Thinking computationally in translational psychiatry. A commentary on Neville et al. (2024).

There is a growing focus on the computational aspects of psychiatric disorders in humans. This idea also is gaining traction in nonhuman animal studies. Commenting on a new comprehensive overview of the benefits of applying this approach in translational research by Neville et al. (Cognitive Affective & Behavioral Neuroscience 1-14, 2024), we discuss the implications for translational model validity within this framework. We argue that thinking computationally in translational psychiatry calls for a change in the way that we evaluate animal models of human psychiatric processes, with a shift in focus towards symptom-producing computations rather than the symptoms themselves. Further, in line with Neville et al.'s adoption of the reinforcement learning framework to model animal behaviour, we illustrate how this approach can be applied beyond simple decision-making paradigms to model more naturalistic behaviours.

Longitudinal decline in striatal dopamine transporter binding in Parkinson's disease: associations with apathy and anhedonia.

BACKGROUND: Motivational symptoms such as apathy and anhedonia are common in Parkinson's disease (PD), respond poorly to treatment, and are hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in PD but the association has never been examined longitudinally. We investigated whether progression of dopaminergic dysfunction was associated with emergent apathy and anhedonia symptoms in PD. METHODS: Longitudinal cohort study of 412 newly diagnosed patients with PD followed over 5 years as part of the Parkinson's Progression Markers Initiative cohort.Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item Geriatric Depression Scale (GDS-15) and part I of the MDS-Unified Parkinson's Disease Rating Scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging. RESULTS: Linear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio (SBR) and apathy/anhedonia symptoms, which emerged as PD progressed (interaction:ß=-0.09, 95% CI (-0.15 to -0.03), p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average 2 years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) (ß=-0.06, 95% CI (-0.13 to 0.01)) or motor symptoms (ß=0.20, 95% CI (-0.25 to 0.65)). CONCLUSIONS: Our findings support a central role for dopaminergic dysfunction in motivational symptoms in PD. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies.

Amygdala activity after subchronic escitalopram administration in healthy volunteers: A pharmaco-functional magnetic resonance imaging study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are used for the treatment of several conditions including anxiety disorders, but the basic neurobiology of serotonin function remains unclear. The amygdala and prefrontal cortex are strongly innervated by serotonergic projections and have been suggested to play an important role in anxiety expression. However, serotonergic function in behaviour and SSRI-mediated neurobiological changes remain incompletely understood. AIMS: To investigate the neural correlates of subchronic antidepressant administration. METHODS: We investigated whether the 2- to 3-week administration of a highly selective SSRI (escitalopram) would alter brain activation on a task robustly shown to recruit the bilateral amygdala and frontal cortices in a large healthy volunteer sample. Participants performed the task during a functional magnetic resonance imaging acquisition before (n = 96) and after subchronic escitalopram (n = 46, days of administration mean (SD) = 15.7 (2.70)) or placebo (n = 40 days of administration mean (SD) = 16.2 (2.90)) self-administration. RESULTS: Compared to placebo, we found an elevation in right amygdala activation to the task after escitalopram administration without significant changes in mood. This effect was not seen in the left amygdala, the dorsomedial region of interest, the subgenual anterior cingulate cortex or the right fusiform area. There were no significant changes in connectivity between the dorsomedial cortex and amygdala or the subgenual anterior cingulate cortex after escitalopram administration. CONCLUSIONS: To date, this most highly powered study of subchronic SSRI administration indicates that, contrary to effects often seen in patients with anxiety disorders, subchronic SSRI treatment may increase amygdala activation in healthy controls. This finding highlights important gaps in our understanding of the functional role of serotonin.

Independent replications reveal anterior and posterior cingulate cortex activation underlying state anxiety-attenuated face encoding.

Anxiety involves the anticipation of aversive outcomes and can impair neurocognitive processes, such as the ability to recall faces encoded during the anxious state. It is important to precisely delineate and determine the replicability of these effects using causal state anxiety inductions in the general population. This study therefore aimed to replicate prior research on the distinct impacts of threat-of-shock-induced anxiety on the encoding and recognition stage of emotional face processing, in a large asymptomatic sample (n = 92). We successfully replicated previous results demonstrating impaired recognition of faces encoded under threat-of-shock. This was supported by a mega-analysis across three independent studies using the same paradigm (n = 211). Underlying this, a whole-brain fMRI analysis revealed enhanced activation in the posterior cingulate cortex (PCC), alongside previously seen activity in the anterior cingulate cortex (ACC) when combined in a mega-analysis with the fMRI findings we aimed to replicate. We further found replications of hippocampus activation when the retrieval and encoding states were congruent. Our results support the notion that state anxiety disrupts face recognition, potentially due to attentional demands of anxious arousal competing with affective stimuli processing during encoding and suggest that regions of the cingulate cortex play pivotal roles in this.

Computational perspectives on human fear and anxiety.

Fear and anxiety are adaptive emotions that serve important defensive functions, yet in excess, they can be debilitating and lead to poor mental health. Computational modelling of behaviour provides a mechanistic framework for understanding the cognitive and neurobiological bases of fear and anxiety, and has seen increasing interest in the field. In this brief review, we discuss recent developments in the computational modelling of human fear and anxiety. Firstly, we describe various reinforcement learning strategies that humans employ when learning to predict or avoid threat, and how these relate to symptoms of fear and anxiety. Secondly, we discuss initial efforts to explore, through a computational lens, approach-avoidance conflict paradigms that are popular in animal research to measure fear- and anxiety-relevant behaviours. Finally, we discuss negative biases in decision-making in the face of uncertainty in anxiety.

Approach-avoidance reinforcement learning as a translational and computational model of anxiety-related avoidance.

Although avoidance is a prevalent feature of anxiety-related psychopathology, differences in the measurement of avoidance between humans and non-human animals hinder our progress in its theoretical understanding and treatment. To address this, we developed a novel translational measure of anxiety-related avoidance in the form of an approach-avoidance reinforcement learning task, by adapting a paradigm from the non-human animal literature to study the same cognitive processes in human participants. We used computational modelling to probe the putative cognitive mechanisms underlying approach-avoidance behaviour in this task and investigated how they relate to subjective task-induced anxiety. In a large online study (n = 372), participants who experienced greater task-induced anxiety avoided choices associated with punishment, even when this resulted in lower overall reward. Computational modelling revealed that this effect was explained by greater individual sensitivities to punishment relative to rewards. We replicated these findings in an independent sample (n = 627) and we also found fair-to-excellent reliability of measures of task performance in a sub-sample retested 1 week later (n = 57). Our findings demonstrate the potential of approach-avoidance reinforcement learning tasks as translational and computational models of anxiety-related avoidance. Future studies should assess the predictive validity of this approach in clinical samples and experimental manipulations of anxiety.

The acute effects of cannabidiol on emotional processing and anxiety: a neurocognitive imaging study.

RATIONALE: There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. OBJECTIVES: We sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety. METHODS: We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during functional magnetic resonance imaging) and cognitive (emotional appraisal) measures as well as subjective response to experimentally induced anxiety. RESULTS: CBD did not produce effects on brain responses to emotional faces and cognitive measures of emotional processing, or modulate experimentally induced anxiety, relative to placebo. CONCLUSIONS: Given the rising popularity of CBD for its putative medical benefits, these findings question whether further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.

Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain.

BACKGROUND: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. AIMS: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). METHOD: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. RESULTS: Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. OUTCOMES: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

How representative are neuroimaging samples? Large-scale evidence for trait anxiety differences between fMRI and behaviour-only research participants.

Over the past three decades, functional magnetic resonance imaging (fMRI) has become crucial to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into fMRI studies differ from participants recruited into other study contexts has received little to no attention. This is particularly pertinent when effects fail to generalize across study contexts: for example, a behavioural effect discovered in a non-imaging context not replicating in a neuroimaging environment. Here, we tested the hypothesis, motivated by preliminary findings (N = 272), that fMRI participants differ from behaviour-only participants on one fundamental individual difference variable: trait anxiety. Analysing trait anxiety scores and possible confounding variables from healthy volunteers across multiple institutions (N = 3317), we found robust support for lower trait anxiety in fMRI study participants, consistent with a sampling or self-selection bias. The bias was larger in studies that relied on phone screening (compared with full in-person psychiatric screening), recruited at least partly from convenience samples (compared with community samples), and in pharmacology studies. Our findings highlight the need for surveying trait anxiety at recruitment and for appropriate screening procedures or sampling strategies to mitigate this bias.

The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers.

BACKGROUND: Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback. HYPOTHESES: We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback. METHODS: We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions. RESULTS: The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo. DISCUSSION: Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders.

The effects of acute cannabidiol on cerebral blood flow and its relationship to memory: An arterial spin labelling magnetic resonance imaging study.

BACKGROUND: Cannabidiol (CBD) is being investigated as a potential treatment for several medical indications, many of which are characterised by altered memory processing. However, the mechanisms underlying these effects are unclear. AIMS: Our primary aim was to investigate how CBD influences cerebral blood flow (CBF) in regions involved in memory processing. Our secondary aim was to determine if the effects of CBD on CBF were associated with differences in working and episodic memory task performance. METHODS: We used a randomised, crossover, double-blind design in which 15 healthy participants were administered 600 mg oral CBD or placebo on separate days. We measured regional CBF at rest using arterial spin labelling 3 h after drug ingestion. We assessed working memory with the digit span (forward, backward) and n-back (0-back, 1-back, 2-back) tasks, and we used a prose recall task (immediate and delayed) to assess episodic memory. RESULTS: CBD increased CBF in the hippocampus (mean (95% confidence intervals) = 15.00 (5.78-24.21) mL/100 g/min, t14 = 3.489, Cohen's d = 0.75, p = 0.004). There were no differences in memory task performance, but there was a significant correlation whereby greater CBD-induced increases in orbitofrontal CBF were associated with reduced reaction time on the 2-back working memory task ( r= -0.73, p = 0.005). CONCLUSIONS: These findings suggest that CBD increases CBF to key regions involved in memory processing, particularly the hippocampus. These results identify potential mechanisms of CBD for a range of conditions associated with altered memory processing, including Alzheimer's disease, schizophrenia, post-traumatic stress disorder and cannabis-use disorders.