Exploring protocol development: Implementing systematic contextual memory to enhance real-time fMRI neurofeedback.

Objective: The goal of this study was to explore the development and implementation of a protocol for real-time fMRI neurofeedback (rtfMRI-nf) and to assess the potential for enhancing the selective brain activation using stimuli from Virtual Reality (VR). In this study we focused on two specific brain regions, supplementary motor area (SMA) and right inferior frontal gyrus (rIFG). Publications by other study groups have suggested impaired function in these specific brain regions in patients with the diagnoses Attention Deficit Hyperactivity Disorder (ADHD) and Tourette's Syndrome (TS). This study explored the development of a protocol to investigate if attention and contextual memory may be used to systematically strengthen the procedure of rtfMRI-nf. Methods: We used open-science software and platforms for rtfMRI-nf and for developing a simulated repetition of the rtfMRI-nf brain training in VR. We conducted seven exploratory tests in which we updated the protocol at each step. During rtfMRI-nf, MRI images are analyzed live while a person is undergoing an MRI scan, and the results are simultaneously shown to the person in the MRI-scanner. By focusing the analysis on specific regions of the brain, this procedure can be used to help the person strengthen conscious control of these regions. The VR simulation of the same experience involved a walk through the hospital toward the MRI scanner where the training sessions were conducted, as well as a subsequent simulated repetition of the MRI training. The VR simulation was a 2D projection of the experience.The seven exploratory tests involved 19 volunteers. Through this exploration, methods for aiming within the brain (e.g. masks/algorithms for coordinate-system control) and calculations for the analyses (e.g. calculations based on connectivity versus activity) were updated by the project team throughout the project. The final procedure involved three initial rounds of rtfMRI-nf for learning brain strategies. Then, the volunteers were provided with VR headsets and given instructions for one week of use. Afterward, a new session with three rounds of rtfMRI-nf was conducted. Results: Through our exploration of the indirect effect parameters - brain region activity (directed oxygenated blood flow), connectivity (degree of correlated activity in different regions), and neurofeedback score - the volunteers tended to increase activity in the reinforced brain regions through our seven tests. Updates of procedures and analyses were always conducted between pilots, and never within. The VR simulated repetition was tested in pilot 7, but the role of the VR contribution in this setting is unclear due to underpowered testing. Conclusion: This proof-of-concept protocol implies how rtfMRI-nf may be used to selectively train two brain regions (SMA and rIFG). The method may likely be adapted to train any given region in the brain, but readers are advised to update and adapt the procedure to experimental needs.

Alterations in inflammatory markers after a 12-week exercise program in individuals with schizophrenia-a randomized controlled trial.

Background: In individuals with schizophrenia, inflammation is associated with depression, somatic comorbidity and reduced quality of life. Physical exercise is known to reduce inflammation in other populations, but we have only limited knowledge in the field of schizophrenia. We assessed inflammatory markers in plasma samples from individuals with schizophrenia participating in an exercise intervention randomized controlled trial. We hypothesized that (i) physical exercise would reduce levels of inflammatory markers and (ii) elevated inflammatory status at baseline would be associated with improvement in cardiorespiratory fitness (CRF) following intervention. Method: Eighty-two individuals with schizophrenia were randomized to a 12-week intervention of either high-intensity interval training (HIIT, n = 43) or active video gaming (AVG, n = 39). Participants were assessed at baseline, post intervention and four months later. The associations between exercise and the inflammatory markers soluble urokinase plasminogen activator receptor, c-reactive protein, tumor necrosis factor (TNF), soluble TNF receptor 1 and interleukin 6 (IL-6) were estimated using linear mixed effect models for repeated measures. For estimating associations between baseline inflammation and change in CRF, we used linear regression models. Results: Our main findings were (i) TNF and IL-6 increased during the intervention period for both groups. Other inflammatory markers did not change during the exercise intervention period; (ii) baseline inflammatory status did not influence change in CRF during intervention, except for a positive association between baseline IL-6 levels and improvements of CRF to post intervention for both groups. Conclusion: In our study, HIIT and AVG for 12-weeks had no reducing effect on inflammatory markers. Patients with high baseline IL-6 levels had a positive change in CRF during intervention. In order to increase our knowledge regarding association between inflammatory markers and exercise in individuals with schizophrenia, larger studies with more frequent and longer exercise bout duration are warranted.

Dialectical behavioral therapy-based group treatment versus treatment as usual for adults with attention-deficit hyperactivity disorder: a multicenter randomized controlled trial.

BACKGROUND: Studies on structured skills training groups have indicated beneficial, although still inconclusive, effects on core symptoms of ADHD in adults. This trial examined effects of Dialectical Behavioral Therapy-based group treatment (DBT-bGT) on the broader and clinically relevant executive functioning and emotional regulation in adults with ADHD. METHODS: In a multicenter randomized controlled trial, adult patients with ADHD were randomly assigned to receive either weekly DBT-bGT or treatment as usual (TAU) during 14 weeks. Subsequently, participants receiving TAU were offered DBT-bGT. All were reassessed six months after ended DBT-bGT. Primary outcomes were the Behavior Rating Inventory of Executive Function (BRIEF-A) and the Difficulties in Emotion Regulation Scale (DERS). Secondary outcomes included self-reported ADHD-symptoms, depressive and anxiety symptoms, and quality of life. We used independent samples t- tests to compare the mean difference of change from pre- to post-treatment between the two treatment groups, and univariate linear models adjusting for differences between sites. RESULTS: In total, 121 participants (68 females), mean age 37 years, from seven outpatient clinics were included, of whom 104 (86%) completed the 14-week trial. Entering the study, 63% used medication for ADHD. Compared to TAU (n = 54), patients initially completing DBT-bGT (n = 50) had a significantly larger mean reduction on the BRIEF-A (-12.8 versus -0.37, P = 0.005, effect size 0.64), and all secondary outcomes, except for symptoms of anxiety. All significant improvements persisted at 6 months follow-up. Change on DERS did not differ significantly between the groups after 14 weeks, but scores continued to decrease between end of group-treatment and follow-up. CONCLUSIONS: This DBT-bGT was superior to TAU in reducing executive dysfunction, core symptoms of ADHD and in improving quality of life in adults with ADHD. Improvements sustained six months after ended treatment. The feasibility and results of this study provide evidence for this group treatment as a suitable non-pharmacological treatment option for adults with ADHD in ordinary clinical settings. TRIAL REGISTRATIONS: The study was pre-registered in the ISRCTN registry (identification number ISRCTN30469893, date February 19th 2016) and at the ClinicalTrials.gov (ID: NCT02685254, date February 18th 2016).

Childhood trauma in adults with ADHD is associated with comorbid anxiety disorders and functional impairment.

BACKGROUND: Child and adolescent psychological trauma exposure is associated with psychopathology in the adult population in general, but literature on childhood trauma (CT) in adults with ADHD is scarce. AIMS: To determine the prevalence of CT among adult patients with ADHD, and whether a history of CT implies different adult outcomes of psychiatric comorbidities, and functional impairment than without. METHOD: Previously unmedicated adult outpatients with ADHD (n = 250, median age 32 years) entered the study. Participants were diagnosed with ADHD using the Diagnostic Interview for ADHD in Adults, second edition (DIVA 2.0), and were assessed by historical data, validated questionnaires, and structured clinical interviews for CT and mental disorders including post-traumatic stress disorder (PTSD) and functional impairment. Analyses compared ADHD patients with and without CT. RESULTS: Prevalence of CT was 44%. Of those with PTSD (n = 21), many had CT (85%, p < 0.001). In binary logistic regression analyses, CT was linked to an increased likelihood of concomitant panic disorder (unadjusted odds ratio, OR = 3.0, p < 0.001, and adjusted OR = 2.7, p < 0.01) and any anxiety disorders and two or more comorbid psychiatric disorders (adjusted OR = 1.9, p < 0.05 and OR = 1.7, p < 0.05, respectively), and was associated with significant functional impairment. CONCLUSIONS: These findings suggest that awareness of child and adolescent trauma is clinically relevant among young to middle-aged adult ADHD patients, and implications for earlier detection of CT and treatment warrant further studies.

Exploring low grade inflammation by soluble urokinase plasminogen activator receptor levels in schizophrenia: a sex-dependent association with depressive symptoms.

BACKGROUND: There is evidence of increased low grade inflammation (LGI) in schizophrenia patients. However, the inter-individual variation is large and the association with demographic, somatic and psychiatric factors remains unclear. Our aim was to explore whether levels of the novel LGI marker soluble urokinase plasminogen activator receptor (suPAR) were associated with clinical factors in schizophrenia and if such associations were sex-dependent. METHOD: In this observational study a total of 187 participants with schizophrenia (108 males, 79 females) underwent physical examination and assessment with clinical interviews (Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Alcohol Use Disorder Identification Test (AUDIT), and Drug Use Disorder Identification Test (DUDIT)). Blood levels of suPAR, glucose, lipids, and high sensitivity C-reactive protein (hsCRP) were determined and body mass index (BMI) calculated. Multivariable linear regression analyses were used adjusting for confounders, and sex interaction tested in significant variables. RESULTS: Adjusting for sex, age, current tobacco smoking and BMI, we found that levels of hsCRP and depressive symptoms (CDSS) were positively associated with levels of suPAR (p < 0.001). The association between suPAR and CDSS score was significant in females (p < 0.001) but not in males. Immune activation measured by hsCRP was not associated with depressive symptoms after adjusting for BMI. CONCLUSION: Our findings indicate that increased suPAR levels are associated with depressive symptoms in females with schizophrenia, suggesting aberrant immune activation in this subgroup. Our results warrant further studies, including longitudinal follow-up of suPAR levels in schizophrenia and experimental studies of mechanisms.

Impact of methylphenidate on sleep problems in adults with ADHD: a pilot polysomnography study.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is associated with disrupted sleep and circadian rhythm. Medication for ADHD may have side effects aggravating sleep-disturbances, however beneficial effects on ADHD may contribute to improve sleep. AIMS: This pilot study aims to examine outcomes of first time stimulant treatment on objective and subjective sleep characteristics, and psychiatric symptoms, in adult ADHD patients with pretreatment sleep problems, but without any primary sleep disorder. METHODS: In total, 9 previously unmedicated adult ADHD subjects who reported pretreatment sleep problems, completed polysomnography (PSG) and questionnaires on subjective sleep disturbances and psychiatric symptoms. Data was collected before and after 6 weeks on first time medication with immediate-release methylphenidate (MPH-IR), mean daily dose 43 mg. RESULTS: Subjects on-medication showed an increased percentage of Stage 2 sleep compared to their non-treated baseline (46.6% versus 55.2%, p = .011). Otherwise, there were no significant changes in PSG variables. There were no firm changes in daytime sleepiness or symptoms of sleep disturbances. CONCLUSIONS: These findings should be interpreted cautiously given the open-label design and small sample size, and should be examined in larger studies with more rigorous study designs.

Individual Variability in Reaction Time and Prediction of Clinical Response to Methylphenidate in Adult ADHD: A Prospective Open Label Study Using Conners' Continuous Performance Test II.

Objective: The aim of this study was to examine whether reaction time parameters in adult patients with ADHD could predict their response to methylphenidate (MPH). Method: Previously unmedicated patients (N = 123) were administered the Conners' Continuous Performance Test II (CPT II) at baseline and after 6 weeks of treatment with immediate-release MPH. In addition to traditional CPT measures, we extracted intraindividual raw data and analyzed time series using linear and nonlinear mathematical models. Results: Clinical responders, assessed with the Clinical Global Impression-Improvement scale, showed significant normalization of target failures, reduced variability and skewness, and increased complexity of reaction time series after 6 weeks of treatment, while nonresponders showed no significant changes. Prior to treatment, responders had significantly higher variability and skewness, combined with lower complexity, compared with nonresponders. Conclusion: These results show that the CPT test is useful in the evaluation of treatment response to MPH.

Increased default-mode variability is related to reduced task-performance and is evident in adults with ADHD.

Insufficient suppression and connectivity of the default mode network (DMN) is a potential mediator of cognitive dysfunctions across various disorders, including attention deficit/hyperactivity disorder (ADHD). However, it remains unclear if alterations in sustained DMN suppression, variability and connectivity during prolonged cognitive engagement are implicated in adult ADHD pathophysiology, and to which degree methylphenidate (MPH) remediates any DMN abnormalities. This randomized, double-blinded, placebo-controlled, cross-over clinical trial of MPH (clinicaltrials.gov/ct2/show/NCT01831622) explored large-scale brain network dynamics in 20 adults with ADHD on and off MPH, compared to 27 healthy controls, while performing a reward based decision-making task. DMN task-related activation, variability, and connectivity were estimated and compared between groups and conditions using independent component analysis, dual regression, and Bayesian linear mixed models. The results show that the DMN exhibited more variable activation patterns in unmedicated patients compared to healthy controls. Group differences in functional connectivity both between and within functional networks were evident. Further, functional connectivity between and within attention and DMN networks was sensitive both to task performance and case-control status. MPH altered within-network connectivity of the DMN and visual networks, but not between-network connectivity or temporal variability. This study thus provides novel fMRI evidence of reduced sustained DMN suppression in adults with ADHD during value-based decision-making, a pattern that was not alleviated by MPH. We infer from multiple analytical approaches further support to the default mode interference hypothesis, in that higher DMN activation variability is evident in adult ADHD and associated with lower task performance.

A candidate gene investigation of methylphenidate response in adult attention-deficit/hyperactivity disorder patients: results from a naturalistic study.

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood onset neuropsychiatric disorder with a complex and heterogeneous symptomatology. Persistence of ADHD symptoms into adulthood is common. Methylphenidate (MPH) is a widely prescribed stimulant compound that may be effective against ADHD symptoms in children and adults. However, MPH does not exert satisfactory effect in all patients. Several genetic variants have been proposed to predict either treatment response or adverse effects of stimulants. We conducted a literature search to identify previously reported variants associated with MPH response and additional variants that were biologically plausible candidates for MPH response. The response to MPH was assessed by the treating clinicians in 564 adult ADHD patients and 20 genetic variants were successfully genotyped. Logistic regression was used to test for association between these polymorphisms and treatment response. Nominal associations (p < 0.05) were meta-analysed with published data from previous comparable studies. In our analyses, rs1800544 in the ADRA2A gene was associated with MPH response at a nominal significance level (OR 0.560, 95 % CI 0.329-0.953, p = 0.033). However, this finding was not affirmed in the meta-analysis. No genetic variants revealed significant associations after correction for multiple testing (p < 0.00125). Our results suggest that none of the studied variants are strong predictors of MPH response in adult ADHD as judged by clinician ratings, potentially except for rs1800544. Consequently, pharmacogenetic testing in routine clinical care is not supported by our analyses. Further studies on the pharmacogenetics of adult ADHD are warranted.

Long-Term Pharmacotherapy of Adults With Attention Deficit Hyperactivity Disorder: A Literature Review and Clinical Study.

This MiniReview reports and discusses the main findings of the author's thesis including a literature study of long-term pharmacological treatment of adults with attention deficit hyperactivity disorder (ADHD), and a clinical study of 1-year medication. Electronic databases were systematically reviewed for original studies on pharmacotherapy of the defined duration, 24 weeks or more. Although few trials were found with limitations such as excluding comorbidities, treatment with stimulants and atomoxetine was reported tolerated and effective compared to non-treatment. The clinical study of the thesis was conducted on 250 medication-naïve patients with ADHD referred to a specialized outpatient clinic. Comorbid psychiatric disorders were diagnosed among 75% of the patients. About 56% had not completed secondary school, and 51% had been unable to work the preceding year. Persisting inattentive symptoms and comorbid mental disorders in adulthood were related to long-term work disability. In the prospective observational study of the thesis, patients were treated with methylphenidate as first-line drug and atomoxetine or dexamphetamine as second-line drugs, according to current treatment guidelines. At 12-month follow-up, 232 patients completed evaluation and 70% persisted on medication. About 80% of these used methylphenidate. Sustained improvement of symptoms and functioning was related to continued medication. Comorbid mental disorders and side effects were related to lower effectiveness and adherence, and 12% stopped medication due to side effects. Summing up the MiniReview, treatment with stimulants and atomoxetine of adults with ADHD has long-term beneficial effects and is tolerated but more longitudinal studies should be performed. With stated limitations, the findings of the thesis should contribute to a relevant guidance for clinical practice.

Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): an open-label prospective study of time in treatment, dose, side-effects and comorbidity.

How to generalize from randomized placebo controlled trials of ADHD drug treatment in adults to 'real-world' clinical practice is intriguing. This open-labeled prospective observational study examined the effectiveness of long-term stimulant and non-stimulant medication in adult ADHD including dose, side-effects and comorbidity in a clinical setting. A specialized ADHD outpatient clinic gave previously non-medicated adults (n=250) with ADHD methylphenidate as first-line drug according to current guidelines. Patients who were non-tolerant or experiencing low efficacy were switched to amphetamine or atomoxetine. Primary outcomes were changes of ADHD-symptoms evaluated with the Adult ADHD Self-Report Scale (ASRS) and overall severity by the Global Assessment of Functioning (GAF). Secondary outcomes were measures of mental distress, and response on the Clinical-Global-Impressions-Improvement Scale. Data at baseline and follow-ups were compared in longitudinal mixed model analyses for time on-medication, dosage, comorbidity, and side-effects. As results, 232 patients (93%) completed examination at the 12 month endpoint, and 163 (70%) remained on medication. Compared with the patients who discontinued medication, those still on medication had greater percentage reduction in ASRS-scores (median 39%, versus 13%, P<0.001) and greater improvement of GAF (median 20% versus 4%, P<0.001) and secondary outcomes. Continued medication and higher cumulated doses showed significant associations to sustained improvement. Conversely, psychiatric comorbidity and side-effects were related to lower effectiveness and more frequent termination of medication. Taken together, one-year treatment with stimulants or atomoxetine was associated with a clinically significant reduction in ADHD symptoms and mental distress, and improvement of measured function. No serious adverse events were observed.

Childhood and persistent ADHD symptoms associated with educational failure and long-term occupational disability in adult ADHD.

Few studies have examined the impact of childhood attention deficit hyperactivity disorder (ADHD) symptoms on adult ADHD functional outcomes. To address this issue dimensionally, ADHD symptoms in childhood and adulthood and their relation to educational deficits and work disability are studied in a clinical sample of adult patients with previously untreated ADHD. About 250 adults diagnosed systematically with ADHD according to DSM-IV were prospectively recruited. Primary outcomes were high school dropout and being out of the work last year. Childhood ADHD symptoms, sex differences, comorbidities of other mental disorders, and adult ADHD symptoms were examined by historical data, clinician interviews, and questionnaires. High levels of ADHD symptom severity in childhood were related to dropping out of high school [odds ratio (OR) = 3.0], as were higher numbers of hyperactive-impulsive symptoms in childhood. Significantly, more women than men were long-term work disabled (OR = 2.0). After adjusting for age and gender, persisting high levels of ADHD inattention symptoms in adulthood (OR = 2.5), number of comorbid disorders, and particularly anxiety disorders were significantly related to long-term work disability. Childhood hyperactive-impulsive symptoms and overall severity of childhood ADHD symptoms were associated with high school dropout rates; however, persisting ADHD inattention symptoms and comorbid mental disorders in adulthood were more correlated to occupational impairment. These findings underline proposals for studies on early recognition and interventions for ADHD and psychiatric comorbidity. They further suggest that inattentive symptoms be a focus of adult ADHD treatment and that workplace interventions be considered to prevent long-term work disability.

Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies.

Attention-deficit/hyperactivity disorder (ADHD) is a common disorder of childhood that often persists into adulthood. Although stimulant medications are recommended as the first-line treatment for ADHD because of their documented short-term effects in children and adults, less is known about their effects on long-term outcome in adults. Here we review the long-term efficacy and safety of the stimulant drugs methylphenidate and amphetamine, as well as the related compound atomoxetine. We performed a systematic review to identify direct and indirect effects of stimulant therapy on long-term outcome in adults. Five randomized controlled trials (RCTs), and 10 open-label extension studies of initial short-term RCTs, with total follow-up of at least 24weeks, were identified. All these RCTs found that medication was significantly more efficacious than placebo in treating ADHD in adults, and the extension studies showed that this favorable effect of medication was maintained during the open-label follow-up period. However, since the maximum duration of these pharmacological trials was 4years, we also reviewed 18 defined naturalistic longitudinal and cross-sectional studies, to provide more information about longer term functional outcomes, side effects and complications. These observational studies also showed positive correlations between early recognition of the disorder, stimulant treatment during childhood and favorable long-term outcome in adult ADHD patients. In conclusion, stimulant therapy of ADHD has long-term beneficial effects and is well tolerated. However, more longitudinal studies of long duration should be performed. In addition, the ethical issues involved in performing double blind RCTs of many years duration should be further explored.