To Örebro University

RATIONALE: Cognitive control is crucial for optimal daily functioning and for emotional well-being. Cognitive control has been shown to be modified by experimental manipulations under widely differing experimental conditions, including cognitive training, and pharmacological intervention mainly probing catecholaminergic systems with little focus on the serotonergic system.

OBJECTIVES: To explore the role of serotonin on cognitive control in emotional and non-emotional settings.

METHODS: Behavioral, electrodermal and prefrontal activity measures were evaluated to compare the effects of single-session task repetition and single-dose serotonergic intervention with escitalopram on cognitive control in healthy participants, using cognitive and emotional Stroop tasks.

RESULTS: For cognitive Stroop, task repetition improved performance both 'on-line' within an ongoing task and 'off-line' after a four-hour delay, and escitalopram had no additional effects on this. In emotional Stroop, escitalopram enhanced the practice-related performance gain, starting from the second stimulus of each block. Compared to placebo, escitalopram also significantly reduced overall rate of premature responses. Regarding brain activation, escitalopram significantly reduced prefrontal activity during cognitive and even more so during emotional Stroop task. Lastly, electrodermal response showed significant habituation during cognitive but not emotional Stroop, in an effect that was not significantly modified by escitalopram.

CONCLUSIONS: Cognitive control in emotional and non-emotional settings may respond differently to behavioral and pharmacological manipulations. Escitalopram may selectively improve cognitive control in an emotional setting compared to cognitive control in non-emotional settings.

Adult ADHD is associated with various health challenges and reduced quality of life. Current guidelines recommend multimodal treatment, and physical exercise has emerged as a promising non-pharmacological alternative, although evidence from randomized controlled trials remains limited. In this randomized controlled trial, we aimed to assess the clinical effectiveness of physical exercise as an add-on treatment for adults with ADHD compared to treatment as usual. The trial included adults with a clinically confirmed diagnosis of ADHD was conducted at one Psychiatric clinic in Sweden. Participants were randomly assigned (2:1, no stratification) using an electronic case-report platform, to either physical exercise (the protocolized 12-week intervention START) or treatment as usual (local community care). Primary outcome was the ASRS-v1.1 Symptom checklist at 12 weeks after inclusion. The analysis followed a modified intention-to-treat principle, excluding participants who provided no data beyond baseline. Of the 63 participants enrolled, 43 were randomly assigned to START physical exercise intervention and 20 to treatment as usual. After accounting for withdrawals (n = 11) and loss to follow up (n = 11), the primary analysis included data from 41 participants (30 assigned to START intervention and 11 to treatment as usual). The START intervention resulted in improved ADHD symptoms after 12 weeks, as measured by ASRS-v1.1. Symptom improvement differed significantly between groups (mean difference -6.98, 95% CI: -12.30 to -1.65; p = 0.012) with an effect size of 0.93 favoring the intervention group. No serious adverse events were reported. The results suggest that physical exercise may be a feasible, safe and clinically meaningful complement to standard care for adults with ADHD. However, the findings should be interpreted in the light of potential confounders and methodological limitations. This trial is registered with the ClinicalTrials.gov. Date of registration: 2021-05-14.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05049239, identifier NCT05049239.

INTRODUCTION AND OBJECTIVE: The cholinergic system has broad implications for affective and cognitive processes, which makes it pertinent for the psychopathology and treatment of mental disorders. Questions concerning its role in schizophrenia, a chronic disorder characterized by psychosis, emotional blunting and cognitive deficits, have been made particularly relevant due to the recent Food and Drug Administration (FDA) approval of a muscarinic agonist as an antipsychotic agent. The present paper details the protocol for a scoping review that will map models, evidence and research gaps concerning the role of the cholinergic system in the positive, negative and cognitive domains implicated in the psychopathology of schizophrenia.

METHODS AND ANALYSIS: The scoping review will be conducted according to JBI (formerly the Joanna Briggs institute) methodology, using articles from the following databases: PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials and PsycInfo. Two independent reviewers will screen the articles using title and abstract, after which full text-analysis will determine inclusion. Only published original peer-reviewed English-language studies from the last 20 years that pertain to the review objective will be included. Clinical studies will be assessed for methodological quality and risk of bias. The results, which the reviewers will extract independently of each other using a data extraction tool, will be presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocol Extension for Scoping Reviews (PRISMA-ScR).

DISCUSSION: Clarifying the research gaps in the field can indicate where future pre-clinical and clinical studies and systematic reviews can be worthwhile, and the risk of bias assessment aids in this by stratifying the included clinical trials according to quality. However, the language and publication date restrictions risk excluding relevant studies, which can introduce bias.

Psychiatric disorders are categorized on the basis of presence and absence of diagnostic criteria using classification systems such as the international classification of diseases (ICD) and the diagnostic and statistical manual for mental disorders (DSM). The research domain criteria (RDoC) initiative provides an alternative dimensional framework for conceptualizing mental disorders. In the present paper, we studied neural and behavioral effects of central stimulant (CS) medication in adults with attention deficit hyperactivity disorder (ADHD) and healthy controls using categorical and dimensional stratifications. AX-Continuous Performance Task (AX-CPT) was utilized for the later purpose, and participants were classified as "reactive" or "proactive" based on their baseline proactive behavioral index (PBI). Out of the 65 individuals who participated (33 healthy controls and 32 patients with ADHD), 53 were included in the final analysis that consisted of 31 healthy controls and 22 ADHD patients. For the dimensional stratification, a median split of PBI scores divided participants into "reactive" and "proactive" groups irrespective of whether they had ADHD or not. Participants performed AX-CPT in conjunction with functional magnetic resonance imaging (fMRI) before and after CS medication. We found no significant within or between group CS effect when participants were categorically assigned as healthy controls and ADHD patients. For the dimensional stratification, however, CS selectively increased activation in frontoparietal cognitive areas and induced a shift towards proactive control mode in the reactive group, without significantly affecting the proactive group. In conclusion, the neural and behavioral effects of CS were more clear-cut when participants were stratified into dimensional groups rather than diagnostic categories.

Background: Emotional dysregulation affects up to two-thirds of adult patients with attention-deficit/hyperactivity disorder (ADHD) and is increasingly seen as a core ADHD symptom that is clinically associated with greater functional impairment and psychiatric comorbidity. We sought to investigate emotional dysregulation in ADHD and explored its neural underpinnings.

Methods: We studied emotion induction and regulation in a clinical cohort of adult patients with ADHD before and after a stimulant challenge. We compared patients with age- and gender-matched healthy controls using behavioural, structural, and functional measures. We hypothesized that patients would demonstrate aberrant emotion processing compared with healthy controls, and sought to find whether this could be normalized by stimulant medication.

Results: Behaviourally, the ADHD group showed reduced emotion induction and regulation capacity. Brain imaging revealed abberant activation and deactivation patterns during emotion regulation, lower grey-matter volume in limbic and paralimbic areas, and greater grey-matter volume in visual and cerebellar areas, compared with healthy controls. The behavioural and functional deficits seen in emotion induction and regulation in the ADHD group were not normalized by stimulant medication.

Conclusion: Patients with ADHD may have impaired emotion induction and emotion regulation capacity, but these deficits are not reversed by stimulant medication. These results have important clinical implications when assessing which aspects of emotional dysregulation are relevant for patients and if and how traditional ADHD pharmacotherapy affects emotion induction and emotion regulation.

RATIONALE: Availability of the dopamine and noradrenaline precursor tyrosine is critical for normal functioning, and deficit in tyrosine transport across cell membrane and the blood-brain barrier has been reported in bipolar disorder and schizophrenia. Clozapine and lithium are two psychoactive agents used to treat psychosis, mood disorders and suicidal behavior, but their mechanism of action remains largely unknown.

OBJECTIVE: To characterize immediate and delayed differences in tyrosine uptake between healthy controls (HC) and bipolar patients (BP) and see if these differences could be normalized by either clozapine, lithium or both. A second objective was to see if clozapine and lithium have additive, antagonistic or synergistic effects in this.

METHOD: Fibroblasts from five HC and five BP were incubated for 5 min or 6 h with clozapine, lithium, or combination of both. Radioactive labelled tyrosine was used to quantify tyrosine membrane transport.

RESULTS: There was significantly reduced tyrosine uptake at baseline in BP compared to HC, a deficit that grew with increasing incubation time. Clozapine selectively increased tyrosine uptake in BP and abolished the deficit seen under baseline conditions, while lithium had no such effect. Combination treatment with clozapine and lithium was less effective than when clozapine was used alone.

CONCLUSIONS: There was significant deficit in tyrosine transport in BP compared to HC that was reversed by clozapine but not lithium. Clozapine was more effective when used alone than when added together with lithium. Potential clinical implications of this will be discussed.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is associated with sedentary lifestyle, low quality of life and low physical fitness. Studies in children with ADHD have shown that regular physical exercise can help reduce core ADHD symptoms, but evidence for this is lacking in adults. Although guidelines recommend multi-modal treatment, central stimulants (CS) remain the mainstay of treatment. CS are effective in the short-term, but their long-term efficacy remains to be established. There is thus huge unmet need for developing non-pharmacological treatment options, and for well-designed randomized controlled trials (RCTs).

OBJECTIVE: The study aimed to test the feasibility and tolerability of structured moderate-intensity 12-week physical exercise program for adults with ADHD, as a prelude to an adequately powered RCT which includes long-term follow-up.

MATERIALS AND METHODS: Fourteen adults with ADHD were recruited, 9 randomized to an intervention group and 5 to a control group. The intervention group received physiotherapist-led 50-minute mixed exercise program, three times a week for 12 weeks, and the control group treatment as usual. Participants were assessed at baseline and after 6 and 12 weeks using clinical and physical evaluations, self-rating questionnaires, and functional magnetic resonance imaging (fMRI) together with paradigms that tested attention, impulsivity and emotion regulation.

RESULTS: Three participants (21%) dropped out shortly after inclusion before receiving any intervention, while roughly 80% completed the intervention according to protocol. One participant from the intervention group participated in less than 60% of treatment sessions, and one who had done baseline fMRI was unwilling to do post-intervention imaging. Four participants in the intervention group (67%) reported increased stress in prioritizing the intervention due to time-management difficulties. Overall, consistent trends were observed that indicated the feasibility and potential benefits of the intervention on core ADHD symptoms, quality of life, body awareness, sleep and cognitive functioning.

CONCLUSION: Physiotherapist-led twelve-week regular physical exercise is a feasible and potentially beneficial intervention for adults with ADHD. There was a 20% drop-out initially and 67% of those who completed the intervention reported stress with time management difficulties due to participation. A third arm was thus added to the planned RCT where cognitive intervention administered by an occupational therapist will be given together with physical exercise. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT05049239.

Schizophrenia (SCZ) is among the world’s top ten causes of long-term disability (World Health Organization, 2004). The major symptoms of SCZ include hallucinations, delusions, affective flattening, and cognitive impairment, and their treatment with antipsychotic medications is far from optimal.Creative and body awareness training (dance/movement therapy, body psychotherapy) and physical training (aerobic and strength training) improve SCZ symptoms (e.g Martin et al., 2016, 2017; Girdler et al., 2019; Millman et a., 2021). In our novel intervention, we bring together creativity and self-awareness with physical training. The 12-week 24-session intervention with 30 participants (Figure 1) includes components like visualization, cardio and strength training, and social interaction. We will measure the impact with standardized clinical questionnaires, EEG-fNIRS, motion capture, and cognitive, affective, and physical tests. We expect our intervention to improve the quality of life and negative symptoms of SCZ by balancing the brain functions and bodily state related to self-awareness, social interaction, and physical fitness. In my talk, I will cover brain dysfunctions related to self-awareness in SCZ (Ferri et al., 2012; Ebisch et al., 2013) and describe the scientific rationale for each component included in our novel intervention (e.g. Lee et al., 2015; Firth et al., 2017).

Background: Schizophrenia is among the world’s top 10 causes of long-term disability with symptoms that lead to major problems in social and occupational functioning, and in self-care. Therefore, it is important to investigate the efficacy of complementary treatment options for conventionally used antipsychotic medication, such as physical training, and psychosocial interventions.

Objective: To combine aerobic and strength training with cognitive, emotional and social stimulation in one intervention for people with schizophrenia and test the feasibility and effects of this intervention.

Methods: The study is a mixed-method randomized controlled trial to evaluate the effects of a 12-week intervention for adults with schizophrenia. The treatment group (30 participants) will receive the intervention in addition to standard care and the control group (30 participants) only standard care. The intervention consists of 24 biweekly sessions with a duration of 60 min. The pre-test (weeks from 4 to 2 prior to the intervention) and post-test (week 12) include clinical measure (PANSS), quality of life, social performance, movement quantity, brain function and eye tracking measures. In addition, a treatment subgroup of 12–15 participants and their family member or other next of kin will complete a qualitative interview as a part of their post-test. Two follow-up tests, including clinical, quality of life, brain function and eye tracking will be made at 6 and 12 months from the completion of the intervention to both study groups. The primary outcome is change in negative symptoms. Secondary outcome measures include general and positive symptoms, quality of life, social performance, movement quantity, brain function and eye tracking. Explorative outcome includes patient and family member or other next of kin interview.

Results: Pilot data was collected by June 2023 and the main data collection will begin in September 2023. The final follow-up is anticipated to be completed by 2026.

Conclusion: The InMotion study will provide new knowledge on the feasibility, efficacy, and experiences of a novel intervention for adults with schizophrenia. The hypothesis is that regular participation in the intervention will reduce clinical symptoms, normalize physiological measures such as brain activation, and contribute to new active habits for the participants.