Residual cognitive deficits following Major Depression : Associations to symptoms, course of illness, and outcomes from Computerized Working Memory Training.

Kognitive vansker ved depresjon har fått økt oppmerksomhet de siste tiårene. Selv om kognitiv funksjon bedrer seg etter affektiv remisjon så vedvarer betydelige kognitive residual symptomer. Dette påvirker daglig fungering, livskvalitet og bidrar til den alarmerende tilbakefallsraten ved depresjon. Det er manglende forståelse for prosessene for tilbakefall, og longitudinelle studier som følger pasienter etter sin første depressive episode over i remisjon, over lengre tid, er nødvendige for å øke kunnskapen rundt dette. Tilgjengelig depresjonsbehandling fokuser lite på remisjonsfasen og kurerer ikke alle kognitive residualsymptomer, selv om det kan være avgjørende for å forbli frisk og forebygge tilbakefall. Avhandlingen undersøkte derfor hvordan kognisjon utvikler seg etter første depresjon. Det ble undersøkt hvordan eksekutive funksjoner, prosesseringshastighet, emosjonelt arbeidsminne og andre residualsymptomer og sykdomsutvikling opptrer, endres og korrelerer, i to grupper; en gruppe fem år etter førstegangsdepresjon (Studie 1; Artikkel 1 & 2), og en i remisjon fra depresjon. Effekten av databasert arbeidsminnetrening på residualsymptomer undersøkt i sistnevnte (Studie 2; Artikkel III). Artikkel I undersøkte utviklingen av eksekutive funksjoner, prosesseringshastighet og symptomer fem år etter første depresjon, og korrelasjon mellom kognitive residualsymptomer og sykdomshistorikk. Teorier rundt utviklingen av kognitive funksjoner ble undersøkt: Funksjoner som bedret seg i samspill med bedring av affektive symptomer kunne forstås som en konsekvens av den depressive tilstanden, vedvarende kognitive vansker som potensielt var med å utløse den, kunne forstås som predisponerende trekk. Dersom vanskene ble verre i samspill med nye episoder og sykdomshistorikk kunne de forstås som depressive forandringer i form av kognitive arr. Tjuetre pasienter og 20 kontrollpersoner skilte seg på de fleste kognitive testene med størst forskjeller på prosesseringshastighet. Forekomst av komorbide tilstander økte. Prosesseringshastighet hang sammen med-, mens eksekutive funksjoner som inhibering fremsto som uavhengige av-, depressive symptomer. Kognitiv funksjon ble ikke dårligere etter fem år. Eksekutive funksjoner hang sammen med sykdomshistorie og nevrotisk grubling, som indikerte risiko for mer alvorlig sykdomsforløp. Artikkel II undersøkte emosjonelt arbeidsminne fem år etter førstegangsdepresjon. Korrelasjon mellom gruppeforskjeller i emosjonelt arbeidsminne, ruminering, og tilbakefallsrisiko ble også undersøkt. Artikkelen var en kryss-seksjonal undersøkelse av forskjeller mellom 23 tidligere førstegangsdeprimerte og 22 kontrollpersoner. På oppgaver som målte emosjonelt arbeidsminne skulle en huske sekvenser av tre ansikter som enten var triste eller glade. Sekvensen skulle enten holdes i korttidsminnet forlengs, i en lavt arbeidsminnebelastende betingelse, eller manipuleres, og holdes baklengs i arbeidsminnet, i en høyt arbeidsminnebelastende betingelse. Deretter skulle plassering i sekvensen for et av ansiktene angis. Det var gruppeforskjeller i riktig svar for glade ansikter i den enkle betingelsen, og for triste ansikter i den vanskelige betingelsen. Sistnevnte betingelse viste negativ korrelasjon med ruminering, som predikerte tilbakefall i gruppen. Tidligere førstegangsdeprimerte hadde vansker med arbeidsminneprosessering av negative stimuli, som hang sammen med ruminering, som igjen var assosiert med tilbakefallsrisiko. Artikkel III undersøkte hvordan arbeidsminnetrening påvirket emosjonelt arbeidsminne, eksekutive funksjoner, prosesseringshastighet, ruminering og depressive symptomer. Tjueni deltakere i remisjon fra depresjon ble rekruttert, hvorav 20 fullførte intervensjonen. Endringer i kognitive residualsymptomer, og samvariasjon dem imellom før og etter trening, ble undersøkt. Hypoteser og statistiske analyser ble preregistrert før data ble analysert. Riktig respons i betingelsen for manipulering triste ansikter viste igjen negativ korrelasjon med ruminering i forkant, men ikke i etterkant av intervensjonen. Det var en bedring i kognitiv funksjon, med størst effekter for tester av eksekutive funksjoner. Symptomer endret seg ikke. Det var samvariasjon mellom forbedret prestasjon for arbeidsminnetrening og kognitive funksjoner. Depresjonshistorikk hang sammen med mindre forbedring av eksekutiv funksjon. Studien fant støtte for forbedring av noen residualsymptomer etter arbeidsminnetrening i remisjon fra depresjon.Cognitive deficits in Major Depressive Disorder (MDD) have received increased attention in recent decades. Even though cognition generally improves following affective remission, some cognitive deficits and other residual symptoms persist, affecting daily functioning and quality of life, thus contributing to the alarming rate of relapse seen in MDD. This is not well understood, and long-term studies of MDD from first onset into remission are needed. Treatments do not target the remitted phase, nor remediate residual symptoms, although cognitive remission is crucial for a successful recovery, and relapse prevention. This thesis, therefore, investigated how different aspects of cognitive functioning developed following MDD. Specifically, how executive function (EF), processing speed (PS), emotional working memory (e-WM), and other residual symptoms in remitted MDD developed, manifested, and were associated with depressive symptoms, relapse risk, and MDD history (Study 1; Papers I & II). Also, outcomes of Computerized Working Memory Training (CWMT) on residual cognitive symptoms and their associations were investigated in a remitted sample (Study 2; Paper III). Paper I investigated the development of EF and PS five years following first episode MDD, the clinical course, and associations between cognitive deficits and other residual symptoms. If cognitive deficits improved after symptom remission, deficits could be caused by depressive symptoms as state-dependent. Conversely, if deficits were stable and relatively independent of symptoms, these could be understood as trait related. If deficits are exacerbated over time relative to MDD history, this could be understood as scar related. Twenty-three patients and 20 controls were assessed in the acute phase, one, and five years following the first episode of MDD. Neuropsychological tests assessed aspects of PS, in addition to EF. Five years following MDD, patients, and controls differed on most cognitive tests with the strongest effects for PS, and comorbid disorders had increased. PS was state-dependent. EF was mostly independent of symptoms, suggestive of trait effects. There was limited support for the scar perspective and no indication of worsening cognition during the five years. There were associations between history of depression, EF, and neurotic rumination that could indicate risk factors for a more severe course of MDD. Paper II investigated e-WM processing and associations with rumination and risk for relapse five years following MDD. The study was a cross-sectional investigation of differences in e-WM between participants who experienced their first MDD five years earlier compared to a matched control group. Twenty-three patients and 22 controls were compared on the e-WM task where sequences of three different sad- or happy faces were maintained in memory in a forward or manipulated in a backward high effortful WM loading condition. Correct sequential placement of one of these images was then assessed. Groups differed on accuracy for the low effortful positively, and high effortful negatively valenced images. Accuracy in the highly effortful negative condition was inversely correlated to rumination. Rumination predicted relapse. Thus, there was support for deficits in maintaining low WM loading positive stimuli and high WM loading manipulation of negative stimuli, with the latter being associated with rumination. Rumination was a risk factor for relapse and recurrence. Paper III explored how systematic computerized training of WM influenced e-WM, EF, PS, rumination, and depressive symptoms. Twenty-nine participants remitted from MDD were recruited, and 20 completed the intervention and follow-up assessments. Improvements in cognitive function and residual symptoms, and their associations, were investigated pre- and post-intervention. Associations between depression history and changes in cognition and improved CWMT were explored. Hypotheses and statistical analyses were preregistered before data was analyzed. Accuracy in the negative high effortful WM manipulation condition showed an inverse correlation to rumination pre- but not post-intervention. Associations between PS and depressive symptoms were not found. Cognitive functioning improved in most conditions with the largest effects for EF. Symptoms did not change. Improved CWMT showed an association with improvements in aspects of EF and PS. History of depression was associated with less improvement in EF. The study supported that CWMT improved cognitive functioning.Doktorgradsavhandlin

Facing recovery: Emotional bias in working memory, rumination, relapse, and recurrence of major depression; an experimental paradigm conducted five years after first episode of major depression

Identifying vulnerability factors for relapse of depression is essential in planning preventive interventions. Emotional face processing in major depression (MDD) shows promise as a potential cognitive marker for depression. The current study investigates how working memory (WM) load in face processing relates to rumination and new episodes of MDD in a novel explorative paradigm. It was expected that history of MDD is associated with reduction of the ability to process sad stimuli in high WM load conditions and reduction of the ability to process happy stimuli in low WM conditions. It was further predicted that these relations are associated with rumination and risk for relapse. The experiment was included as a cross sectional part in a follow-up study of a population that previously experienced first episode (FE) depression. The FE (N = 23) and a healthy control group (N = 22) completed a WM face processing task. In the task, three happy or sad faces were presented, processed in either a high or low WM taxing manner, followed by a target stimulus consisting of one of the previous pictures. Response time and accuracy were dependent variables. Rumination and number of relapses or recurrences were measured. The FE group recalled the placement of significantly fewer happy faces in the low WM load condition, and significantly fewer sad faces in the high WM load condition compared to controls. Significantly different scores between groups predicted trait rumination. Poor accuracy in the sad high WM load condition correlated with high degree of rumination. Relapse or recurrence was predicted by rumination. The present study supports an emotional WM deficit in remitted MDD. This suggests that deficits in manipulation of sad faces could represent a trait bias related to rumination and depression.acceptedVersio

Improvement in self-reported cognitive functioning but not in rumination following online working memory training in a two-year follow-up study of remitted major depressive disorder

Self-reported subjective cognitive difficulties (subjective deficits) and rumination are central residual cognitive symptoms following major depressive disorder (MDD). These are risk factors for more a severe course of illness, and despite the considerable relapse risk of MDD, few interventions target the remitted phase, a high-risk period for developing new episodes. Online distribution of interventions could help close this gap. Computerized working memory training (CWMT) shows promising results, but findings are inconclusive regarding which symptoms improve following this intervention, and its long-term effects. This study reports results from a longitudinal open-label two-year follow-up pilot-study of self-reported cognitive residual symptoms following 25 sessions (40 min), five times a week of a digitally delivered CWMT intervention. Ten of 29 patients remitted from MDD completed two-year follow-up assessment. Significant large improvements in self-reported cognitive functioning on the behavior rating inventory of executive function-adult version appeared after two-years (d = 0.98), but no significant improvements were found in rumination (d < 0.308) measured by the ruminative responses scale. The former showed moderate non-significant associations to improvement in CWMT both post-intervention (r = 0.575) and at two-year follow-up (r = 0.308). Strengths in the study included a comprehensive intervention and long follow-up time. Limitations were small sample and no control group. No significant differences between completers and drop-outs were found, however, attrition effects cannot be ruled out and demand characteristics could influence findings. Results suggested lasting improvements in self-reported cognitive functioning following online CWMT. Controlled studies with larger samples should replicate these promising preliminary findings

Computerized Working Memory Training in Remission From Major Depressive Disorder: Effects on Emotional Working Memory, Processing Speed, Executive Functions, and Associations With Symptoms

Introduction: Remission from major depressive disorder (MDD) is associated with residual symptoms related to reduced functioning, quality of life, and relapse risk. Previous studies have raised questions about mechanisms involved-in and affected by cognitive training. This study investigated the associations and changes among depressive symptoms, rumination, processing speed (PS), executive functioning (EF), and emotional working memory (e-WM) pre- post computerized working memory training (CWMT). Method: Twenty-nine remitted participants were included in a pre- post pilot study of within-subject effects of online CWMT. A total of 20 participants completed the intervention and pre- post tests of EF and PS, e-WM, in addition to symptom and rumination measures. Associations between changes in symptoms and cognition were investigated pre- post. Associations between improvements in CWMT, depression history, and changes in cognition were explored. Hypotheses and statistics were preregistered before data were analyzed. Results: Manipulation of negatively valanced stimuli in e-WM showed an inverse association with rumination pre-intervention, but the association disappeared post-intervention. Cognitive functioning improved in most conditions with largest effects in EF. Symptoms did not change in the remitted sample. CWMT improvements were related to improvements in some aspects of EF and PS, but also to worse self-reported attention. Depression history was related to less improvement in EF. Limitations: Sample size was small and there was dropout from the study. There was no control group, thus precluding practice and placebo effects and causal relationships. Conclusions: Computerized WM training improves cognitive functions and could influence associations between e-WM and rumination. This could counteract functional impairment following MDD.publishedVersio

Cognitive Impairment and Neurocognitive Profiles in Major Depression—A Clinical Perspective

Increasingly, studies have investigated cognitive functioning from the perspective of acute state- to remitted phases of Major Depressive Disorder (MDD). Some cognitive deficits observed in the symptomatic phase persist in remission as traits or scars. The etiological origin and clinical consequences of the neurocognitive profiles reported in the literature are still unclear and may vary across populations. Deficits are suspected to influence the association between MDD and neurodegenerative disorders and could thus be of particular clinical consequence. The aim of this review is to describe the clinical neuropsychological profile in MDD and how it is related to research during the past decade on cognitive deficits in MDD from a state, trait, and scar perspective. This review, with a clinical perspective, investigates research from the past decade regarding cognitive functioning in MDD in a long-term perspective. We focus on the clinical manifestation of deficits, and the potential neurodegenerative consequences of the neurocognitive profile in MDD. Searches in Medline, PsycINFO and Embase were conducted targeting articles published between 2010 and 2020. Examination of the evidence for long-lasting neurocognitive deficits in major depression within the cognitive domains of Memory, Executive Functions, Attention, and Processing Speed was conducted and was interpreted in the context of the State, Scar and Trait hypotheses. Defining the neurocognitive profiles in MDD will have consequences for personalized evaluation and treatment of residual cognitive symptoms, and etiological understanding of mood disorders, and treatments could potentially reduce or delay the development of neurodegenerative disorders.publishedVersio

Neurocognitive Functioning in Patients with Painful Temporomandibular Disorders

Aim: To investigate psychosocial factors in painful TMD (pTMD) which could have consequences for mastering chronic pain. Methods: Our study included 22 patients (20 women, 2 men) with pTMD, refractory to conservative treatment, and 19 healthy controls. The control group was matched for gender, age, and educational level, and IQ tested on the Wechsler Abbreviated Scale of Intelligence. Neurocognitive function was tested with the Color-Word Interference Test (CWIT). Pain intensity was reported according to the General Pain Intensity Questionnaire (GPI), using the Numeric Rating Scale (NRS). Self-perceived cognitive difficulties were reported by the Perceived Deficits Questionnaire-Depression 5-item (PDQ-5). Two measures of rumination were included: the Rumination-Reflection Questionnaire (RRQ) and the Ruminative Response Scale (RRS). The Montgomery Åsberg Depression Rating Scale Self-report (MADRS-S) was used to measure depressive symptoms, and the Oral Health Impact Profile-TMD (OHIP-TMD) to measure QoL related to oral health. Results: There were no statistical differences in age (median pTMD: 55 years, median control: 53 years), educational level, and IQ between pTMD and controls. Median pain intensity in pTMD was NRS 8 at maximum and the median pain duration was 18 years. There were no significant differences in CWIT between pTMD and controls. Self-perceived cognitive function (PDQ) was significantly poorer in pTMD. Rumination scores from both measures, and the depression score from MADRS, were significantly higher in pTMD. The OHIP-TMD score revealed a significantly poorer QoL in pTMD. Conclusion: The group of pTMD patients have self-perceived cognitive difficulties that may make it more difficult to master chronic pain and common everyday tasks. They reported significantly more self-perceived cognitive difficulties, higher rumination, more depressive symptoms, and lower QoL compared to healthy controls, suggesting that these psychosocial factors could be targeted in treatment and interventions. However, the tested neurocognitive performance was equivalent to the control group.publishedVersio

Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression

Concurrent with recent insights into the neuroprogressive nature of depression, ketamine shows promise in interfering with several neuroprogressive factors, and has been suggested to reverse neuropathological patterns seen in depression. These insights come at a time of great need for novel approaches, as prevalence is rising and current treatment options remain inadequate for a large number of people. The rapidly growing literature on ketamine’s antidepressant potential has yielded multiple proposed mechanisms of action, many of which have implications for recently elucidated aspects of depressive pathology. This review aims to provide the reader with an understanding of neuroprogressive aspects of depressive pathology and how ketamine is suggested to act on it. Literature was identified through PubMed and Google Scholar, and the reference lists of retrieved articles. When reviewing the evidence of depressive pathology, a picture emerges of four elements interacting with each other to facilitate progressive worsening, namely stress, inflammation, neurotoxicity and neurodegeneration. Ketamine acts on all of these levels of pathology, with rapid and potent reductions of depressive symptoms. Converging evidence suggests that ketamine works to increase stress resilience and reverse stress-induced dysfunction, modulate systemic inflammation and neuroinflammation, attenuate neurotoxic processes and glial dysfunction, and facilitate synaptogenesis rather than neurodegeneration. Still, much remains to be revealed about ketamine’s antidepressant mechanisms of action, and research is lacking on the durability of effect. The findings discussed herein calls for more longitudinal approaches when determining efficacy and its relation to neuroprogressive factors, and could provide relevant considerations for clinical implementation.publishedVersio

Working Memory Training as Cognitive Enhancement in Remission from MDD

The current data was collected as a part of a pilot study on the feasibility, acceptability, and cognitive benefits of cognitive enhancement (Computerized working memory training) in remission from depression (Hammar et al., 2020), and is a pre- post study of how computerized working memory training influences cognitive functions and their relationship to depressive symptoms

Computerized Working Memory Training in Remission From Major Depressive Disorder: Effects on Emotional Working Memory, Processing Speed, Executive Functions, and Associations With Symptoms

Introduction: Remission from major depressive disorder (MDD) is associated with residual symptoms related to reduced functioning, quality of life, and relapse risk. Previous studies have raised questions about mechanisms involved-in and affected by cognitive training. This study investigated the associations and changes among depressive symptoms, rumination, processing speed (PS), executive functioning (EF), and emotional working memory (e-WM) pre- post computerized working memory training (CWMT). Method: Twenty-nine remitted participants were included in a pre- post pilot study of within-subject effects of online CWMT. A total of 20 participants completed the intervention and pre- post tests of EF and PS, e-WM, in addition to symptom and rumination measures. Associations between changes in symptoms and cognition were investigated pre- post. Associations between improvements in CWMT, depression history, and changes in cognition were explored. Hypotheses and statistics were preregistered before data were analyzed. Results: Manipulation of negatively valanced stimuli in e-WM showed an inverse association with rumination pre-intervention, but the association disappeared post-intervention. Cognitive functioning improved in most conditions with largest effects in EF. Symptoms did not change in the remitted sample. CWMT improvements were related to improvements in some aspects of EF and PS, but also to worse self-reported attention. Depression history was related to less improvement in EF. Limitations: Sample size was small and there was dropout from the study. There was no control group, thus precluding practice and placebo effects and causal relationships. Conclusions: Computerized WM training improves cognitive functions and could influence associations between e-WM and rumination. This could counteract functional impairment following MDD

A longitudinal 5-year follow-up study of cognitive function after first episode major depressive disorder: Exploring state, scar and trait effects

Major depression (MDD) is associated with cognitive deficits in processing speed and executive function (EF) following first episode (FE). It is unclear whether deficits are state or trait related. Studies following FE MDD over longer periods are lacking, making it uncertain how cognition and symptoms develop after the initial episode. The present study assessed cognitive function and symptoms 5 years following FE MDD. In addition, the study explored relationships between MDD symptoms, rumination, and cognitive deficits with regards to the trait, state, and scar perspective. Twenty-three participants with previous FE MDD, and 20 matched control participants were compared on Delis-Kaplan Executive Function System measures of processing speed and EF, in a 5-year longitudinal follow-up study. Correlations between current symptoms- and history of MDD, rumination, cognition were investigated. Findings indicated that cognitive deficits persisted with no clear signs of exacerbation after initial episode. Inhibition appeared independent of current and previous symptoms of depression. Processing speed was related to depressive- symptoms and rumination. In conclusion, results indicated persisting, stable deficits in both EFs and processing speed. Findings further suggest that depressive symptoms could be related to deficits in processing speed, indicating state effects. There was limited support for worsening of cognition after initial episode. Some aspects of EF like Inhibition could show persistent deficits independent of depressive symptoms indicating trait effects