MINDflex Training for Cognitive Flexibility in Chronic Pain: A Randomized, Controlled Cross-Over Trial.

Impairments in executive functioning are prevalent in chronic pain conditions, with cognitive inflexibility being the most frequently reported. The current randomized, cross-over trial, piloted a computerized cognitive training (CCT) program based on Relational Frame Theory, targeting improvement in cognitive flexibility. At baseline, 73 chronic pain patients completed testing on pre-selected outcomes of executive functioning, alongside IQ measures. When tested three times over the course of 5 months, there was a drop-out rate of 40% at the third time point, leaving 44 patients who had data at all time points. The results showed that there was a substantial learning effect from the MINDFLEX training and a substantial time-dependent improvement on the primary outcomes of increased flexibility, but that this could not be tied to active training. In conclusion, this small study indicated a learning effect as well as improvement on primary outcomes. Based on the current results, a larger trial with improved feasibility of training is warranted.

Attentional bias modification is associated with fMRI response toward negative stimuli in individuals with residual depression: a randomized controlled trial

Background: Attentional bias modification (ABM) may lead to more adaptive emotion perception and emotion regulation. Understanding the neural basis of these effects may lead to greater precision for the development of future treatments. Task-related functional MRI (fMRI) after ABM training has not been investigated in depression so far. The main aim of this randomized controlled trial was to explore differences in brain activity after ABM training, in response to emotional stimuli. Methods: A total of 134 people with previous depression, who had been treated for depression and had various degrees of residual symptoms, were randomized to 14 days of active ABM or a closely matched placebo training, followed by an fMRI emotion regulation task. The training procedure was a classical dot­probe task with emotional face stimuli. In the active ABM condition, the probes replaced the more positively valenced face of a given pair. As participants implicitly learned to predict the probe location, this would be likely to induce a more positive attentional bias. The placebo condition was identical, except for the contingency of the probe, which appeared equally behind positive and negative stimuli. We compared depression symptoms and subjective ratings of perceived negativity during fMRI between the training groups. We explored brain activation in predefined regions of interest and across the whole brain. We explored activation in areas associated with changes in attentional bias and degree of depression. Results: Compared with the placebo group, the ABM group showed reduced activation in the amygdala and the anterior cingulate cortex when passively viewing negative images. We found no group differences in predefined regions of interest associated with emotion regulation strategies. Response in the temporal cortices was associated with the degree of change in attentional bias and the degree of depressive symptoms in ABM versus placebo. Limitations: These findings should be replicated in other samples of patients with depression, and in studies using fMRI designs that allow analyses of within-group variability from baseline to follow-up. Conclusion: Attentional bias modification training has an effect on brain function in the circuitry associated with emotional appraisal and the generation of affective states. Clinicaltrials.gov identifier: NCT02931487

Within-Network Connectivity in the Salience Network After Attention Bias Modification Training in Residual Depression: Report From a Preregistered Clinical Trial.

Alterations in resting state networks (RSNs) are associated with emotional- and attentional control difficulties in depressed individuals. Attentional bias modification (ABM) training may lead to more adaptive emotional processing in depression, but little is known about the neural underpinnings associated with ABM. In the current study a sample of 134 previously depressed individuals were randomized into 14 days of computerized ABM- or a closely matched placebo training regime followed by a resting state magnetic resonance imaging (MRI) scan. Using independent component analysis (ICA) we examined within-network connectivity in three major RSN's, the default mode network (DMN), the salience network (SN) and the central executive network (CEN) after 2 weeks of ABM training. We found a significant difference between the training groups within the SN, but no difference within the DMN or CEN. Moreover, a significant symptom improvement was observed in the ABM group after training. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02931487.

Fatigue and cognition: Pupillary responses to problem-solving in early multiple sclerosis patients.

INTRODUCTION: In early multiple sclerosis (MS) patients, cognitive changes and fatigue are frequent and troublesome symptoms, probably related to both structural and functional brain changes. Whether there is a common cause of these symptoms in MS is unknown. In theory, an altered regulation of central neuropeptides can lead to changes in regulation of autonomic function, cognitive difficulties, and fatigue. Direct measurements of central neuropeptides are difficult to perform, but measurements of the eye pupil can be used as a reliable proxy of function. METHODS: This study assesses pupil size during problem-solving in early MS patients versus controls. A difference in pupil size to a cognitive challenge could signal altered activity within the autonomic system because of early functional brain changes associated with cognitive load. We recruited MS patients (mean disease duration: 2.6 years, N = 41) and age-matched healthy controls (N = 43) without eye pathology. Neurological impairment, magnetic resonance imaging, visual evoked potentials, depression, and fatigue were assessed in all of the patients. In both groups, we assessed processing speed and retinal imaging. Pupil size was recorded with an eye-tracker during playback of multiplication tasks. RESULTS: Both groups performed well on the cognitive test. The groups showed similar pupillary responses with a mean of 0.55 mm dilation in patients and 0.54 mm dilation in controls for all the tasks collapsed together. However, controls (N = 9) with low cognitive scores (LCS) had an increased pupillary response to cognitive tasks, whereas LCS MS patients (N = 6) did not (p < .05). There was a tendency toward a smaller pupillary response in patients with fatigue. CONCLUSIONS: This is the first study to investigate pupillary responses to cognitive tasks in MS patients. Our results suggest that MS-related changes in cognition and fatigue may be associated with changes in arousal and the autonomic regulation of task-related pupillary responses. This supports the theory of a link between cognition and fatigue in MS.

Dysfunctional Metacognitive Beliefs Are Associated with Decreased Executive Control.

Dysfunctional metacognitive beliefs ("metacognitions") and executive control are important factors in mental disorders such as depression and anxiety, but the relationship between these concepts has not been studied systematically. We examined whether there is an association between metacognitions and executive control and hypothesized that decreased executive control statistically predicts increased levels of metacognitions. Two hundred and ninety-nine individuals recruited from the general population and outpatient psychiatric clinics completed the Metacognitions Questionnaire-30 and three subtests from the Cambridge Neuropsychological Test Automated Battery corresponding to the three-component model of executive functions. Controlling for current depression and anxiety symptoms, decreased ability to shift between mental sets was associated with increased negative beliefs about the uncontrollability and danger of worry and beliefs about the need to control thoughts. The results suggest a basic association between metacognitions and executive control. Individual differences in executive control could prove important in the personalization of metacognitive therapy.

Do Executive Functions Predict Binge-Drinking Patterns? Evidence from a Longitudinal Study in Young Adulthood.

Background: Impairments in executive functions (EFs) are related to binge drinking in young adulthood, but research on how EFs influence future binge drinking is lacking. The aim of the current report is therefore to investigate the association between various EFs and later severity of, and change in, binge drinking over a prolonged period during young adulthood. Methods: At baseline, 121 students reported on their alcohol habits (Alcohol use disorder identification test; Alcohol use questionnaire). Concurrently, EFs [working memory, reversal, set-shifting, response inhibition, response monitoring and decision-making (with ambiguity and implicit risk)] were assessed. Eighteen months later, information on alcohol habits for 103 of the participants were gathered. Data were analyzed by means of multilevel regression modeling. Results: Future severity of binge drinking was uniquely predicted by performance on the Information sampling task, assessing risky decision-making (ß = -1.86, 95% CI: -3.69, -0.04). None of the study variables predicted severity or change in binge drinking. Conclusion: Future severity of binge drinking was associated with making risky decisions in the prospect for gain, suggesting reward hypersensitivity. Future studies should aim at clarifying whether there is a causal association between decision-making style and binge drinking. Performance on all executive tasks was unrelated to change in binge drinking patterns; however, the finding was limited by overall small changes, and needs to be confirmed with longer follow-up periods.

Metacognitions Are Associated with Subjective Memory Problems in Individuals on Sick Leave due to Chronic Fatigue.

BACKGROUND: Subjective cognitive impairments are frequent, but poorly understood in patients with chronic fatigue. We hypothesized that maladaptive metacognitive beliefs at baseline were associated with baseline subjective cognitive impairments, that they predict subjective cognitive impairments at treatment termination, and that a reduction in maladaptive metacognitive beliefs was associated with less subjective cognitive impairments at treatment termination, independent of changes in fatigue, pain, insomnia, depression, and anxiety. METHODS: In this non-controlled study, patients (n = 137) on sick leave due to chronic fatigue received a 3.5-week inpatient RTW rehabilitation program. Of these patients 69 (50.4%) was referred with a ICPC-2 diagnosis of chronic fatigue. Patients completed questionnaires about metacognitive beliefs, somatic complaints, psychological complaints, and cognitive impairments before and after treatment. To test the hypotheses we performed paired t-tests of change, as well as seven hierarchical linear regressions. RESULTS: RESULTS showed that baseline maladaptive metacognitive beliefs were significantly associated with subjective cognitive impairments at baseline, controlling for symptoms. Score on baseline metacognitive beliefs did not predict impairments post-treatment. Testing specific maladaptive beliefs, pre-treatment scores on cognitive confidence were associated with subjective cognitive impairments both pre and post-treatment, controlling for symptoms. Post-treatment metacognitive beliefs and post-treatment cognitive confidence were associated with post-treatment subjective cognitive impairments, controlling for pre-treatment impairments and pre-treatment metacognitive beliefs, as well as pre and post-scores on symptom measures. CONCLUSION: This study reports associations between maladaptive metacognitive beliefs and subjective cognitive impairments in patients with chronic fatigue. Targeting metacognitive beliefs could prove an effective therapeutic intervention for subjective cognitive impairments in these patients.

Effectiveness of Working Memory Training among Subjects Currently on Sick Leave Due to Complex Symptoms.

Introduction: The current study examined if adaptive working memory training (Cogmed QM) has the potential to improve inhibitory control, working memory capacity, and perceptions of memory functioning in a group of patients currently on sick leave due to symptoms of pain, insomnia, fatigue, depression and anxiety. Participants who were referred to a vocational rehabilitation center volunteered to take part in the study. Methods: Participants were randomly assigned to either a training condition (N = 25) or a control condition (N = 29). Participants in the training condition received working memory training in addition to the clinical intervention offered as part of the rehabilitation program, while participants in the control condition received treatment as usual i.e., the rehabilitation program only. Inhibitory control was measured by The Stop Signal Task, working memory was assessed by the Spatial Working Memory Test, while perceptions of memory functioning were assessed by The Everyday Memory Questionnaire-Revised. Results: Participants in the training group showed a significant improvement on the post-tests of inhibitory control when compared with the comparison group (p = 0.025). The groups did not differ on the post-tests of working memory. Both groups reported less memory problems at post-testing, but there was no sizeable difference between the two groups. Conclusions: Results indicate that working memory training does not improve general working memory capacity per se. Nor does it seem to give any added effects in terms of targeting and improving self-perceived memory functioning. Results do, however, provide evidence to suggest that inhibitory control is accessible and susceptible to modification by adaptive working memory training.

Subjective memory complaints among patients on sick leave are associated with symptoms of fatigue and anxiety.

OBJECTIVE: The aim of this study was to identify symptoms associated with subjective memory complaints (SMCs) among subjects who are currently on sick leave due to symptoms of chronic pain, fatigue, depression, anxiety, and insomnia. METHODS: This was a cross-sectional study, subjects (n = 167) who were currently on sick leave were asked to complete an extensive survey consisting of the following: items addressing their sociodemographics, one item from the SF-8 health survey measuring pain, Chalder Fatigue Questionnaire, Hospital Anxiety and Depression Scale, Insomnia Severity Index, and Everyday Memory Questionnaire - Revised. General linear modeling was used to analyze variables associated with SMCs. RESULTS: Symptoms of fatigue (p-value < 0.001) and anxiety (p-value = 0.001) were uniquely and significantly associated with perceived memory failures. The associations with symptoms of pain, depression, and insomnia were not statistically significant. CONCLUSIONS: Subjective memory complaints should be recognized as part of the complex symptomatology among patients who report multiple symptoms, especially in cases of fatigue and anxiety. Self-report questionnaires measuring perceived memory failures may be a quick and easy way to incorporate and extend this knowledge into clinical practice.

A Longitudinal Study of Disability, Cognition and Gray Matter Atrophy in Early Multiple Sclerosis Patients According to Evidence of Disease Activity.

New treatment options may make "no evidence of disease activity" (NEDA: no relapses or disability progression and no new/enlarging MRI lesions, as opposed to "evidence of disease activity" (EDA) with at least one of the former), an achievable goal in relapsing-remitting multiple sclerosis (RRMS). The objective of the present study was to determine whether early RRMS patients with EDA at one-year follow-up had different disability, cognition, treatment and gray matter (GM) atrophy rates from NEDA patients and healthy controls (HC). RRMS patients (mean age 34 years, mean disease duration 2.2 years) were examined at baseline and one-year follow-up with neurological (n = 72), neuropsychological (n = 56) and structural MRI (n = 57) examinations. Matched HC (n = 61) were retested after three years. EDA was found in 46% of RRMS patients at follow-up. EDA patients used more first line and less second line disease modifying treatment than NEDA (p = 0.004). While the patients groups had similar disability levels at baseline, they differed in disability at follow-up (p = 0.010); EDA patients progressed (EDSS: 1.8-2.2, p = 0.010), while NEDA patients improved (EDSS: 2.0-1.7, p<0.001). Cognitive function was stable in both patient groups. Subcortical GM atrophy rates were higher in EDA patients than HC (p<0.001). These results support the relevance of NEDA as outcome in RRMS and indicate that pathological neurodegeneration in RRMS mainly occur in patients with evidence of disease activity.

A particular effect of sleep, but not pain or depression, on the blood-oxygen-level dependent response during working memory tasks in patients with chronic pain.

BACKGROUND: Patients with chronic pain (CP) are often reported to have deficits in working memory. Pain impairs working memory, but so do depression and sleep problems, which are also common in CP. Depression has been linked to changes in brain activity in CP during working memory tasks, but the effect of sleep problems on working memory performance and brain activity remains to be investigated. METHODS: Fifteen CP patients and 17 age-, sex-, and education-matched controls underwent blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging at 3T while performing block design 0-back, 2-back, and paced visual serial addition test paradigms. Subjects also reported their level of pain (Brief Pain Inventory), depression (Beck Depression Inventory II), and sleep problems (Pittsburgh Sleep Quality Index) and were tested outside the scanner with neuropsychological tests of working memory. RESULTS: The CP group reported significantly higher levels of pain, depression, and sleep problems. No significant performance difference was found on the neuropsychological tests in or outside the scanner between the two groups. There were no correlations between level of pain, depression, and sleep problems or between these and the neuropsychological test scores. CP patients exhibited significantly less brain activation and deactivation than controls in parietal and frontal lobes, which are the brain areas that normally show activation and deactivation during working memory tasks. Sleep problems independently and significantly modulated the BOLD response to the complex working memory tasks and were associated with decreased brain activation in task-positive regions and decreased deactivation in the default mode network in the CP group compared to the control group. The pain and depression scores covaried with working memory activation. DISCUSSION: Sleep problems in CP patients had a significant impact on the BOLD response during working memory tasks, independent of pain level and depression, even when performance was shown not to be significantly affected.

Cortical thickness and surface area relate to specific symptoms in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cortical atrophy is common in early relapsing-remitting multiple sclerosis (RRMS). Whether this atrophy is caused by changes in cortical thickness or cortical surface area is not known, nor is their separate contributions to clinical symptoms. OBJECTIVES: To investigate the difference in cortical surface area, thickness and volume between early RRMS patients and healthy controls; and the relationship between these measures and neurological disability, cognitive decline, fatigue and depression. METHODS: RRMS patients (n = 61) underwent magnetic resonance imaging (MRI), neurological and neuropsychological examinations. We estimated cortical surface area, thickness and volume and compared them with matched healthy controls (n = 61). We estimated the correlations between clinical symptoms and cortical measures within the patient group. RESULTS: We found no differences in cortical surface area, but widespread differences in cortical thickness and volume between the groups. Neurological disability was related to regionally smaller cortical thickness and volume. Better verbal memory was related to regionally larger surface area; and better visuo-spatial memory, to regionally larger cortical volume. Higher depression scores and fatigue were associated with regionally smaller cortical surface area and volume. CONCLUSIONS: We found that cortical thickness, but not cortical surface area, is affected in early RRMS. We identified specific structural correlates to the main clinical symptoms in early RRMS.

The effects of acute tryptophan depletion on impulsivity and mood in adolescents engaging in non-suicidal self-injury.

OBJECTIVE: Non-suicidal self-injury (NSSI) is associated with impaired emotion regulation and impulsivity. Low serotonin (5-hydroxytryptamine) function is associated with NSSI, impaired emotion regulation and impulsivity. We investigated the effects of experimentally lowered 5-hydroxytryptamine activity, via acute tryptophan depletion (ATD), on impulsive action, reflection impulsivity and mood in female adolescents engaging in NSSI. METHODS: Thirty-two female adolescents engaging in NSSI participated in a parallel group ATD study. Following ATD, impulsive action was assessed using the Continuous Performance Test, Identical Pairs Version. Reflection impulsivity was assessed using the Matching Familiar Figures Test. Mood-lowering was examined using the Profile of Mood States. RESULTS: Following ATD, the participants showed an impulsive response style (as reflected in their low ß) and increased attentional capacity (as reflected in their elevated d'). ATD did not affect reflection impulsivity or mood. CONCLUSIONS: Acute tryptophan depletion caused an impulsive response style and increased attentional capacity. Importantly, the findings suggest that low serotonin function is a vulnerability among female adolescents for engaging in NSSI when in emotional distress.

Associations between serotonin transporter polymorphisms and cognitive processing applying the Emo 1-back task.

Down regulation of serotonin transporter (5-HTT) expression has been associated with brain function and major depression. The aim of this study was to explore the allelic variation (short and long) of the 5-HTTLPR polymorphism in attention bias associated with top-down processing of emotion. One hundred sixty-two healthy participants underwent genotyping (5-HTTLPR), background interviews, psychological screening, and a computerised test session (The Emo 1-back task). Carriers of the short 5-HTTLPR alleles in the serotonin transporter gene (SLC6A4) demonstrated less accuracy in The Emo 1-back task when presented with successive images of sad or fearful faces, but not for happy or neutral emotional faces. The study suggests an association between 5-HTTLPR variation in the serotonin transporter gene and altered emotion processing.

The effects of the serotonin transporter polymorphism and age on frontal white matter integrity in healthy adult women.

Studies of populations at genetic risk have the potential to explore the underlying structural and functional mechanisms in the development of psychological disorders. The polymorphic region (5-HTTLPR) in the serotonin transporter gene (SLC6A4) has been associated with major depression (MDD) (Caspi et al., 2003). In healthy women, variation in the human brain white matter microstructure integrity in the uncinate fascicule (UF) has been suggested as an endophenotypes in the development of MDD. Pacheco et al. (2009) found a unique effect of age and 5-HTTLPR within the left frontal UF. The present study examined whether these associations persist along the adult life span. Thirty-seven right-handed healthy women between 21 and 61 years of age were invited for a diffusion MRI study. The functional polymorphism 5-HTTLPR located in the promoter region of the SLC6A4 gene was genotyped using polymerase chain reaction (PCR). Fractional anisotropy (FA) was generated for the UF based on Tract-Based Spatial Statistics (TBSS). Models of emotion regulation circuitry suggest that working memory is important in conscious emotion regulation (Price and Drevets, 2010). To explore if 5-HTTLPR is related to this aspects of emotion processing, a working memory pathway, the superior longitudinal fascicule (SLF) was included. The results demonstrate that age may explain the hypothesized association between 5-HTTLPR and frontal UF white matter integrity in healthy adult women. Both white matter changes associated with the aging process and those associated with growth and development may explain why the earlier reported unique effects of genotype in frontal UF FA do not persist into adulthood.

Exploring the relationship between white matter microstructure and working memory functioning following stroke: a single case study of computerized cognitive training.

Cognitive impairment is a well-known consequence of acquired brain injuries, including stroke. Computerized cognitive training (CCT) is a rehabilitation approach intended to enhance cognitive functioning. It is unclear whether CCT leads to generalized cognitive improvements in daily life functioning, or if the subjects improve performance only on the exercises involved in the training. The current study explores whether fractional anisotropy (FA), a measure of white matter microstructure, may serve as an indirect biological indicator of enhanced neuropsychological functioning, particularly working memory, following CCT. The findings suggest a possible relationship between changes in FA measures and working memory.

Errorless learning and working memory: the impact of errors, distractors, and memory span load on immediate recall in healthy adults.

Errorless learning represents an important contribution to current neuropsychological rehabilitation. Previous research has mainly explained the benefits of errorless learning through properties of long-term memory. This study aims to explore how errors affect immediate recall performance. A new, supplementary perspective focusing on the role of working memory in errorless learning is introduced. Sixty university students participated in a within-subject design experiment measuring the effect of errors, memory span load, and attentional distractors on a digit recall task. Errors were found to have significant negative impact on immediate recall, while distractors had an effect only in interaction with errors.

Driving functions in a video simulator in chronic non-malignant pain patients using and not using codeine.

BACKGROUND AND AIMS: A considerable number of Europeans suffer from chronic pain and are using opioids, particularly of the weak type. It is a clinical impression that many of these are driving or wish to drive a car. The aims of this study were to investigate if codeine influences driving ability in a simulator, and to examine if chronic pain per se might impair such functions. METHODS: Twenty patients with chronic pain on long-term codeine therapy were compared to 20 chronic pain patients not using codeine in a video driving simulator test. The chronic pain patients were then compared to 20 healthy controls. The primary outcome measures were reaction time and number of missed reactions. RESULTS: The patients using codeine 120-270 mg (mean 180 mg) daily showed the same driving skills as patients not using codeine, and the codeine level did not affect the results. This was the case both 1h after intake of a single dose of 60 mg codeine and five or more hours after the last codeine intake. The reaction times were significantly slower for the chronic pain patients, in both rural and urban driving conditions, compared to the healthy controls (difference 0.11s. and 0.12s., respectively). The chronic pain patients missed almost twice as many reactions to traffic signs. There were no difference between the groups in steering precision. CONCLUSION: The main finding in this simulator study was that codeine does not impair driving-related abilities over and above what is associated with chronic pain per se.