal cortex activity, but which has seldom been directly examined with fMRI due to its small size. Increased activity was also identified in the medial prefrontal cortex (MPFC), a region consistently activated by internally focused mental processing, as well as in lateral prefrontal regions associated with regulating emotional reactivity. Using Dynamic Causal Modelling (DCM), evidence was found to support the MD as having a strong excitatory effect on the activity of regions within the broader network mediating cognitive restructuring. Moreover, the degree to which participants modulated MPFC-to-MD effective connectivity during cognitive restructuring predicted their individual tendency to engage in repetitive negative thinking. Our findings represent a major shift from a cortico-centric framework of cognition and provide important mechanistic insights into how the MD facilitates key processes in cognitive interventions for common psychiatric disorders. In addition to relaying integrative information across basal ganglia and the cortex, we propose a multifaceted role for the MD whose broad excitatory pathways act to increase synchrony between cortical regions to sustain complex mental representations, including the self.

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