Changes in the heartbeat-evoked potential are associated with functional seizures.

BACKGROUND: Patients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation reflects disembodiment, which may be related to changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalogram (EEG) marker of interoceptive processing. AIM: To assess whether alterations in interoceptive processing indexed by HEP occur prior to FS and compare this with epileptic seizures (ES). METHODS: HEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and were compared between interictal and preictal states. HEP amplitude difference was calculated as preictal HEP amplitude minus interictal HEP amplitude. A receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of HEP amplitude difference in discriminating FS from ES. RESULTS: The FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (effect size rB=0.612, false discovery rate (FDR)-corrected q=0.030) and C4 (rB=0.600, FDR-corrected q=0.035). No differences in HEP amplitude were found between states in the ES group. Between diagnostic groups, HEP amplitude difference differed between the FS and ES groups at F8 (rB=0.423, FDR-corrected q=0.085) and C4 (rB=0.457, FDR-corrected q=0.085). Using HEP amplitude difference at frontal and central electrodes plus sex, we found that the ROC curve demonstrated an area under the curve of 0.893, with sensitivity=0.840 and specificity=0.842. CONCLUSION: Our data support the notion that aberrant interoception occurs prior to FS. Changes in HEP amplitude may reflect a neurophysiological biomarker of FS and may have diagnostic utility in differentiating FS and ES.

Impaired cardiac modulation in patients with functional seizures: Results from a face intensity judgment task.

OBJECTIVE: Although interoceptive abnormality in patients with functional seizure (FSs) has been demonstrated using explicit tasks, implicit measurements of interoception such as the effect of interoception on perceptual brain processes have not been investigated. It has been shown that perception is normally modulated by interoceptive signals related to the different phases (systole vs diastole) of the cardiac cycle (cardiac modulation effect). Given our previous findings using explicit measures of interoception, we hypothesized that cardiac modulation would be impaired in FSs. METHODS: Thirty-two patients with FSs and 30 age- and sex-matched non-clinical individuals conducted a face intensity judgment task, in which their intensity rating when fearful or neutral faces was presented was compared between systolic and diastolic phases. They also conducted the heartbeat discrimination task as a measure of their capacity to integrate both interoceptive and exteroceptive information. RESULTS: Patients with FSs had impaired cardiac modulation of the perception of neutral faces (corrected p = .044). Individual differences in the heartbeat discrimination task predicted the degree to which cardiac modulation occurred across the whole group (p = .028). This cardiac modulation effect was significantly associated with seizure severity (p = .021). Regardless of cardiac phase, patients rated fearful facial expressions as less intense compared to control participants (p = .006). SIGNIFICANCE: These findings highlight impaired implicit cardiac modulation effects in patients with FSs. This reflects interoceptive dysfunction in patients with FSs, and an inability of the brain to integrate interoceptive signaling with perceptual processing. This may have implications for our understanding of the pathophysiology in FSs and inform novel diagnostic approaches.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Voice Hearing in Borderline Personality Disorder Across Perceptual, Subjective, and Neural Dimensions.

BACKGROUND: Auditory verbal hallucinations (AVH) commonly occur in the context of borderline personality disorder (BPD) yet remain poorly understood. AVH are often perceived by patients with BPD as originating from inside the head and hence viewed clinically as "pseudohallucinations," but they nevertheless have a detrimental impact on well-being. METHODS: The current study characterized perceptual, subjective, and neural expressions of AVH by using an auditory detection task, experience sampling and questionnaires, and functional neuroimaging, respectively. RESULTS: Perceptually, reported AVH correlated with a bias for reporting the presence of a voice in white noise. Subjectively, questionnaire measures indicated that AVH were significantly distressing and persecutory. In addition, AVH intensity, but not perceived origin (i.e., inside vs outside the head), was associated with greater concurrent anxiety. Neurally, fMRI of BPD participants demonstrated that, relative to imagining or listening to voices, periods of reported AVH induced greater blood oxygenation level-dependent activity in anterior cingulate and bilateral temporal cortices (regional substrates for language processing). AVH symptom severity was associated with weaker functional connectivity between anterior cingulate and bilateral insular cortices. CONCLUSION: In summary, our results indicate that AVH in participants with BPD are (1) underpinned by aberrant perceptual-cognitive mechanisms for signal detection, (2) experienced subjectively as persecutory and distressing, and (3) associated with distinct patterns of neural activity that inform proximal mechanistic understanding. Our findings are like analogous observations in patients with schizophrenia and validate the clinical significance of the AVH experience in BPD, often dismissed as "pseudohallucinations." These highlight a need to reconsider this experience as a treatment priority.

Hypermobility in patients with functional seizures: Toward a pathobiological understanding of complex conditions.

BACKGROUND: Functional seizures (FS), otherwise known as psychogenic nonepileptic seizures (PNES), are a common symptom presenting to neurology and epilepsy clinics. There is a pressing need for further research to understand the neurobiology of FS to develop mechanistically targeted treatments. Joint hypermobility is an expression of variation in connective tissue structure along a spectrum, and it has received increasing attention in functional neurological disorders, but there is lack of evidence of its relevance in FS. METHODS: In the present study, forty-two patients with FS and a non-clinical comparison group of 34 age/sex-matched controls were recruited. Joint hypermobility of all participants was quantified using the Beighton scale. RESULTS: In our sample, 24 (57%) patients with FS, and 7 (21%) of the comparison group met criteria for joint hypermobility (p = 0.002). Our statistical model revealed that patients with FS showed a significant degree of hypermobility compared to the comparison group (odds ratio = 11.1; Confidence interval: 2.1-78.0, p = 0.008), even after controlling age, sex, anxiety, and depression. CONCLUSION: We found a significant association between FS and joint hypermobility, which was independent of anxiety and depression.

A cross-sectional study of auditory verbal hallucinations experienced by people with a diagnosis of borderline personality disorder.

BACKGROUND: The presence of auditory verbal hallucinations (AVHs) does not currently feature in the main diagnostic criteria for borderline personality disorder (BPD). However, there is accumulating evidence that a high proportion of BPD patients report longstanding and frequent AVHs which constitute a significant risk factor for suicide plans and attempts, and hospitalization. AIM: This study addressed questions about the validity and phenomenology of AVHs in the context of BPD. The longer-term aim is to facilitate the development and translation of treatment approaches to address the unmet need of this population. METHOD: This was a cross-sectional study, combining phenomenological and psychological assessments administered in person and online. We explored the experiences of 48 patients with a diagnosis of BPD who were hearing AVHs. RESULTS: Participants gave 'consistent' reports on the measure of AVH phenomenology, suggesting that these experiences were legitimate. Similar to AVHs in a psychosis context, AVHs were experienced as distressing and appraised as persecutory. AVHs were found to be weakly associated with BPD symptoms. AVHs were also rated highly as a treatment priority by the majority of participants. CONCLUSION: The findings suggest that AVH is a legitimate and distressing symptom of BPD and a treatment priority for some patients. The relative independence of AVHs from other BPD symptoms and emotional states suggests that psychological treatment may need to be targeted specifically at the symptom of AVHs. This treatment could be adapted from cognitive behaviour therapy, the psychological intervention that is recommended for the treatment of AVHs in the context of psychosis.

Sensitivity to changes in rate of heartbeats as a measure of interoceptive ability.

Individuals vary in their ability to perceive, as conscious sensations, signals like the beating of the heart. Tests of such interoceptive ability are, however, constrained in nature and reliability. Performance of the heartbeat tracking task, a widely used test of cardiac interoception, often corresponds well with individual differences in emotion and cognition, yet is susceptible to reporting bias and influenced by higher-order knowledge, e.g., of expected heart rate. The present study introduces a new way of assessing cardiac interoceptive ability, focusing on sensitivity to short-term, naturalistic changes in frequency of heartbeats. At rest, such heart rate variability typically reflects the dominant influence of respiration on vagus parasympathetic control of the sinoatrial pacemaker. We observed an overall tendency of healthy participants to report feeling fewer heartbeats during increases in heart rate, which we speculate reflects a reduction in heartbeat strength and salience during inspiratory periods when heart rate typically increases to maintain a stable cardiac output. Within-participant performance was more variable on this measure of cardiac interoceptive sensitivity relative to the "classic" heartbeat tracking task. Our findings indicate that cardiac interoceptive ability, rather than reflecting the veridical monitoring of subtle variations in physiology, appears to involve more interpolation wherein interoceptive decisions are informed by dynamic working estimates derived from the integration of afferent signaling and higher-order predictions.NEW & NOTEWORTHY This study presents a new method for evaluating cardiac interoceptive ability, measuring sensitivity to naturalistic changes in the number of heartbeats over time periods. Results show participants have an overall tendency toward sensing fewer heartbeats during higher heart rates. This likely reflects the influence of changing heartbeat strength on cardiac interoception at rest, which should be taken into account when evaluating cardiac interoceptive ability and its relationship to anxiety and psychosomatic conditions.

Variant connective tissue (joint hypermobility) and dysautonomia are associated with multimorbidity at the intersection between physical and psychological health.

The symptoms of joint hypermobility extend beyond articular pain. Hypermobile people commonly experience autonomic symptoms (dysautonomia), and anxiety or related psychological issues. We tested whether dysautonomia might mediate the association between hypermobility and anxiety in adults diagnosed with mental health disorders and/or neurodevelopmental conditions (hereon referred to as patients), by quantifying joint hypermobility and symptoms of autonomic dysfunction. Prevalence of generalized joint laxity (hypermobility) in 377 individuals with diagnoses of mental health disorders and/or neurodevelopmental conditions was compared to prevalence recorded in the general population. Autonomic symptom burden was compared between hypermobile and non-hypermobile patients. Mediation analysis explored relationships between hypermobility, autonomic dysfunction, and anxiety. Patient participants had elevated prevalence of generalized joint laxity (38%) compared to the general population rate of 19% (odds ratio: 2.54 [95% confidence interval: 2.05, 3.16]). Hypermobile participants reported significantly more autonomic symptoms. Symptoms of orthostatic intolerance mediated the relationship between hypermobility and diagnosis of an anxiety disorder. Patients with mental health disorders and/or neurodevelopmental conditions have high rates of joint hypermobility. Accompanying autonomic dysfunction mediates the association between joint hypermobility and clinical anxiety status. Increased recognition of this association can enhance mechanistic understanding and improve the management of multimorbidity expressed in physical symptoms and mental health difficulties.

Self-awareness in Dementia: a Taxonomy of Processes, Overview of Findings, and Integrative Framework.

PURPOSE OF REVIEW: Self-awareness, the capacity of becoming the object of one's own awareness, has been a frontier of knowledge, but only recently scientific approaches to the theme have advanced. Self-awareness has important clinical implications, and a finer understanding of this concept may improve the clinical management of people with dementia. The current article aims to explore self-awareness, from a neurobiological perspective, in dementia. RECENT FINDINGS: A taxonomy of self-awareness processes is presented, discussing how these can be structured across different levels of cognitive complexity. Findings on self-awareness in dementia are reviewed, indicating the relative preservation of capacities such as body ownership and agency, despite impairments in higher-level cognitive processes, such as autobiographical memory and emotional regulation. An integrative framework, based on predictive coding and compensatory abilities linked to the resilience of self-awareness in dementia, is discussed, highlighting possible avenues for future research into the topic.

Correction: Spelling Errors and Shouting Capitalization Lead to Additive Penalties to Trustworthiness of Online Health Information: Randomized Experiment With Laypersons.

[This corrects the article DOI: 10.2196/15171.].

Attention orientation to pleasantness and depressive symptomatology predict autonomic reactivity.

Depression is characterised by attentional bias to emotional information and dysregulated autonomic reactivity. Despite its relevance to understanding depressive mechanisms, the association between attentional bias and autonomic reactivity to emotional information remains poorly characterised. This study compared behavioural and autonomic responses to emotional images in 32 participants in whom subclinical depressive symptomatology was quantified using the Beck Depression Inventory. Pairs of emotional and neutral images (unpleasant-neutral, U-N; pleasant-neutral, P-N; neutral-neutral, N-N) were presented while attentional indices (eye movements) and autonomic activity (skin conductance responses, SCRs; heart rate, HR) were recorded. Results showed that all recorded ocular parameters indicated a preferential orientation and maintenance of attention to emotional images. SCRs were associated with a valence effect on fixation latency: lower fixation latency to pleasant stimuli leads to lower SCRs whereas the opposite was observed for unpleasant stimuli. Finally, stepwise linear regression analysis revealed that latency of fixation to pleasant images and scores of depression predicted SCRs of participants. Thus, our research reveals an association between autonomic reactivity and attentional bias to pleasant information, on the one hand, and depressive symptomatology on the other. Present findings therefore suggest that depressive individuals may benefit from attention training towards pleasant information in association with autonomic biofeedback procedures.

Trait and state interoceptive abnormalities are associated with dissociation and seizure frequency in patients with functional seizures.

OBJECTIVE: Dissociative traits represent a disturbance in selfhood that may predispose to, and trigger, functional seizures (FSs). The predictive representation and control of the internal physiological state of the body (interoception) are proposed to underpin the integrity of the sense of self ("minimal selfhood"). Therefore, discrepancies between objective and subjective aspects of interoception may relate to symptom expression in patients with FSs. Here, we tested whether individual differences in trait measures of interoception relate to dissociative symptoms, and whether state interoceptive deficits predict FS occurrence. METHODS: Forty-one participants with FSs and 30 controls completed questionnaire ratings of dissociation, and measures of (1) interoceptive accuracy (IA)-objective performance on heartbeat detection tasks; (2) trait interoceptive sensibility-subjective sensitivity to internal sensations (using the Porges Body Perception Questionnaire); and (3) state interoceptive sensibility-subjective trial-by-trial measures of confidence in heartbeat detection. Interoceptive trait prediction error (ITPE) was calculated from the discrepancy between IA and trait sensibility, and interoceptive state prediction error (ISPE) from the discrepancy between IA and state sensibility. RESULTS: Patients with FSs had significantly lower IA and greater trait interoceptive sensibility than healthy controls. ITPE was the strongest predictor of dissociation after controlling for trait anxiety and depression in a regression model. ISPE correlated significantly with FS frequency after controlling for state anxiety. SIGNIFICANCE: Patients with FSs have disturbances in interoceptive processing that predict both dissociative traits reflecting the disrupted integrity of self-representation, and the expression of FSs. These findings provide insight into the pathophysiology of functional neurological disorder, and could lead to novel diagnostic and therapeutic approaches.

Effect of alcohol on the sense of agency in healthy humans.

Even at low to moderate doses, ingestion of the widely used recreational drug alcohol (ethanol) can impact cognitive and emotional processing. Recent studies show that the sense of agency (SoA; ie, the subjective experience of voluntary control over actions) can be modulated by specific pharmacological manipulations. The SoA, as quantified by the intentional binding (IB) paradigm, is enhanced by direct or indirect dopaminergic agonists in patients with Parkinson's disease and by ketamine (an N-methyl-D-aspartate (NMDA) receptor antagonist) in healthy individuals. These findings implicate dopaminergic and glutamatergic neurotransmission in mechanisms underlying SoA. Alcohol has a complex set of actions, including disinhibition of dopaminergic neurotransmission and allosteric antagonism at NMDA receptors. Here, we tested the hypothesis that low to moderate doses of alcohol would enhance SoA, and impact impulsivity and subjective emotional state. We conducted two experiments in 59 healthy male and female social drinkers, who ingested either a placebo "vehicle," or one of two doses of ethanol: 0.4 and 0.6 g/kg. In both experiments, we observed increased SoA/IB at both doses of alcohol exposure, relative to the placebo condition. We found no correlation between the effects of alcohol on IB and on impulsivity or subjective emotional state. Our findings might have implications for social and legal responsibility related to alcohol use, particularly in states prior to overt intoxication. Further studies are necessary to investigate the effects of alcohol and other addictive substances on the SoA.

Spelling Errors and Shouting Capitalization Lead to Additive Penalties to Trustworthiness of Online Health Information: Randomized Experiment With Laypersons.

BACKGROUND: The written format and literacy competence of screen-based texts can interfere with the perceived trustworthiness of health information in online forums, independent of the semantic content. Unlike in professional content, the format in unmoderated forums can regularly hint at incivility, perceived as deliberate rudeness or casual disregard toward the reader, for example, through spelling errors and unnecessary emphatic capitalization of whole words (online shouting). OBJECTIVE: This study aimed to quantify the comparative effects of spelling errors and inappropriate capitalization on ratings of trustworthiness independently of lay insight and to determine whether these changes act synergistically or additively on the ratings. METHODS: In web-based experiments, 301 UK-recruited participants rated 36 randomized short stimulus excerpts (in the format of information from an unmoderated health forum about multiple sclerosis) for trustworthiness using a semantic differential slider. A total of 9 control excerpts were compared with matching error-containing excerpts. Each matching error-containing excerpt included 5 instances of misspelling, or 5 instances of inappropriate capitalization (shouting), or a combination of 5 misspelling plus 5 inappropriate capitalization errors. Data were analyzed in a linear mixed effects model. RESULTS: The mean trustworthiness ratings of the control excerpts ranged from 32.59 to 62.31 (rating scale 0-100). Compared with the control excerpts, excerpts containing only misspellings were rated as being 8.86 points less trustworthy, those containing inappropriate capitalization were rated as 6.41 points less trustworthy, and those containing the combination of misspelling and capitalization were rated as 14.33 points less trustworthy (P<.001 for all). Misspelling and inappropriate capitalization show an additive effect. CONCLUSIONS: Distinct indicators of incivility independently and additively penalize the perceived trustworthiness of online text independently of lay insight, eliciting a medium effect size.

Heart rate variability as a biomarker in health and affective disorders: A perspective on neuroimaging studies.

The dynamic embodiment of psychological processes is evident in the association of health outcomes, behavioural traits and psychological functioning with Heart Rate Variability (HRV). The dominant high-frequency component of HRV is an index of the central neural control of heart rhythm, mediated via the parasympathetic vagus nerve. HRV provides a potential objective measure of action policies for the adaptive and predictive allostatic regulation of homeostasis within the cardiovascular system. In its support, a network of brain regions (referred to as the 'central autonomic network') maps internal state, and controls autonomic responses. This network includes regions of prefrontal cortex, anterior cingulate cortex, insula, amygdala, periaqueductal grey, pons and medulla. Human neuroimaging studies of neural activation and functional connectivity broadly endorse this architecture, and its link with cardiac regulation at rest and dysregulation in clinical states that include affective disorders. In this review, we appraise neuroimaging research and related evidence for HRV as an informative marker of autonomic integration with affect and cognition, taking a perspective on function and organisation. We consider evidence for the utility of HRV as a metric to inform targeted interventions to improve autonomic and affective dysregulation, and suggest research questions for further investigation.

Response time as a proxy of ongoing mental state: A combined fMRI and pupillometry study in Generalized Anxiety Disorder.

In Generalized Anxiety Disorder (GAD), fluctuations in ongoing thoughts (i.e., mind-wandering) often take the form of rigid and intrusive perseverative cognition, such as worry. Here, we sought to characterise the neural correlates of mind-wandering and perseverative cognition, alongside autonomic nervous system indices of central arousal, notably pupil dilation. We implemented a protocol incorporating the dynamic delivery of thought-probes within a functional neuroimaging task. Sixteen individuals with GAD and sixteen matched healthy controls (HC) underwent functional magnetic resonance imaging with concomitant pupillometry. Participants performed a series of low-demand tracking tasks, responding to occasional changes in a target stimulus. Such a task is typically accompanied by self-generated, off-task thinking. Thought-probes were triggered based on an individual's response time (RT) when responding to the change in the target. Subjective reports showed that long RT predicted off-task thinking/mind-wandering. Moreover, long RT and mind-wandering were also associated with larger pupil diameter. This effect was exaggerated in GAD patients during perseverative cognition. Within brain, during both pre-target periods and target events, there were distinct neural correlates for mind-wandering (e.g., anterior cingulate and paracingulate activation at target onset) and perseverative cognition (e.g., opposite patterns of activation in posterior cingulate and cerebellum at target onset in HC and GAD). Results suggest that not only attention systems but also sensory-motor cortices are important during off-task states. Interestingly, changes across the 'default mode network' also tracked fluctuations in pupillary size. Autonomic expression in pupillary changes mirrors brain activation patterns that occur during different forms of repetitive thinking.

Binge drinking is associated with attenuated frontal and parietal activation during successful response inhibition in fearful context.

Binge drinking is associated with increased impulsivity and altered emotional processing. This study investigated, in a group of university students who differed in their level of binge drinking, whether the ability to inhibit a pre-potent response and to delay gratification is disrupted in the presence of emotional context. We further tested whether functional connectivity within intrinsic resting-state networks was associated with alcohol use. Higher incidence of binge drinking was associated with enhanced activation of the lateral occipital cortex, angular gyrus, the left frontal pole during successful response inhibition irrespective of emotional context. This observation suggests a compensatory mechanism. However, higher binge drinking attenuated frontal and parietal activation during successful response inhibition within a fearful context, indicating the selective emotional facilitation of inhibitory control. Similarly, higher binge drinking was associated with attenuated frontopolar activation when choosing a delayed reward over an immediate reward within the fearful, relative to the neutral, context. Resting-state functional data analysis revealed that binge drinking decreased coupling between the right supramarginal gyrus and Ventral Attention Network, indicating alcohol-associated disruption of functional connectivity within brain substrates directing attention. Together, our results suggest that binge drinking makes response inhibition more effortful, yet emotional (more arousing) contexts may mitigate this; disrupted functional connectivity between regions underlying adaptive attentional control, is a likely mechanism underlying these response inhibition effects associated with binge drinking.

Computerized Exposure Therapy for Spider Phobia: Effects of Cardiac Timing and Interoceptive Ability on Subjective and Behavioral Outcomes.

OBJECTIVE: Spider phobia is a common form of anxiety disorder for which exposure therapy is an effective first-line treatment. Motivated by the observed modulation of threat processing by afferent cardiac signals, we tested the hypothesis that interoceptive information concerning cardiovascular arousal can influence the outcomes of computerized exposure therapy for spider phobia. METHOD: Fifty-three normal healthy participants with high spider phobia scores underwent one of the following three modified computerized exposure protocols, defined by the timing of exposure to brief spider stimuli within the cardiac cycle: systole (during afferent baroreceptor firing); diastole (during baroreceptor-quiescent interbeat interval); random (noncontingent on cardiac cycle). Outcomes were judged on phobic and anxiety measures and physiological data (skin conductance). Individuals were also rated on interoceptive accuracy. RESULTS: MANCOVA analysis showed that timing group affected the outcome measures (F(10,80) = 2.405, p = .015) and there was a group interaction with interoception ability (F(15,110) = 1.808, p = .045). Subjective symptom reduction was greatest in the systolic group relative to the other two groups (diastolic (t = 3.115, ptukey = .009); random (t = 2.438, ptukey = .048)), with greatest reductions in those participants with lower interoceptive accuracy. Behavioral aversion reduced more in cardiac-contingent groups than the noncontingent (random) group (diastolic (t = 3.295, ptukey = .005); systolic (t = 2.602, ptukey = .032)). Physiological (skin conductance response) responses remained strongest for spider stimuli presented at cardiac systole. CONCLUSIONS: Interoceptive information influences exposure benefit. The reduction in the subjective expression of fear/phobia is facilitated by "bottom-up" afferent signals, whereas improvement in the behavioral expression is further dependent on "top-down" representation of self-related physiology (heart rhythm). Individual interoceptive differences moderate these effects, suggesting means to personalize therapy.

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis.

Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients' quality of life. Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms. Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients. This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments.

A neurocomputational account of reward and novelty processing and effects of psychostimulants in attention deficit hyperactivity disorder.

Computational models of reinforcement learning have helped dissect discrete components of reward-related function and characterize neurocognitive deficits in psychiatric illnesses. Stimulus novelty biases decision-making, even when unrelated to choice outcome, acting as if possessing intrinsic reward value to guide decisions toward uncertain options. Heightened novelty seeking is characteristic of attention deficit hyperactivity disorder, yet how this influences reward-related decision-making is computationally encoded, or is altered by stimulant medication, is currently uncertain. Here we used an established reinforcement-learning task to model effects of novelty on reward-related behaviour during functional MRI in 30 adults with attention deficit hyperactivity disorder and 30 age-, sex- and IQ-matched control subjects. Each participant was tested on two separate occasions, once ON and once OFF stimulant medication. OFF medication, patients with attention deficit hyperactivity disorder showed significantly impaired task performance (P = 0.027), and greater selection of novel options (P = 0.004). Moreover, persistence in selecting novel options predicted impaired task performance (P = 0.025). These behavioural deficits were accompanied by a significantly lower learning rate (P = 0.011) and heightened novelty signalling within the substantia nigra/ventral tegmental area (family-wise error corrected P < 0.05). Compared to effects in controls, stimulant medication improved attention deficit hyperactivity disorder participants' overall task performance (P = 0.011), increased reward-learning rates (P = 0.046) and enhanced their ability to differentiate optimal from non-optimal novel choices (P = 0.032). It also reduced substantia nigra/ventral tegmental area responses to novelty. Preliminary cross-sectional evidence additionally suggested an association between long-term stimulant treatment and a reduction in the rewarding value of novelty. These data suggest that aberrant substantia nigra/ventral tegmental area novelty processing plays an important role in the suboptimal reward-related decision-making characteristic of attention deficit hyperactivity disorder. Compared to effects in controls, abnormalities in novelty processing and reward-related learning were improved by stimulant medication, suggesting that they may be disorder-specific targets for the pharmacological management of attention deficit hyperactivity disorder symptoms.