A Dynamical Systems View of Psychiatric Disorders-Theory: A Review.

Importance: Psychiatric disorders may come and go with symptoms changing over a lifetime. This suggests the need for a paradigm shift in diagnosis and treatment. Here we present a fresh look inspired by dynamical systems theory. This theory is used widely to explain tipping points, cycles, and chaos in complex systems ranging from the climate to ecosystems. Observations: In the dynamical systems view, we propose the healthy state has a basin of attraction representing its resilience, while disorders are alternative attractors in which the system can become trapped. Rather than an immutable trait, resilience in this approach is a dynamical property. Recent work has demonstrated the universality of generic dynamical indicators of resilience that are now employed globally to monitor the risks of collapse of complex systems, such as tropical rainforests and tipping elements of the climate system. Other dynamical systems tools are used in ecology and climate science to infer causality from time series. Moreover, experiences in ecological restoration confirm the theoretical prediction that under some conditions, short interventions may invoke long-term success when they flip the system into an alternative basin of attraction. All this implies practical applications for psychiatry, as are discussed in part 2 of this article. Conclusions and Relevance: Work in the field of dynamical systems points to novel ways of inferring causality and quantifying resilience from time series. Those approaches have now been tried and tested in a range of complex systems. The same tools may help monitoring and managing resilience of the healthy state as well as psychiatric disorders.

A Dynamical Systems View of Psychiatric Disorders-Practical Implications: A Review.

Importance: Dynamical systems theory is widely used to explain tipping points, cycles, and chaos in complex systems ranging from the climate to ecosystems. It has been suggested that the same theory may be used to explain the nature and dynamics of psychiatric disorders, which may come and go with symptoms changing over a lifetime. Here we review evidence for the practical applicability of this theory and its quantitative tools in psychiatry. Observations: Emerging results suggest that time series of mood and behavior may be used to monitor the resilience of patients using the same generic dynamical indicators that are now employed globally to monitor the risks of collapse of complex systems, such as tropical rainforest and tipping elements of the climate system. Other dynamical systems tools used in ecology and climate science open ways to infer personalized webs of causality for patients that may be used to identify targets for intervention. Meanwhile, experiences in ecological restoration help make sense of the occasional long-term success of short interventions. Conclusions and Relevance: Those observations, while promising, evoke follow-up questions on how best to collect dynamic data, infer informative timescales, construct mechanistic models, and measure the effect of interventions on resilience. Done well, monitoring resilience to inform well-timed interventions may be integrated into approaches that give patients an active role in the lifelong challenge of managing their resilience and knowing when to seek professional help.

Parallel cognitive maps for multiple knowledge structures in the hippocampal formation.

The hippocampal-entorhinal system uses cognitive maps to represent spatial knowledge and other types of relational information. However, objects can often be characterized by different types of relations simultaneously. How does the hippocampal formation handle the embedding of stimuli in multiple relational structures that differ vastly in their mode and timescale of acquisition? Does the hippocampal formation integrate different stimulus dimensions into one conjunctive map or is each dimension represented in a parallel map? Here, we reanalyzed human functional magnetic resonance imaging data from Garvert et al. (2017) that had previously revealed a map in the hippocampal formation coding for a newly learnt transition structure. Using functional magnetic resonance imaging adaptation analysis, we found that the degree of representational similarity in the bilateral hippocampus also decreased as a function of the semantic distance between presented objects. Importantly, while both map-like structures localized to the hippocampal formation, the semantic map was located in more posterior regions of the hippocampal formation than the transition structure and thus anatomically distinct. This finding supports the idea that the hippocampal-entorhinal system forms parallel cognitive maps that reflect the embedding of objects in diverse relational structures.

Prefrontal signals precede striatal signals for biased credit assignment in motivational learning biases.

Actions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear. Specifically, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and control beyond stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dorsal anterior and posterior cingulate cortices) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism.

The effects of an 8-week mindful eating intervention on anticipatory reward responses in striatum and midbrain.

Introduction: Accumulating evidence suggests that increased neural responses during the anticipation of high-calorie food play an important role in the tendency to overeat. A promising method for counteracting enhanced food anticipation in overeating might be mindfulness-based interventions (MBIs). However, the neural mechanisms by which MBIs can affect food reward anticipation are unclear. In this randomized, actively controlled study, the primary objective was to investigate the effect of an 8-week mindful eating intervention on reward anticipation. We hypothesized that mindful eating would decrease striatal reward anticipation responses. Additionally, responses in the midbrain-from which the reward pathways originate-were explored. Methods: Using functional magnetic resonance imaging (fMRI), we tested 58 healthy participants with a wide body mass index range (BMI: 19-35 kg/m2), motivated to change their eating behavior. During scanning they performed an incentive delay task, measuring neural reward anticipation responses to caloric and monetary cues before and after 8 weeks of mindful eating or educational cooking (active control). Results: Compared with the educational cooking intervention, mindful eating affected neural reward anticipation responses, with reduced caloric relative to monetary reward responses. This effect was, however, not seen in the striatum, but only in the midbrain. The secondary objective was to assess temporary and long-lasting (1 year follow-up) intervention effects on self-reported eating behavior and anthropometric measures [BMI, waist circumference, waist-to-hip-ratio (WHR)]. We did not observe effects of the mindful eating intervention on eating behavior. Instead, the control intervention showed temporary beneficial effects on BMI, waist circumference, and diet quality, but not on WHR or self-reported eating behavior, as well as long-lasting increases in knowledge about healthy eating. Discussion: These results suggest that an 8-week mindful eating intervention may have decreased the relative salience of food cues by affecting midbrain but not striatal reward responses, without necessarily affecting regular eating behavior. However, these exploratory results should be verified in confirmatory research.The primary and secondary objectives of the study were registered in the Dutch Trial Register (NTR): NL4923 (NTR5025).

Methylphenidate undermines or enhances divergent creativity depending on baseline dopamine synthesis capacity.

Catecholamine-enhancing psychostimulants, such as methylphenidate have long been argued to undermine creative thinking. However, prior evidence for this is weak or contradictory, stemming from studies with small sample sizes that do not consider the well-established large variability in psychostimulant effects across different individuals and task demands. We aimed to definitively establish the link between psychostimulants and creative thinking by measuring effects of methylphenidate in 90 healthy participants on distinct creative tasks that measure convergent and divergent thinking, as a function of individuals' baseline dopamine synthesis capacity, indexed with 18F-FDOPA PET imaging. In a double-blind, within-subject design, participants were administered methylphenidate, placebo or selective D2 receptor antagonist sulpiride. The results showed that striatal dopamine synthesis capacity and/or methylphenidate administration did not affect divergent and convergent thinking. However, exploratory analysis demonstrated a baseline dopamine-dependent effect of methylphenidate on a measure of response divergence, a creativity measure that measures response variability. Response divergence was reduced by methylphenidate in participants with low dopamine synthesis capacity but enhanced in those with high dopamine synthesis capacity. No evidence of any effect of sulpiride was found. These results show that methylphenidate can undermine certain forms of divergent creativity but only in individuals with low baseline dopamine levels.

Impulse control disorder in Parkinson's disease is associated with abnormal frontal value signalling.

Dopaminergic medication is well established to boost reward- versus punishment-based learning in Parkinson's disease. However, there is tremendous variability in dopaminergic medication effects across different individuals, with some patients exhibiting much greater cognitive sensitivity to medication than others. We aimed to unravel the mechanisms underlying this individual variability in a large heterogeneous sample of early-stage patients with Parkinson's disease as a function of comorbid neuropsychiatric symptomatology, in particular impulse control disorders and depression. One hundred and ninety-nine patients with Parkinson's disease (138 ON medication and 61 OFF medication) and 59 healthy controls were scanned with functional MRI while they performed an established probabilistic instrumental learning task. Reinforcement learning model-based analyses revealed medication group differences in learning from gains versus losses, but only in patients with impulse control disorders. Furthermore, expected-value related brain signalling in the ventromedial prefrontal cortex was increased in patients with impulse control disorders ON medication compared with those OFF medication, while striatal reward prediction error signalling remained unaltered. These data substantiate the hypothesis that dopamine's effects on reinforcement learning in Parkinson's disease vary with individual differences in comorbid impulse control disorder and suggest they reflect deficient computation of value in medial frontal cortex, rather than deficient reward prediction error signalling in striatum. See Michael Browning (https://doi.org/10.1093/brain/awad248) for a scientific commentary on this article.

Evidence for absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity.

Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity, and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, 'off-the-shelf' tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [18F]-FDOPA PET in a large sample of healthy volunteers (N = 94) and assessed the correlation with simple, short tests of working memory capacity, trait impulsivity, and sEBR. We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.

Learning progress mediates the link between cognitive effort and task engagement.

While a substantial body of work has shown that cognitive effort is aversive and costly, a separate line of research on intrinsic motivation suggests that people spontaneously seek challenging tasks. According to one prominent account of intrinsic motivation, the learning progress motivation hypothesis, the preference for difficult tasks reflects the dynamic range that these tasks yield for changes in task performance (Kaplan & Oudeyer, 2007). Here we test this hypothesis, by asking whether greater engagement with intermediately difficult tasks, indexed by subjective ratings and objective pupil measurements, is a function of trial-wise changes in performance. In a novel paradigm, we determined each individual's capacity for task performance and used difficulty levels that are low, intermediately challenging or high for that individual. We demonstrated that challenging tasks resulted in greater liking and engagement scores compared with easy tasks. Pupil size tracked objective task difficulty, where challenging tasks were associated with greater pupil responses than easy tasks. Most importantly, pupil responses were predicted by trial-to-trial changes in average accuracy as well as learning progress (derivative of average accuracy), while greater pupil responses also predicted greater subjective engagement scores. Together, these results substantiate the learning progress motivation hypothesis stating that the link between task engagement and cognitive effort is mediated the dynamic range for changes in task performance.

Effect of striatal dopamine on Pavlovian bias. A large [¹8F]-DOPA PET study.

Interaction between Pavlovian and instrumental control systems is key for adaptive motivated behavior, but also plays an important role in various neuropsychiatric disorders, including depression, addiction, and anxiety. Here, we employed the flouorodopa positron emission tomography ([¹8F]-DOPA PET) in healthy participants (N = 100) to assess whether dopamine synthesis capacity (Ki), specifically in the ventral striatum, accounts for individual variation in Pavlovian-to-instrumental transfer (PIT). Surprisingly, this was not the case. Rather, the relationship of ventral striatal Ki with PIT depended on working memory (WM) capacity. Ventral striatal dopamine boosted the effects of Pavlovian cues on instrumental responding to a greater degree in participants with higher WM capacity. Caution is warranted to interpret this post hoc four-way interaction given the modest sample size. Nonetheless, these results chime with prior findings demonstrating that dopaminergic drugs boost Pavlovian biases to a greater degree in participants with greater WM capacity and highlight the importance of interactions between striatal dopamine and WM capacity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Choice Boosts Curiosity.

In our connected era, we spend significant time and effort satisfying our curiosity. Often, we choose which information we seek, but sometimes the selection is made for us. We hypothesized that humans exhibit enhanced curiosity in the context of choice. We designed a task in which healthy participants saw two lotteries on each trial. On some trials, participants chose which lottery to play. On other trials, the lottery was selected for them. Participants then indicated their curiosity about the outcome of the to-be-played lottery via self-report ratings (Experiment 1, N = 34) or willingness-to-wait decisions (Experiment 2, N = 34). We found that participants exhibited higher curiosity ratings and greater willingness to wait for the outcome of lotteries they had chosen than for lotteries that had been selected for them (controlling for initial preference). This demonstrates that choice boosts curiosity, which may have implications for boosting learning, memory, and motivation.

Psychopathic tendency in violent offenders is associated with reduced aversive Pavlovian inhibition of behavior and associated striatal BOLD signal.

Background: Violent offenders with psychopathic tendencies are characterized by instrumental, i.e., planned, callous, and unemotional (aggressive) behavior and have been shown to exhibit abnormal aversive processing. However, the consequences of abnormal aversive processing for instrumental action and associated neural mechanisms are unclear. Materials and methods: Here we address this issue by using event-related functional magnetic resonance imaging (fMRI) in 15 violent offenders with high psychopathic tendencies and 18 matched controls during the performance of an aversive Pavlovian-to-instrumental transfer paradigm. This paradigm allowed us to assess the degree to which aversive Pavlovian cues affect instrumental action and associated neural signaling. Results: Psychopathic tendency scores were associated with an attenuation of aversive Pavlovian inhibition of instrumental action. Moreover, exploratory analyses revealed an anomalous positive association between aversive inhibition of action and aversive inhibition of BOLD signal in the caudate nucleus of violent offenders with psychopathic tendencies. In addition, psychopathic tendency also correlated positively with amygdala reactivity during aversive versus neutral cues in Pavlovian training. Conclusion: These findings strengthen the hypothesis that psychopathic tendencies in violent offenders are related to abnormal impact of aversive processing on instrumental behavior. The neural effects raise the possibility that this reflects deficient transfer of aversive Pavlovian inhibitory biases onto neural systems that implement instrumental action, including the caudate nucleus.

Amygdala response predicts clinical symptom reduction in patients with borderline personality disorder: A pilot fMRI study.

Borderline personality disorder (BPD) is a prevalent, devastating, and heterogeneous psychiatric disorder. Treatment success is highly variable within this patient group. A cognitive neuroscientific approach to BPD might contribute to precision psychiatry by identifying neurocognitive factors that predict who will benefit from a specific treatment. Here, we build on observations that BPD is accompanied by the enhanced impact of the aversive effect on behavior and abnormal neural signaling in the amygdala. We assessed whether BPD is accompanied by abnormal aversive regulation of instrumental behavior and associated neural signaling, in a manner that is predictive of symptom reduction after therapy. We tested a clinical sample of 15 female patients with BPD, awaiting dialectical behavior therapy (DBT), and 16 matched healthy controls using fMRI and an aversive Pavlovian-to-instrumental transfer (PIT) task that assesses how instrumental behaviors are influenced by aversive Pavlovian stimuli. Patients were assessed 1 year after the start of DBT to quantify changes in BPD symptom severity. At baseline, behavioral aversive PIT and associated neural signaling did not differ between groups. However, the BOLD signal in the amygdala measured during aversive PIT was associated with symptom reduction at 1-year follow-up: higher PIT-related aversive amygdala signaling before treatment was associated with reduced clinical improvement at follow-up. Thus, within the evaluated group of BPD patients, the BOLD signal in the amygdala before treatment was related to clinical symptom reduction 1 year after the start of treatment. The results suggest that less PIT-related responsiveness of the amygdala increases the chances of treatment success. We note that the relatively small sample size is a limitation of this study and that replication is warranted.

Aversive Pavlovian inhibition in adult attention-deficit/hyperactivity disorder and its restoration by mindfulness-based cognitive therapy.

Background: Control over the tendency to make or withhold responses guided by contextual Pavlovian information plays a key role in understanding impulsivity and hyperactivity. Here we set out to assess (1) the understudied relation between contextual Pavlovian inhibitory control and hyperactivity/impulsivity in adults with ADHD and (2) whether this inhibition can be enhanced by mindfulness based cognitive therapy (MBCT). Methods: Within the framework of a randomized controlled trial 50 Adult ADHD patients were assessed before and after 8 weeks of treatment as usual (TAU) with (n = 24) or without (n = 26) MBCT. We employed a well-established behavioral Pavlovian-to-instrumental transfer task that quantifies Pavlovian inhibitory control over instrumental behavior. Results: Task results revealed (1) less aversive Pavlovian inhibition in ADHD patients with clinically relevant hyperactivity/impulsivity than in those without; and (2) enhanced Pavlovian inhibition across all ADHD patients after TAU+MBCT compared with TAU. Conclusion: These findings offer new insights in the neurocognitive mechanisms of hyperactivity/impulsivity in ADHD and its treatment: We reveal a role for Pavlovian inhibitory mechanisms in understanding hyperactive/impulsive behaviors in ADHD and point toward MBCT as an intervention that might influence these mechanisms.

Striatal dopamine dissociates methylphenidate effects on value-based versus surprise-based reversal learning.

Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults (N = 100) were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D2/3-receptor antagonist sulpiride. Striatal dopamine synthesis capacity was indexed with [18F]DOPA positron emission tomography. Methylphenidate improved and sulpiride decreased overall accuracy and response speed. Both drugs boosted reward versus punishment learning signals to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate gates both attention and reward learning.

Correction: Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context.

[This corrects the article DOI: 10.1371/journal.pone.0260952.].

Stress-sensitive inference of task controllability.

Estimating the controllability of the environment enables agents to better predict upcoming events and decide when to engage controlled action selection. How does the human brain estimate controllability? Trial-by-trial analysis of choices, decision times and neural activity in an explore-and-predict task demonstrate that humans solve this problem by comparing the predictions of an 'actor' model with those of a reduced 'spectator' model of their environment. Neural blood oxygen level-dependent responses within striatal and medial prefrontal areas tracked the instantaneous difference in the prediction errors generated by these two statistical learning models. Blood oxygen level-dependent activity in the posterior cingulate, temporoparietal and prefrontal cortices covaried with changes in estimated controllability. Exposure to inescapable stressors biased controllability estimates downward and increased reliance on the spectator model in an anxiety-dependent fashion. Taken together, these findings provide a mechanistic account of controllability inference and its distortion by stress exposure.

Role of dopamine and clinical heterogeneity in cognitive dysfunction in Parkinson's disease.

Parkinson's disease (PD) is commonly treated with dopaminergic medication, which enhances some, while impairing other cognitive functions. It can even contribute to impulse control disorder and addiction. We describe the history of research supporting the dopamine overdose hypothesis, which accounts for the large within-patient variability in dopaminergic medication effects across different tasks by referring to the spatially non-uniform pattern of dopamine depletion in dorsal versus ventral striatum. However, there is tremendous variability in dopaminergic medication effects not just within patients across distinct tasks, but also across different patients. In the second part of this chapter we review recent studies addressing the large individual variability in the negative side effects of dopaminergic medication on functions that implicate dopamine, such as value-based learning and choice. These studies begin to unravel the mechanisms of dopamine overdosing, thus revising the strict version of the overdose hypothesis. For example, the work shows that the canonical boosting of reward-versus punishment-based choice by medication is greater in patients with depression and a non-tremor phenotype, which both implicate, among other pathology, more rather than less severe dysregulation of the mesolimbic dopamine system. Future longitudinal cohort studies are needed to identify how to optimally combine different clinical, personality, cognitive, neural, genetic and molecular predictors of detrimental medication effects in order to account for as much of the relevant variability as possible. This will provide a useful tool for precision neurology, allowing individual and contextual tailoring of (the dose of) dopaminergic medication in order to maximize its cognitive benefits, yet minimize its side effects.

Challenging the negative learning bias hypothesis of depression: reversal learning in a naturalistic psychiatric sample.

BACKGROUND: Classic theories posit that depression is driven by a negative learning bias. Most studies supporting this proposition used small and selected samples, excluding patients with comorbidities. However, comorbidity between psychiatric disorders occurs in up to 70% of the population. Therefore, the generalizability of the negative bias hypothesis to a naturalistic psychiatric sample as well as the specificity of the bias to depression, remain unclear. In the present study, we tested the negative learning bias hypothesis in a large naturalistic sample of psychiatric patients, including depression, anxiety, addiction, attention-deficit/hyperactivity disorder, and/or autism. First, we assessed whether the negative bias hypothesis of depression generalized to a heterogeneous (and hence more naturalistic) depression sample compared with controls. Second, we assessed whether negative bias extends to other psychiatric disorders. Third, we adopted a dimensional approach, by using symptom severity as a way to assess associations across the sample. METHODS: We administered a probabilistic reversal learning task to 217 patients and 81 healthy controls. According to the negative bias hypothesis, participants with depression should exhibit enhanced learning and flexibility based on punishment v. reward. We combined analyses of traditional measures with more sensitive computational modeling. RESULTS: In contrast to previous findings, this sample of depressed patients with psychiatric comorbidities did not show a negative learning bias. CONCLUSIONS: These results speak against the generalizability of the negative learning bias hypothesis to depressed patients with comorbidities. This study highlights the importance of investigating unselected samples of psychiatric patients, which represent the vast majority of the psychiatric population.

Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine.

The primate prefrontal cortex (PFC) subserves our highest order cognitive operations, and yet is tremendously dependent on a precise neurochemical environment for proper functioning. Depletion of noradrenaline and dopamine, or of acetylcholine from the dorsolateral PFC (dlPFC), is as devastating as removing the cortex itself, and serotonergic influences are also critical to proper functioning of the orbital and medial PFC. Most neuromodulators have a narrow inverted U dose response, which coordinates arousal state with cognitive state, and contributes to cognitive deficits with fatigue or uncontrollable stress. Studies in monkeys have revealed the molecular signaling mechanisms that govern the generation and modulation of mental representations by the dlPFC, allowing dynamic regulation of network strength, a process that requires tight regulation to prevent toxic actions, e.g., as occurs with advanced age. Brain imaging studies in humans have observed drug and genotype influences on a range of cognitive tasks and on PFC circuit functional connectivity, e.g., showing that catecholamines stabilize representations in a baseline-dependent manner. Research in monkeys has already led to new treatments for cognitive disorders in humans, encouraging future research in this important field.