Neural effects of deep brain stimulation on reward and loss anticipation and food viewing in anorexia nervosa: a pilot study.

BACKGROUND: Anorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Initial studies on deep brain stimulation (DBS) in severe, treatment-refractory AN have shown clinical effects. However, the working mechanisms of DBS in AN remain largely unknown. Here, we used a task-based functional MRI approach to understand the pathophysiology of AN. METHODS: We performed functional MRI on four AN patients that participated in a pilot study on the efficacy, safety, and functional effects of DBS targeted at the ventral limb of the capsula interna (vALIC). The patients and six gender-matched healthy controls (HC) were investigated at three different time points. We used an adapted version of the monetary incentive delay task to probe generic reward processing in patients and controls, and a food-specific task in patients only. RESULTS: At baseline, no significant differences for reward anticipation were found between AN and HC. Significant group (AN and HC) by time (pre- and post-DBS) interactions were found in the right precuneus, right putamen, right ventral and medial orbitofrontal cortex (mOFC). No significant interactions were found in the food viewing task, neither between the conditions high-calorie and low-calorie food images nor between the different time points. This could possibly be due to the small sample size and the lack of a control group. CONCLUSION: The results showed a difference in the response of reward-related brain areas post-DBS. This supports the hypotheses that the reward circuitry is involved in the pathogenesis of AN and that DBS affects responsivity of reward-related brain areas. Trial registration Registered in the Netherlands Trial Register ( https://www.trialregister.nl/trial/3322 ): NL3322 (NTR3469).

Anorexia Nervosa (An) is a severe eating disorder with many, sometimes life-threatening, complications. A substantial number of AN patients do not respond to the available treatment options and remain chronically ill or even die as a consequence of the AN. Because part of the causes of AN may reside in the brain, we studied the efficacy and safety of a potential new treatment option for AN, namely deep brain stimulation (DBS). DBS has proven to be an effective treatment option for movements disorders like Parkinson's Disease and other psychiatric disorders such as obsessive compulsive disorder. Our previous pilot study and other research have shown that DBS leads to improvements in weight, mood, anxiety, and eating disorder symptoms. In this substudy, we examined the effects of DBS on specific brain circuitries that are implicated in AN. We conducted brain scans (fMRI) to measure brain activity while patients performed tasks. We observed a difference in brain response when we compared scans taken before and after the DBS, which supports our thoughts on the involvement of specific parts of the brain in AN.

Polyunsaturated fatty acids changes during electroconvulsive therapy in major depressive disorder.

Polyunsaturated fatty acids (PUFAs) have important electrochemical properties and have been implicated in the pathophysiology of major depressive disorder (MDD) and its treatment. However, the relation of PUFAs with electroconvulsive therapy (ECT) has never been investigated. Therefore, we aimed to explore the associations between PUFA concentrations and response to ECT in patients with MDD. We included 45 patients with unipolar MDD in a multicentre study. To determine PUFA concentrations, we collected blood samples at the first (T0) and twelfth (T12) ECT-session. We assessed depression severity using the Hamilton Rating Scale for Depression (HAM-D) at T0, T12 and at the end of the ECT-course. ECT-response was defined as 'early response' (at T12), 'late response' (after ECT-course) and 'no' response (after the ECT-course). The PUFA chain length index (CLI), unsaturation index (UI) and peroxidation index (PI) and three individual PUFAs (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA] and nervonic acid [NA]) were associated with response to ECT using linear mixed models. Results showed a significant higher CLI in 'late responders' compared to 'non responders'. For NA, 'late responders' showed significantly higher concentrations compared to 'early'- and 'non responders'. In conclusion, this study provides the first indication that PUFAs are associated with the efficacy of ECT. This indicates that PUFAs' influence on neuronal electrochemical properties and neurogenesis may affect ECT outcomes. Thereby, PUFAs form a potentially modifiable factor predicting ECT outcomes, that warrants further investigation in other ECT-cohorts.

Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Psychological distress modulates dorsal anterior cingulate cortex responses to salient stimuli in obsessive-compulsive disorder.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) experience an exacerbation of symptoms under psychological distress. The neurobiological underpinnings of this effect of stress remain elusive. Here, we induced psychological distress to explore its effect on neural reactivity of the salience network during a symptom provocation task. METHODS: Twenty-three patients with OCD and twenty-three healthy volunteers underwent functional magnetic resonance imaging scanning after stress induction and a control condition in a cross-over design. Psychological distress was induced using the socially evaluated cold pressor test (SECPT) and neural responses were measured during a symptom provocation task. RESULTS: OCD participants showed a blunted cortisol response to the stressor. We found a group by stress interaction effect in the dorsal anterior cingulate cortex (dACC), such that psychological distress reduced dACC reactivity to emotionally salient pictures in OCD participants, whereas it increased dACC reactivity in healthy controls. LIMITATIONS: A considerable proportion of OCD participants was on medication, and the neuroimaging session was conducted more than 1 h after the initial stressor. CONCLUSIONS: Considering this timeline, we speculate that the blunted dACC reactivity towards emotionally salient pictures in OCD participants may reflect impaired emotion regulation in the aftermath of stress.

Electroencephalography for predicting antidepressant treatment success: A systematic review and meta-analysis.

BACKGROUND: Patients suffering from major depressive disorder (MDD) regularly experience non-response to treatment for their depressive episode. Personalized clinical decision making could shorten depressive episodes and reduce patient suffering. Although no clinical tools are currently available, machine learning analysis of electroencephalography (EEG) shows promise in treatment response prediction. METHODS: With a systematic review and meta-analysis, we evaluated the accuracy of EEG for individual patient response prediction. Importantly, we included only prediction studies that used cross-validation. We used a bivariate model to calculate prediction success, as expressed by area-under the curve, sensitivity and specificity. Furthermore, we analyzed prediction success for separate antidepressant interventions. RESULTS: 15 studies with 12 individual patient samples and a total of 479 patients were included. Research methods varied considerably between studies. Meta-analysis of results from this heterogeneous set of studies resulted in an area under the curve of 0.91, a sensitivity of 83 % (95 % CI 74-89 %), and a specificity of 86 % (95 % CI 81-90 %). Classification performance did not significantly differ between treatments. Although studies were all internally validated, no externally validated studies have been reported. We found substantial risk of bias caused by methodological shortcomings such as non-independent feature selection, though performance of non-biased studies was comparable. LIMITATIONS: Sample sizes were relatively small and no study used external validation, increasing the risk of overestimation of accuracy. CONCLUSIONS: Electroencephalography can predict the response to antidepressant treatment with high accuracy. However, future studies with more rigorous validation are needed to produce a clinical tool to guide interventions in MDD. PROSPERO REGISTRATION NUMBER: CRD42021268169.

[Functional brain networks for diagnostics and the prediction of treatment outcome]. / Functionele hersennetwerken voor diagnostiek en de voorspelling van behandeluitkomst.

BACKGROUND: Functional MRI offers insight into the functioning of brain networks of patients with psychiatric disorders. Machine learning analysis can be used to create diagnostic models and to predict treatment outcome. AIM: To provide an overview of recent insights on diagnostic and predictive neuroimaging biomarkers. METHOD: Narrative review based on recent literature. RESULTS: Large-scale studies suggest that diagnostic models for most disorders have limited accuracy. In contrast, meta-analyses of small-scale studies suggest that treatment outcome for depression and psychotic disorders can be predicted well. CONCLUSION: This creates the opportunity to develop prediction models that can help practitioners in making a treatment plan and thereby improve treatment outcomes.

Multimodal multi-center analysis of electroconvulsive therapy effects in depression: Brainwide gray matter increase without functional changes.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for severe depression and induces gray matter (GM) increases in the brain. Small-scale studies suggest that ECT also leads to changes in brain functioning, but findings are inconsistent. In this study, we investigated the influence of ECT on changes in both brain structure and function and their relation to clinical improvement using multicenter neuroimaging data from the Global ECT-MRI Research Collaboration (GEMRIC). METHODS: We analyzed T1-weighted structural magnetic resonance imaging (MRI) and functional resting-state MRI data of 88 individuals (49 male) with depressive episodes before and within one week after ECT. We performed voxel-based morphometry on the structural data and calculated fractional amplitudes of low-frequency fluctuations, regional homogeneity, degree centrality, functional connectomics, and hippocampus connectivity for the functional data in both unimodal and multimodal analyses. Longitudinal effects in the ECT group were compared to repeated measures of healthy controls (n = 27). RESULTS: Wide-spread increases in GM volume were found in patients following ECT. In contrast, no changes in any of the functional measures were observed, and there were no significant differences in structural or functional changes between ECT responders and non-responders. Multimodal analysis revealed that volume increases in the striatum, supplementary motor area and fusiform gyrus were associated with local changes in brain function. CONCLUSION: These results confirm wide-spread increases in GM volume, but suggest that this is not accompanied by functional changes or associated with clinical response. Instead, focal changes in brain function appear related to individual differences in brain volume increases.

Attachment in OCD: A meta-analysis.

INTRODUCTION: It has been proposed to extend the cognitive-behavioural model of obsessive-compulsive disorder (OCD) with attachment theory to shed light on the affective and developmental factors underlying the disease. With a growing number of empirical studies on the subject, this meta-analysis aims to quantify a possible relationship between attachment insecurity and OCD. METHODS: A systematic search was conducted for studies in adult populations of patients with OCD as well as general populations displaying symptoms of OCD. Effect sizes of attachment anxiety and attachment avoidance were calculated separately. Covariates of demographic variables were used in meta-regressions. RESULTS: Sixteen studies were included. Meta-analyses showed an association of medium to large effect size (Hedges' g = 0.69; 95 % CI 0.58 - 0.80; p < 0.001) between OCD and attachment anxiety, and an association of medium effect size (Hedges' g = 0.47; 95 % CI 0.39 - 0.54; p < 0.001) between OCD and attachment avoidance. Effect sizes in OCD population and general population studies did not differ significantly. DISCUSSION: Robust effect sizes of both attachment anxiety and avoidance in relation to OCD symptomatology corroborate an attachment-centred view of OCD. These findings furthermore suggest that integrating cognitive and attachment-based therapeutic approaches to OCD may benefit patients in which developmental or emotional factors hinder successful treatment.

[Reaction on 'Persistant underuse of ECT for persistant depressive disorder?'] / Reactie op 'Persisterend ondergebruik van ECT bij persisterende depressieve stoornis?'.

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[Electroconvulsion therapy for persistent depression in the Netherlands; very low application rate]. / Elektroconvulsietherapie bij persisterende depressie in Nederland; zeer lage toepassingsgraad.

BACKGROUND: Of all depressive disorders, 20% has a persistent course. For persistent depressive patients, electroconvulsive therapy (ect) is recommended for this patient population, since it is the most potent treatment for depression. The Dutch depression guideline advises the use of ect for persistent depressive disorder at approximately 12 months after inadequate efficacy of psychotherapy and/or pharmacological treatment.
AIM: To quantify the use of electroconvulsive therapy in persistent depressive patients in the Netherlands.
METHOD: Quantitative research using the Dutch registration system (diagnosis-treatment-combination; dbc) information system (dis) of the Dutch Healthcare Authority (nza).
RESULTS: Of the patients within the dbc system (in 2014) with the main diagnosis of unipolar depression, 23,597 (26%) were registered for more than two years and could be classified as having a persistent depressive episode. Of these latter patients, only 278 (1.2%) received ect.
CONCLUSION: In the Netherlands, only 1.2% of patients with a persistent depression received ect, whereas this treatment could have been considered for 26% of this group. The low application rate might be caused by professionals' inadequate knowledge about ect and the premature use of the handicap model.

Individual white matter bundle trajectories are associated with deep brain stimulation response in obsessive-compulsive disorder.

BACKGROUND: The ventral anterior limb of the internal capsule (vALIC) is a target for deep brain stimulation (DBS) in obsessive-compulsive disorder (OCD). Conventional surgical planning is based on anatomical landmarks. OBJECTIVE/HYPOTHESIS: We hypothesized that treatment response depends on the location of the active DBS contacts with respect to individual white matter bundle trajectories. This study thus aimed to elucidate whether vALIC DBS can benefit from bundle-specific targeting. METHODS: We performed tractography analysis of two fiber bundles, the anterior thalamic radiation (ATR) and the supero-lateral branch of the medial forebrain bundle (MFB), using diffusion-weighted magnetic resonance imaging (DWI) data. Twelve patients (10 females) who had received bilateral vALIC DBS for at least 12 months were included. We related the change in OCD symptom severity on the Yale-Brown obsessive-compulsive scale (Y-BOCS) between baseline and one-year follow-up with the distances from the active contacts to the ATR and MFB. We further analyzed the relation between treatment response and stimulation sites in standard anatomical space. RESULTS: We found that active stimulation of the vALIC closer to the MFB than the ATR was associated with better treatment outcome (p = 0.04; r2 = 0.34). In standard space, stimulation sites were largely overlapping between treatment (non)responders, suggesting response is independent of the anatomically defined electrode position. CONCLUSION: These findings suggest that vALIC DBS for OCD may benefit from MFB-specific implantation and highlight the importance of corticolimbic connections in OCD response to DBS. Prospective investigation is necessary to validate the clinical use of MFB targeting.

Conflicted between Goal-Directed and Habitual Control, an fMRI Investigation.

"Slips of action" occur in everyday life when we momentarily lose sight of a goal (for example, when in a rush or distracted). Associative models propose that these habitual responses can be activated via a direct stimulus-response (S-R) mechanism, regardless of the current hedonic value of the outcome. The slips-of-action task (SOAT) has been extensively used in both healthy and pathological populations to measure habit tendencies, the likelihood of making erroneous responses for devalued outcomes. Inspection of behavioral performance does not reveal, however, whether the impairments were due to impaired goal-directed control or aberrantly strong habit formation. In the current study, we used functional MRI while human participants performed both the instrumental training and SOAT test phases, to elucidate the relative contributions of these mechanisms to performance on the SOAT. On trials in which conflict arises between competing goal-directed and habitual responses, we observed increased activation across areas including the anterior cingulate cortex, paracingulate gyrus, lateral orbitofrontal cortex (OFC), insula, and inferior frontal gyrus (IFG). Responding for devalued outcomes was related to increased activation in the premotor cortex and cerebellum, implicating these regions in habitual responding. Increased activation in the caudate, dorsolateral prefrontal cortex (dlPFC), and frontal pole during training was associated with better performance during the test phase, indicative of goal-directed action control. These results endorse interpretation of the SOAT in terms of competing goal-directed and habitual mechanisms and highlight that cognitive control processes present an additional bottleneck for successful performance on this task.

The relation between gray matter volume and the use of alcohol, tobacco, cocaine and cannabis in male polysubstance users.

BACKGROUND: Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use. METHODS: In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine. RESULTS: Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively. CONCLUSION: These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders.

Impact of treatment on resting cerebral blood flow and metabolism in obsessive compulsive disorder: a meta-analysis.

Neurobiological models of obsessive-compulsive disorder (OCD) posit that its clinical symptoms such as repetitive thoughts and behaviors are related to hyperactivity in the cortico-striato-thalamo-cortical (CSTC) circuit. Small scale neuroimaging studies have shown that treatment of OCD is associated with reduced activity across different brain structures within this circuitry. We performed the first meta-analysis of positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies that investigated cerebral blood flow or glucose metabolism in patients with OCD before and after pharmacological or psychological treatment. We calculated standardized mean differences for the regions-of-interest most often reported. The meta-analysis revealed small reductions in activity in the caudate nucleus and orbitofrontal cortex after treatment with a serotonin reuptake inhibitor or cognitive behavioral therapy. Small reductions were also observed in the thalamus when one SPECT study with a large opposite effect was excluded from the analysis. Meta-regression analyses for the caudate nucleus showed no significant effect of the type of treatment, decrease in symptom severity, mean duration until the follow-up scan, or year of publication. These results show that pharmacological and psychological treatments reduce resting CSTC circuit activity, and provide further support for the CSTC circuit model in OCD.

Rhythmic finger tapping reveals cerebellar dysfunction in essential tremor.

INTRODUCTION: Cerebellar circuits are hypothesized to play a central role in the pathogenesis of essential tremor. Rhythmic finger tapping is known to strongly engage the cerebellar motor circuitry. We characterize cerebellar and, more specifically, dentate nucleus function, and neural correlates of cerebellar output in essential tremor during rhythmic finger tapping employing functional MRI. METHODS: Thirty-one propranolol-sensitive essential tremor patients with upper limb tremor and 29 healthy controls were measured. T2*-weighted EPI sequences were acquired. The task consisted of alternating rest and finger tapping blocks. A whole-brain and region-of-interest analysis was performed, the latter focusing on the cerebellar cortex, dentate nucleus and inferior olive nucleus. Activations were also related to tremor severity. RESULTS: In patients, dentate activation correlated positively with tremor severity as measured by the tremor rating scale part A. Patients had reduced activation in widespread cerebellar cortical regions, and additionally in the inferior olive nucleus, and parietal and frontal cortex, compared to controls. CONCLUSION: The increase in dentate activation with tremor severity supports involvement of the dentate nucleus in essential tremor. Cortical and cerebellar changes during a motor timing task in essential tremor might point to widespread changes in cerebellar output in essential tremor.

A functional MRI marker may predict the outcome of electroconvulsive therapy in severe and treatment-resistant depression.

Electroconvulsive therapy (ECT) is effective even in treatment-resistant patients with major depression. Currently, there are no markers available that can assist in identifying those patients most likely to benefit from ECT. In the present study, we investigated whether resting-state network connectivity can predict treatment outcome for individual patients. We included forty-five patients with severe and treatment-resistant unipolar depression and collected functional magnetic resonance imaging scans before the course of ECT. We extracted resting-state networks and used multivariate pattern analysis to discover networks that predicted recovery from depression. Cross-validation revealed two resting-state networks with significant classification accuracy after correction for multiple comparisons. A network centered in the dorsomedial prefrontal cortex (including the dorsolateral prefrontal cortex, orbitofrontal cortex and posterior cingulate cortex) showed a sensitivity of 84% and specificity of 85%. Another network centered in the anterior cingulate cortex (including the dorsolateral prefrontal cortex, sensorimotor cortex, parahippocampal gyrus and midbrain) showed a sensitivity of 80% and a specificity of 75%. These preliminary results demonstrate that resting-state networks may predict treatment outcome for individual patients and suggest that resting-state networks have the potential to serve as prognostic neuroimaging biomarkers to guide personalized treatment decisions.

Allopregnanolone and mood disorders.

UNLABELLED: Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone. CONCLUSION: These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor.