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Reliable predictors for electroconvulsive therapy (ECT) effectiveness would allow a more precise and personalized approach for the treatment of major depressive disorder (MDD). Prediction models were created using a priori selected clinical variables based on previous meta-analyses. Multivariable linear regression analysis was used, applying backwards selection to determine predictor variables while allowing non-linear relations, to develop a prediction model for depression outcome post-ECT (and logistic regression for remission and response as secondary outcome measures). Internal validation and internal-external cross-validation were used to examine overfitting and generalizability of the model's predictive performance. In total, 1892 adult patients with MDD were included from 22 clinical and research cohorts of the twelve sites within the Dutch ECT Consortium. The final primary prediction model showed several factors that significantly predicted a lower depression score post-ECT: higher age, shorter duration of the current depressive episode, severe MDD with psychotic features, lower level of previous antidepressant resistance in the current episode, higher pre-ECT global cognitive functioning, absence of a comorbid personality disorder, and a lower level of failed psychotherapy in the current episode. The optimism-adjusted R² of the final model was 19%. This prediction model based on readily available clinical information can reduce uncertainty of ECT outcomes and hereby inform clinical decision-making, as prompt referral for ECT may be particularly beneficial for individuals with the above-mentioned characteristics. However, despite including a large number of pretreatment factors, a large proportion of the variance in depression outcome post-ECT remained unpredictable.
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Childhood adversity (CA), including childhood adverse life events, increases the risk for development of psychiatric disorders later in life. Both CA and psychiatric disorders are associated with structural brain changes and dysfunctional hypothalamic-pituitary-adrenal-axis. However, many studies investigated single diagnostic and single regions of interest of the brain, and did not take stress reactivity into account. We investigated associations of CA and cortisol levels with gray matter volume and cortical thickness, in a whole-brain manner. Primary analysis constituted of a transdiagnostic approach, followed by a moderation analysis to investigate the influence of diagnosis. Patients with stress-related and/or neurodevelopmental disorders and matched healthy controls underwent an magnetic resonance imaging scan, next to assessing hair cortisol levels and CA/life events. CA was reported by 62-72% of the patients versus 33% of the controls. Primary transdiagnostic linear regression analyses revealed that CA was not associated with gray matter volume, while childhood life events were associated with lower right thalamic volume. Hair cortisol was not associated with any lobe volume. None of the associations were moderated by diagnosis. In conclusion, CA is a risk factor that needs to be taken into account when investigating psychiatric disorders. Yet the relationship with structural brain changes and stress reactivity is less clear than postulated on the basis of more seed-based studies.
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Experiências Adversas da Infância , Substância Cinzenta , Cabelo , Hidrocortisona , Imageamento por Ressonância Magnética , Transtornos do Neurodesenvolvimento , Estresse Psicológico , Humanos , Feminino , Masculino , Estresse Psicológico/diagnóstico por imagem , Estresse Psicológico/patologia , Estudos Transversais , Hidrocortisona/metabolismo , Cabelo/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Adulto , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Comorbidade , Adulto Jovem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Electroconvulsive therapy (ECT) is the most effective intervention for patients with treatment resistant depression. A clinical decision support tool could guide patient selection to improve the overall response rate and avoid ineffective treatments with adverse effects. Initial small-scale, monocenter studies indicate that both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) biomarkers may predict ECT outcome, but it is not known whether those results can generalize to data from other centers. The objective of this study was to develop and validate neuroimaging biomarkers for ECT outcome in a multicenter setting. METHODS: Multimodal data (i.e. clinical, sMRI and resting-state fMRI) were collected from seven centers of the Global ECT-MRI Research Collaboration (GEMRIC). We used data from 189 depressed patients to evaluate which data modalities or combinations thereof could provide the best predictions for treatment remission (HAM-D score ⩽7) using a support vector machine classifier. RESULTS: Remission classification using a combination of gray matter volume and functional connectivity led to good performing models with average 0.82-0.83 area under the curve (AUC) when trained and tested on samples coming from the three largest centers (N = 109), and remained acceptable when validated using leave-one-site-out cross-validation (0.70-0.73 AUC). CONCLUSIONS: These results show that multimodal neuroimaging data can be used to predict remission with ECT for individual patients across different treatment centers, despite significant variability in clinical characteristics across centers. Future development of a clinical decision support tool applying these biomarkers may be feasible.
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Transtorno Depressivo Maior , Eletroconvulsoterapia , Humanos , Eletroconvulsoterapia/métodos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Maior/patologia , Depressão , Neuroimagem , Imageamento por Ressonância Magnética/métodos , Biomarcadores , Aprendizado de Máquina , Resultado do TratamentoRESUMO
OBJECTIVE: Changes in microbial composition are observed in various psychiatric disorders, but their specificity to certain symptoms or processes remains unclear. This study explores the associations between the gut microbiota composition and the Research Domain Criteria (RDoC) domains of functioning, representing symptom domains, specifically focusing on stress-related and neurodevelopmental disorders in patients with and without psychiatric comorbidity. METHODS: The gut microbiota was analyzed in 369 participants, comprising 272 individuals diagnosed with a mood disorder, anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, and/or substance use disorder, as well as 97 psychiatrically unaffected individuals. The RDoC domains were estimated using principal component analysis (PCA) with oblique rotation on a range of psychiatric, psychological, and personality measures. Associations between the gut microbiota and the functional domains were assessed using multiple linear regression and permanova, adjusted for age, sex, diet, smoking, medication use and comorbidity status. RESULTS: Four functional domains, aligning with RDoC's negative valence, social processes, cognitive systems, and arousal/regulatory systems domains, were identified. Significant associations were found between these domains and eight microbial genera, including associations of negative valence with the abundance of the genera Sellimonas, CHKCI001, Clostridium sensu stricto 1, Oscillibacter, and Flavonifractor; social processes with Sellimonas; cognitive systems with Sporobacter and Hungatella; and arousal/regulatory systems with Ruminococcus torques (all pFDR < 0.05). CONCLUSION: Our findings demonstrate associations between the gut microbiota and the domains of functioning across patients and unaffected individuals, potentially mediated by immune-related processes. These results open avenues for microbiota-focused personalized interventions, considering psychiatric comorbidity. However, further research is warranted to establish causality and elucidate mechanistic pathways.
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Microbioma Gastrointestinal , Transtornos Mentais , Humanos , Microbioma Gastrointestinal/fisiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Transtornos Mentais/microbiologia , Transtorno do Espectro Autista/microbiologia , Transtorno do Deficit de Atenção com Hiperatividade/microbiologia , Transtornos de Ansiedade/microbiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem , Transtornos do Humor/microbiologia , Transtornos do Humor/psicologiaRESUMO
Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.
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OBJECTIVES: It is assumed that neuroplasticity plays a central role in the effect of electroconvulsive therapy (ECT) on patients with major depressive disorder. We carried out an explorative study to map out the extent in which gray matter volume changes could be found directly after ECT treatment and after follow-up. METHODS: Initially, 12 patients with treatment-resistant depression were recruited from the Radboud Medical Center. Magnetic resonance imaging scans were conducted at the following 3 time points: before ECT (n = 12), after ECT (n = 10), and at 3-month follow-up (n = 8). Subcortical volume, hippocampal subfield volume, and cortical thickness were analyzed using FreeSurfer. RESULTS: The extensive, generalized changes in gray matter volume are largely transient after treatment with ECT, with the noted exceptions being a sustained increase in volume of the right amygdala and a part of the left cornu ammonis. Post hoc testing revealed no significant correlation with clinical response. DISCUSSION: Our results suggest that the neuroplastic effects of ECT may not be mediators of clinical response and could be transient epiphenomena.
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Transtorno Depressivo Maior , Eletroconvulsoterapia , Imageamento por Ressonância Magnética , Humanos , Eletroconvulsoterapia/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Transtorno Depressivo Maior/terapia , Adulto , Idoso , Transtorno Depressivo Resistente a Tratamento/terapia , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Seguimentos , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Encéfalo/diagnóstico por imagem , Resultado do Tratamento , Hipocampo/diagnóstico por imagem , Plasticidade Neuronal , Tonsila do Cerebelo/diagnóstico por imagem , Escalas de Graduação PsiquiátricaRESUMO
The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject-specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e-4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R2 = 0.041, p = 5e-4) but not others. This study adds evidence to the ongoing discussion about the misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.
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Transtorno do Deficit de Atenção com Hiperatividade , Psiquiatria , Transtornos Relacionados ao Uso de Substâncias , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Psicopatologia , Transtornos de Ansiedade , Herança Multifatorial/genéticaRESUMO
ABSTRACT: Converging evidence suggests that COVID-19 infects not only the respiratory system, but also has a large impact on the central nervous system (CNS), leading to acute neuropsychiatric symptoms (NPSs) such as anxiety and delirium. It is thus far unclear which acute NPSs are most common in COVID-19 and if NPSs are associated with an altered COVID-19 disease course. We used data from two independent retrospective cohort studies performed in an academic hospital. A total of 93 patients with NPS and 125 patients without NPS were included. Main outcome measures consisted of type of acute NPS, COVID-19 severity (based on CT severity score), admission to the intensive care unit (ICU), and mortality. Most common acute NPSs were delirium, anxiety, and mood symptoms. NPS patients were more often admitted to the ICU than patients without NPS. However, there was no difference in duration of ICU admission, CT severity score, and mortality. Somatic comorbidity was similar between the two groups. These data suggest that delirium, anxiety, and mood symptoms were the most common NPS. Independent of other clinical characteristics, ICU admission in COVID-19 patients was associated with NPS. We recommend that all COVID-19 patients should be actively screened for acute NPS such as delirium, anxiety, and mood symptoms, especially when admitted to an ICU.
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COVID-19 , Delírio , Humanos , Estudos Retrospectivos , Estudos de Coortes , Ansiedade/epidemiologia , Ansiedade/etiologia , Unidades de Terapia Intensiva , Delírio/epidemiologia , Delírio/etiologiaRESUMO
BACKGROUND: Major depressive disorder and bipolar depression in adolescents and young adults are prevalent and major contributors to the global burden of disease, whereas effective interventions are limited. Available evidence is insufficient to assess effectiveness and tolerability of electroconvulsive therapy in depressed adolescents and young adults. METHODS: A retrospective chart review was conducted in patients with major depressive disorder or bipolar depression who underwent electroconvulsive therapy from 2001 to 2021 in 12 centers in the Netherlands. Patients were classified as young (15-25 years) and older adults (26-80 years). Primary outcome was effectiveness, expressed as response (≥50% reduction in rating scale score compared with baseline) and remission. Rating scale scores were cross-sectionally assessed at baseline and at the end of the index course. Outcomes of remitters were included in responders. Secondary outcome was occurrence of subjective cognitive impairment and adverse events. Long-term outcomes were not available. RESULTS: In the young (n = 57) and older adult (n = 41) group, 40.4% and 56.1% (P = 0.153) of patients achieved response and 28.1% and 39.0% (P = 0.281) remission, respectively. Subjective cognitive impairment (80.5% vs 56.3%; P = 0.001) and transient cardiac arrhythmia (14.6% vs 2.8%; P = 0.020) were reported significantly more frequently in the older adult group. CONCLUSIONS: Despite significantly more comorbidity of personality disorders, autism spectrum disorders, and anxiety disorders, effectiveness in the young was similar to the older adults. Tolerability was even superior in the young, despite significantly more bilateral treatment. Electroconvulsive therapy could be considered a viable treatment option in depressed adolescents and young adults.
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BACKGROUND: Major depressive disorder (MDD) is one of the most common psychiatric disorders, however, current treatment options are insufficiently effective for about 35% of patients, resulting in treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neuromodulation that is effective in treating TRD. Not much is known about the comparative efficacy of rTMS and other treatments and their timing within the treatment algorithm, making it difficult for the treating physician to establish when rTMS is best offered as a treatment option. This study aims to investigate the (cost-)effectiveness of rTMS (in combination with cognitive behavioral therapy (CBT) and continued antidepressant medication), compared to the next step in the treatment algorithm. This will be done in a sample of patients with treatment resistant non-psychotic unipolar depression. METHODS: In this pragmatic multicenter randomized controlled trial 132 patients with MDD are randomized to either rTMS or the next pharmacological step within the current treatment protocol (a switch to a tricyclic antidepressant or augmentation with lithium or a second-generation antipsychotic). Both groups also receive CBT. The trial consists of 8 weeks of unblinded treatment followed by follow-up of the cohort at four and 6 months. A subgroup of patients (n = 92) will have an extended follow-up at nine and 12 months to assess effect decay or retention. We expect that rTMS is more (cost-)effective than medication in reducing depressive symptoms in patients with TRD. We will also explore the effects of both treatments on symptoms associated with depression, e.g. anhedonia and rumination, as well as the effect of expectations regarding the treatments on its effectiveness. DISCUSSION: The present trial aims to inform clinical decision making about whether rTMS should be considered as a treatment option in patients with TRD. The results may improve treatment outcomes in patients with TRD and may facilitate adoption of rTMS in the treatment algorithm for depression and its implementation in clinical practice. TRIAL REGISTRATION: This trial is registered within the Netherlands Trial Register (code: NL7628 , date: March 29th 2019).
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Terapia Cognitivo-Comportamental , Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/psicologia , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estimulação Magnética Transcraniana/métodosRESUMO
OBJECTIVE: Perseverative cognition (PC) is the repeated or long-term activation of the cognitive representation of psychological stressors and is associated with prolonged stress including somatic and mental consequences. Hence, PC might represent a cognitive process linking mental and somatic pathology, but current research on this link is limited by investigating healthy samples, markers of somatic disease, and single disorders. The present study explored the importance of PC for different mental and somatic disorders in psychiatric patients. METHODS: Data from 260 naturalistic psychiatric outpatients were used. Psychiatric diagnoses were based on structured clinical interviews. Somatic diseases were assessed using a well-validated questionnaire and were clustered into (cardio)vascular and immune/endocrine diseases. PC was operationalized using the Perseverative Thinking Questionnaire (PTQ). RESULTS: Multiple regression complemented with relative importance analyses showed that the PTQ total and subscale scores were associated with the presence of mood disorders, addiction, and anxiety. Unexpectedly, no relatively important associations were found between the PTQ and autism spectrum disorder, attention-deficit/hyperactivity disorder, or somatic disease. CONCLUSIONS: Our data complement previous work linking PC to stress-related mental disorders but question its immediate role in neurodevelopmental and somatic disorders. Targeting PC in the treatment of mood disorders and perhaps also in addiction seems promising.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Transtornos Mentais , Transtornos de Ansiedade , Cognição , Humanos , Transtornos Mentais/diagnóstico , Transtornos do HumorRESUMO
Major depressive disorder (MDD) is amongst the most prevalent of psychiatric disorders. Unfortunately, a third of patients will not respond to conventional treatments and suffer from treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) has been proven effective in treating TRD. The research suggests that rTMS acts via neuroplastic effects on the brain, which can be measured by changes in hippocampal and amygdala volume as well as cortical thickness. This sham-controlled study investigates longitudinal effects of rTMS on the volumes of the hippocampus and amygdala and cortical thickness in patients with chronic TRD. 31 patients received 20 sessions of high-frequency rTMS (N = 15) or sham treatment (N = 16) over the left dorsolateral prefrontal cortex during 4 consecutive weeks. Using structural magnetic resonance imaging, we investigated longitudinal treatment effects on hippocampus and amygdala volume as well as thickness of the paralimbic cortex. We found no clinical differences between the active and sham rTMS group. Longitudinal changes in hippocampal and amygdala volume did not differ significantly, although males showed a significant decrease in left amygdala volume, irrespective of treatment group. Changes in cortical thickness of the paralimbic cortex differed significantly between the active and sham groups. Most notably, the increase in cortical thickness of the isthmus of the left cingulate gyrus was greater in the active as compared to the sham rTMS group. Our data suggest that rTMS can induce neuroplastic changes, particularly in cortical thickness, independent of treatment response. We also found longitudinal changes in amygdala volume in males. For clinical effects to follow these neuroplastic effects, more intensive rTMS treatment might be needed in chronically depressed patients.Trial registration number: ISRCTN 15535800, registered on 29-06-2017.
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Transtorno Depressivo Maior/terapia , Transtorno Depressivo Resistente a Tratamento/terapia , Plasticidade Neuronal , Estimulação Magnética Transcraniana , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Córtex Pré-Frontal Dorsolateral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Mood-congruent memory bias is a critical characteristic of depression, but the underlying neural mechanism is largely unknown. Negative memory schemas might enhance encoding and consolidation of negative experiences, thereby contributing to the genesis and perpetuation of depressive pathology. To investigate this relationship, we aimed to perturb medial prefrontal cortex (mPFC) processing, using neuronavigated transcranial magnetic stimulation (TMS) targeting the mPFC. Forty healthy volunteers first underwent a negative mood induction to activate negative schema processing after which they received either active inhibitory (N = 20) or control (N = 20) stimulation to the mPFC. Then, all participants performed the encoding of an emotional false memory task. Recall and recognition performance was tested the following morning. Polysomnographic data were recorded continuously during the night before and after encoding. We observed a significantly lower false recognition of negative critical lures following mPFC inhibition, but no differences in veridical memory. These findings were supported by reaction time data, showing a relative slower response to negative compared with positive critical lures. The current findings support previous causal evidence for a role of the mPFC in schema memory processing and further suggest a role of the mPFC in memory bias.
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Depressão/psicologia , Emoções , Memória , Córtex Pré-Frontal , Estimulação Magnética Transcraniana , Adolescente , Adulto , Afeto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Rememoração Mental , Reconhecimento Psicológico , Adulto JovemRESUMO
BACKGROUND: Already a major health concern, late-life depression (LLD) is expected to form an increasing problem in the aging population. Moreover, despite current treatments, LLD is associated with a poor long-term prognosis and high rate of chronicity. Treatment provision and treatment accordingly warrant improvement, where add-on treatments might contribute to the efficacy of conventional therapies. Although it is known that impaired cognitive control contributes to LDD, it is not targeted sufficiently by current interventions. Research on cognitive control training (CCT) shows promising results on depressive symptoms, cognitive performance, and overall functioning. However, further research is needed to determine the long-term effects of CCT on LLD, its cost-effectiveness, and mechanisms of change. METHODS: In the current multicenter randomized controlled trial (RCT) with a between-subjects design participants aged 60 years and over with a current LLD receiving treatment as usual (TAU) are randomized to add-on CCT or placebo training. Randomization is stratified by depression severity. Participants will receive eight online CCT or placebo sessions spread across four consecutive weeks. They will complete a post-training assessment after 1 month and three follow-up assessments scheduled three, six and 12 months after completing the training. We expect CCT and TAU to be more (cost-)effective in reducing depressive symptoms than placebo training and TAU. Additionally, we will be looking at secondary clinical, cognitive and global functioning outcomes and likely mechanisms of change (e.g., improved cognitive functioning, reduced rumination, and improved inhibition of negative stimuli). DISCUSSION: The proposed RCT aims to contribute to the clinical and scientific knowledge on the long-term effects of CCT as an add-on treatment for LLD. Cost-effectiveness is particularly relevant considering the expected volume of the target demographic. The study will be a pragmatic trial with few inclusion restrictions, providing information on feasibility of web-based trainings in clinical settings. The outcomes are potentially generalizable to guidelines for treatment of LLD. TRIAL REGISTRATION: This trial is registered in the Netherlands Trial Register (code: NL7639 ). Registered 3 april 2019.
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Disfunção Cognitiva , Depressão , Idoso , Cognição , Disfunção Cognitiva/terapia , Análise Custo-Benefício , Depressão/terapia , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: Major depressive disorder (MDD) is a considerable public health concern. In spite of evidence-based treatments for MDD, many patients do not improve and relapse is common. Therefore, improving treatment outcomes is much needed and adjunct exercise treatment may have great potential. Exercise was shown to be effective as monotherapy for depression and as augmentation strategy, with evidence for increasing neuroplasticity. Data on the cost-effectiveness and the long-term effects of adjunct exercise treatment are missing. Similarly, the cognitive pathways toward remission are not well understood. METHODS: The present study is designed as a multicenter randomized superiority trial in two parallel groups with follow-up assessments up to 15 months. Currently depressed outpatients (N = 120) are randomized to guideline concordant Standard Care (gcSC) alone or gcSC with adjunct exercise treatment for 12 weeks. Randomization is stratified by gender and setting, using a four, six, and eight block design. Exercise treatment is offered in accordance with the NICE guidelines and empirical evidence, consisting of one supervised and two at-home exercise sessions per week at moderate intensity. We expect that gcSC with adjunct exercise treatment is more (cost-)effective in decreasing depressive symptoms compared to gcSC alone. Moreover, we will investigate the effect of adjunct exercise treatment on other health-related outcomes (i.e. functioning, fitness, physical activity, health-related quality of life, and motivation and energy). In addition, the mechanisms of change will be studied by exploring any change in rumination, self-esteem, and memory bias as possible mediators between exercise treatment and depression outcomes. DISCUSSION: The present trial aims to inform the scientific and clinical community about the (cost-)effectiveness and psychosocial mechanisms of change of adjunct exercise treatment when implemented in the mental health service setting. Results of the present study may improve treatment outcomes in MDD and facilitate implementation of prescriptive exercise treatment in outpatient settings. TRIAL REGISTRATION: This trial is registered within the Netherlands Trial Register (code: NL8432 , date: 6th March, 2020).
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Transtorno Depressivo Maior , Análise Custo-Benefício , Depressão , Transtorno Depressivo Maior/terapia , Exercício Físico , Humanos , Países Baixos , Qualidade de Vida , Resultado do TratamentoRESUMO
Type 2 diabetes (T2D) is associated with an accelerated episodic memory decline, but the underlying pathophysiological mechanisms are not well understood. Hallmarks of T2D comprise impairment of insulin secretion and insulin sensitivity. Insulin signaling modulates cerebral neurotransmitter activity, including the excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) systems. Here we tested the hypothesis that the glutamate and GABA systems are altered in T2D patients and this relates to memory decline and insulin resistance. Using 1 H-magnetic resonance spectroscopy (MRS), we examined glutamate and GABA concentrations in episodic memory relevant brain regions (medial prefrontal cortex and precuneus) of T2D patients and matched controls. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps and memory performance was assessed using a face-profession associations test. T2D patients exhibited peripheral insulin resistance and had a decreased memory for face-profession associations as well as elevated GABA concentration in the medial prefrontal cortex but not precuneus. In addition, medial prefrontal cortex GABA concentration was negatively associated with memory performance suggesting that abnormal GABA levels in the medial prefrontal cortex are linked to the episodic memory decline that occurs in T2D patients.
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Diabetes Mellitus Tipo 2/metabolismo , Transtornos da Memória/metabolismo , Memória Episódica , Córtex Pré-Frontal/metabolismo , Ácido gama-Aminobutírico/metabolismo , Adulto , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Transtornos da Memória/etiologia , Pessoa de Meia-Idade , Ácido gama-Aminobutírico/análiseRESUMO
The ability to temporarily prioritize rapid and vigilant reactions over slower higher-order cognitive functions is essential for adaptive responding to threat. This reprioritization is believed to reflect shifts in resource allocation between large-scale brain networks that support these cognitive functions, including the salience and executive control networks. However, how changes in communication within and between such networks dynamically unfold as a function of threat-related arousal remains unknown. To address this issue, we collected functional MRI data and continuously assessed the heart rate from 120 healthy human adults as they viewed emotionally arousing and ecologically valid cinematographic material. We then developed an analysis method that tracks dynamic changes in large-scale network cohesion by quantifying the level of within-network and between-network interaction. We found a monotonically increasing relationship between heart rate, a physiological index of arousal, and within-network cohesion in the salience network, indicating that coordination of activity within the salience network dynamically tracks arousal. Strikingly, salience-executive control between-network cohesion peaked at moderate arousal. These findings indicate that at moderate arousal, which has been associated with optimal noradrenergic signaling, the salience network is optimally able to engage the executive control network to coordinate cognitive activity, but is unable to do so at tonically elevated noradrenergic levels associated with acute stress. Our findings extend neurophysiological models of the effects of stress-related neuromodulatory signaling at the cellular level to large-scale neural systems, and thereby explain shifts in cognitive functioning during acute stress, which may play an important role in the development and maintenance of stress-related mental disorders. SIGNIFICANCE STATEMENT: How does brain functioning change in arousing or stressful situations? Extant literature suggests that through global projections, arousal-related neuromodulatory changes can rapidly alter coordination of neural activity across brain-wide neural systems or large-scale networks. Since it is unknown how such processes unfold, we developed a method to dynamically track levels of within-network and between-network interaction. We applied this technique to human neuroimaging data acquired while participants watched realistic and emotionally arousing cinematographic material. Results demonstrate that cohesion within the salience network monotonically increases with arousal, while cohesion of this network with the executive control network peaks at moderate arousal. Our findings explain how cognitive performance shifts as a function of arousal, and provide new insights into vulnerability for stress-related psychopathology.
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Nível de Alerta/fisiologia , Encéfalo/fisiologia , Função Executiva/fisiologia , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/fisiologia , Adulto , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Childhood adversity (CA) leads to greater vulnerability for psychopathology by causing structural as well as functional brain abnormalities. Recent findings on gray matter effects point towards the importance of identifying CA outcome as a function of different CA types, varying in the dimensions of threat and deprivation. Using diffusion tensor imaging, we investigate whether different forms of CA impact differently on white matter connectivity in a healthy cohort not confounded by other aspects of disease. METHODS: In 120 healthy young males, we assessed different forms of maltreatment during childhood with the Childhood Trauma Questionnaire (CTQ). Fractional anisotropy (FA) and mean diffusivity (MD) images were generated and projected onto a white matter skeleton using tract-based spatial statistics. Correlational analysis between FA, MD, and CTQ subscores was then performed using voxelwise statistics. RESULTS: Of all CTQ-subscores, only physical neglect (PN) predicted a decrease of FA but not MD in the bilateral anterior thalamic radiation around the middle frontal gyrus and the right inferior fronto-occipital fasciculus, the inferior longitudinal fasciculus, the cingulum and precuneus. Reduced FA in the posterior cingulum was related to the effects of PN during childhood on anxiety levels at trend level. CONCLUSIONS: PN may have severe consequences and should be considered equally important to more active forms of abuse. FA changes, particularly in the cingulum, actually appear to a functional consequence and are linked to trait anxiety, a personality dimension that is suggested to be a transdiagnostic risk factor of affective disorders. Potentially this reveals a mechanistic chain that forms one pathyway from CA to disease.
Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis , Encéfalo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adolescente , Adulto , Ansiedade , Estudos de Coortes , Imagem de Tensor de Difusão , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Personalidade , Adulto JovemRESUMO
The classical model of the declarative memory system describes the hippocampus and its interactions with representational brain areas in posterior neocortex as being essential for the formation of long-term episodic memories. However, new evidence suggests an extension of this classical model by assigning the medial prefrontal cortex (mPFC) a specific, yet not fully defined role in episodic memory. In this study, we utilized 1H magnetic resonance spectroscopy (MRS) and psychophysiological interaction (PPI) analysis to lend further support for the idea of a mnemonic role of the mPFC in humans. By using MRS, we measured mPFC γ-aminobutyric acid (GABA) and glutamate/glutamine (GLx) concentrations before and after volunteers memorized face-name association. We demonstrate that mPFC GLx but not GABA levels increased during the memory task, which appeared to be related to memory performance. Regarding functional connectivity, we used the subsequent memory paradigm and found that the GLx increase was associated with stronger mPFC connectivity to thalamus and hippocampus for associations subsequently recognized with high confidence as opposed to subsequently recognized with low confidence/forgotten. Taken together, we provide new evidence for an mPFC involvement in episodic memory by showing a memory-related increase in mPFC excitatory neurotransmitter levels that was associated with better memory and stronger memory-related functional connectivity in a medial prefrontal-thalamus-hippocampus network.