Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face-viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two-time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. This effect was not dependent on emotional valence. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices, which was not significantly different between responders and non-responders. These results suggest that vALIC DBS restores amygdala responsivity and behavioral vigilance in TRD, which may contribute to the DBS-induced antidepressant effect.

Development and validation of the Autonomy Scale Amsterdam.

This paper describes the development and validation of the Autonomy Scale Amsterdam (ASA). We propose that a new measure of autonomy is needed and, as such, we developed and validated an autonomy scale relevant for psychiatry. Based on literature, an expert meeting and three samples of the general population (N = 298, N = 207, N = 309) we provide evidence (a) that supports a 6-factor structure model as a better fit than alternative models with a high reliability to capture the concept of autonomy consisting of: Self-integration, Engagement with life, Goal-directedness, Self-control, External constraints and Social support, (b) for the scale's convergent and discriminant validity with constructs in autonomy's nomological network and (c) for the scale's criterion validity with well-established well-being outcomes, and (d) that the measure is not redundant with a prior measure of autonomy, the autonomy-connectedness scale, and demonstrates incremental validity in the prediction of mental health over and above an existing measure of autonomy. Taken together, the results suggest that the ASA is a useful scale that shows positive evidence of psychometric quality to measure autonomy in a sample of the general population (total N = 856), accounting for a unique predictive value over and above an existing measure of autonomy concerning several mental health outcomes. The ASA can further help our understanding of the role of autonomy in mental disorders.

Differences in metacognitive functioning between obsessive-compulsive disorder patients and highly compulsive individuals from the general population.

BACKGROUND: Our confidence, a form of metacognition, guides our behavior. Confidence abnormalities have been found in obsessive-compulsive disorder (OCD). A first notion based on clinical case-control studies suggests lower confidence in OCD patients compared to healthy controls. Contrarily, studies in highly compulsive individuals from general population samples showed that obsessive-compulsive symptoms related positively or not at all to confidence. A second notion suggests that an impairment in confidence estimation and usage is related to compulsive behavior, which is more often supported by studies in general population samples. These opposite findings call into question whether findings from highly compulsive individuals from the general population are generalizable to OCD patient populations. METHODS: To test this, we investigated confidence at three hierarchical levels: local confidence in single decisions, global confidence in task performance and higher-order self-beliefs in 40 OCD patients (medication-free, no comorbid diagnoses), 40 controls, and 40 matched highly compulsive individuals from the general population (HComp). RESULTS: In line with the first notion we found that OCD patients exhibited relative underconfidence at all three hierarchical levels. In contrast, HComp individuals showed local and global overconfidence and worsened metacognitive sensitivity compared with OCD patients, in line with the second notion. CONCLUSIONS: Metacognitive functioning observed in a general highly compulsive population, often used as an analog for OCD, is distinct from that in a clinical OCD population, suggesting that OC symptoms in these two groups relate differently to (meta)cognitive processes. These findings call for caution in generalizing (meta)cognitive findings from general population to clinical samples.

Metacognition and the effect of incentive motivation in two compulsive disorders: Gambling disorder and obsessive-compulsive disorder.

AIMS: Compulsivity is a common phenotype among psychiatric disorders, such as obsessive-compulsive disorder (OCD) and gambling disorder (GD). Deficiencies in metacognition, such as the inability to estimate one's performance via confidence judgments could contribute to pathological decision-making. Earlier research has shown that patients with OCD exhibit underconfidence, while patients with GD exhibit overconfidence. Moreover, it is known that motivational states (e.g. monetary incentives) influence metacognition, with gain (respectively loss) prospects increasing (respectively decreasing) confidence. Here, we reasoned that OCD and GD symptoms might correspond to an exacerbation of this interaction between metacognition and motivation. METHODS: We hypothesized GD's overconfidence to be exaggerated during gain prospects, while OCD's underconfidence to be worsened in loss context, which we expected to see represented in ventromedial prefrontal cortex (VMPFC) blood-oxygen-level-dependent activity. We tested those hypotheses in a task-based functional magnetic resonance imaging (fMRI) design (27 patients with GD, 28 patients with OCD, 55 controls). The trial is registered in the Dutch Trial Register (NL6171). RESULTS: We showed increased confidence for patients with GD versus patients with OCD, which could partly be explained by sex and IQ. Although our primary analyses did not support the hypothesized interaction between incentives and groups, exploratory analyses did show increased confidence in patients with GD specifically in gain context. fMRI analyses confirmed a central role for VMPFC in the processing of confidence and incentives, but no differences between the groups. CONCLUSION: Patients with OCD and those with GD reside at opposite ends of the confidence spectrum, while no interaction with incentives was found, nor group differences in neuronal processing of confidence.

Deep brain stimulation modulates directional limbic connectivity in obsessive-compulsive disorder.

Deep brain stimulation is effective for patients with treatment-refractory obsessive-compulsive disorder. Deep brain stimulation of the ventral anterior limb of the internal capsule rapidly improves mood and anxiety with optimal stimulation parameters. To understand these rapid effects, we studied functional interactions within the affective amygdala circuit. We compared resting state functional MRI data during chronic stimulation versus 1 week of stimulation discontinuation in patients, and obtained two resting state scans from matched healthy volunteers to account for test-retest effects. Imaging data were analysed using functional connectivity analysis and dynamic causal modelling. Improvement in mood and anxiety following deep brain stimulation was associated with reduced amygdala-insula functional connectivity. Directional connectivity analysis revealed that deep brain stimulation increased the impact of the ventromedial prefrontal cortex on the amygdala, and decreased the impact of the amygdala on the insula. These results highlight the importance of the amygdala circuit in the pathophysiology of obsessive-compulsive disorder, and suggest a neural systems model through which negative mood and anxiety are modulated by stimulation of the ventral anterior limb of the internal capsule for obsessive-compulsive disorder and possibly other psychiatric disorders.

Efficacy of Invasive and Non-Invasive Brain Modulation Interventions for Addiction.

It is important to find new treatments for addiction due to high relapse rates despite current interventions and due to expansion of the field with non-substance related addictive behaviors. Neuromodulation may provide a new type of treatment for addiction since it can directly target abnormalities in neurocircuits. We review literature on five neuromodulation techniques investigated for efficacy in substance related and behavioral addictions: transcranial direct current stimulation (tDCS), (repetitive) transcranial magnetic stimulation (rTMS), EEG, fMRI neurofeedback and deep brain stimulation (DBS) and additionally report on effects of these interventions on addiction-related cognitive processes. While rTMS and tDCS, mostly applied at the dorsolateral prefrontal cortex, show reductions in immediate craving for various addictive substances, placebo-responses are high and long-term outcomes are understudied. The lack in well-designed EEG-neurofeedback studies despite decades of investigation impedes conclusions about its efficacy. Studies investigating fMRI neurofeedback are new and show initial promising effects on craving, but future trials are needed to investigate long-term and behavioral effects. Case studies report prolonged abstinence of opioids or alcohol with ventral striatal DBS but difficulties with patient inclusion may hinder larger, controlled trials. DBS in neuropsychiatric patients modulates brain circuits involved in reward processing, extinction and negative-reinforcement that are also relevant for addiction. To establish the potential of neuromodulation for addiction, more randomized controlled trials are needed that also investigate treatment duration required for long-term abstinence and potential synergy with other addiction interventions. Finally, future advancement may be expected from tailoring neuromodulation techniques to specific patient (neurocognitive) profiles.

Defining Compulsive Behavior.

Compulsive tendencies are a central feature of problematic human behavior and thereby are of great interest to the scientific and clinical community. However, no consensus exists about the precise meaning of 'compulsivity,' creating confusion in the field and hampering comparison across psychiatric disorders. A vague conceptualization makes compulsivity a moving target encompassing a fluctuating variety of behaviors, which is unlikely to improve the new dimension-based psychiatric or psychopathology approach. This article aims to help progress the definition of what constitutes compulsive behavior, cross-diagnostically, by analyzing different definitions in the psychiatric literature. We searched PubMed for articles in human psychiatric research with 'compulsive behavior' or 'compulsivity' in the title that focused on the broader concept of compulsivity-returning 28 articles with nine original definitions. Within the definitions, we separated three types of descriptive elements: phenomenological, observational and explanatory. The elements most applicable, cross-diagnostically, resulted in this definition: Compulsive behavior consists of repetitive acts that are characterized by the feeling that one 'has to' perform them while one is aware that these acts are not in line with one's overall goal. Having a more unified definition for compulsive behavior will make its meaning precise and explicit, and therefore more transferable and testable across clinical and non-clinical populations.

Deep brain stimulation for treatment-refractory obsessive compulsive disorder: a systematic review.

BACKGROUND: Obsessive-compulsive disorder is one of the most disabling of all psychiatric illnesses. Despite available pharmacological and psychotherapeutic treatments about 10% of patients remain severely affected and are considered treatment-refractory. For some of these patients deep brain stimulation offers an appropriate treatment method. The scope of this article is to review the published data and to compare different target structures and their effectiveness. METHODS: PubMed search, last update June 2013, was conducted using the terms "deep brain stimulation" and "obsessive compulsive disorder". RESULTS: In total 25 studies were found that reported five deep brain stimulation target structures to treat obsessive-compulsive disorder: the anterior limb of the internal capsule (five studies including 14 patients), nucleus accumbens (eight studies including 37 patients), ventral capsule/ventral striatum (four studies including 29 patients), subthalamic nucleus (five studies including 23 patients) and inferior thalamic peduncle (two studies including 6 patients). Despite the anatomical diversity, deep brain stimulation treatment results in similar response rates for the first four target structures. Inferior thalamic peduncle deep brain stimulation results in higher response rates but these results have to be interpreted with caution due to a very small number of cases. Procedure and device related adverse events are relatively low, as well as stimulation or therapy related side effects. Most stimulation related side effects are transient and decline after stimulation parameters have been changed. CONCLUSION: Deep brain stimulation in treatment-refractory obsessive-compulsive disorder seems to be a relatively safe and promising treatment option. However, based on these studies no superior target structure could be identified. More research is needed to better understand mechanisms of action and response predictors that may help to develop a more personalized approach for these severely affected obsessive compulsive patients.

Learning and metacognition under volatility in GD: Lower learning rates and distorted coupling between action and confidence.

Background and aims: Decisions and learning processes are under metacognitive control, where confidence in one's actions guides future behaviour. Indeed, studies have shown that being more confident results in less action updating and learning, and vice versa. This coupling between action and confidence can be disrupted, as has been found in individuals with high compulsivity symptoms. Patients with Gambling Disorder (GD) have been shown to exhibit both higher confidence and deficits in learning. Methods: In this study, we tested the hypotheses that patients with GD display increased confidence, reduced action updating and lower learning rates. Additionally, we investigated whether the action-confidence coupling was distorted in patients with GD. To address this, 27 patients with GD and 30 control participants performed a predictive inference task designed to assess action and confidence dynamics during learning under volatility. Action-updating, confidence and their coupling were assessed and computational modeling estimated parameters for learning rates, error sensitivity, and sensitivity to environmental changes. Results: Contrary to our expectations, results revealed no significant group differences in action updating or confidence levels. Nevertheless, GD patients exhibited a weakened coupling between confidence and action, as well as lower learning rates. Discussion and conclusions: This suggests that patients with GD may underutilize confidence when steering future behavioral choices. Ultimately, these findings point to a disruption of metacognitive control in GD, without a general overconfidence bias in neutral, non-incentivized volatile learning contexts.

Lower confidence and increased error sensitivity in OCD patients while learning under volatility.

A decoupling between confidence and action could relate to compulsive behaviour as seen in obsessive-compulsive disorder (OCD). The link between confidence and action in OCD has been investigated in clinical case-control studies and in the general population with discrepant findings. The generalizability of findings from highly-compulsive general population samples to clinical OCD samples has been questioned. Here, we investigate action-confidence coupling for 38 OCD patients compared to 37 healthy controls (HC), using a predictive inference task. We compared those results to a comparison between matched high and low compulsive individuals from the general population. Action-updating, confidence and their coupling were compared between the groups. Moreover, computational modeling was performed to compare groups on error sensitivity and environmental parameters. OCD patients showed lower confidence and higher learning rates in reaction to (small) prediction errors than HC, signaling hyperactive error signaling and lower confidence estimation. No evidence was found for differences in action-confidence coupling between groups. In contrast high the compulsive group showed higher confidence and stronger decoupling than the low compulsive group, both of which were related to symptoms. The underlying mechanisms of obsessive-compulsive behaviour might differ between clinical and highly-compulsive general population samples, resulting in different (meta)cognitive profiles.

Defining Autonomy in Psychiatry.

Mental illness undermines a patient's personal autonomy: the capacities of a person that enables them to live a meaningful life of their own making. So far there has been very little attention given to personal autonomy within psychiatry. This is unfortunate as personal autonomy is disturbed in different ways in psychiatric disorders, and understanding how autonomy is affected by mental illness is crucial for differential diagnosis and treatment, and also for understanding personal recovery. We will argue that disturbance of personal autonomy is related to patient's diminished quality of life and suffering that motivates seeking treatment. We hypothesize that (1) personal autonomy is generally reduced by mental illness but (2) the effects on autonomy are expressed differently according to the underlying psychopathology, and also vary according to the (3) context, and perspective of the individual patient. We provide a discussion of how autonomy can be affected in five prototypical mental disorders; Major Depressive Disorder, Substance-use Disorders, Obsessive Compulsive Disorder, Anorexia Nervosa and Schizophrenia. We take these disorders to be illustrative of how diminished autonomy is a central but overlooked dimension of mental illness. We will use our discussion of these disorders as the basis for identifying key dimensions of autonomy that could be relevant to innovate treatment of psychiatric disorders.

Motivational signals disrupt metacognitive signals in the human ventromedial prefrontal cortex.

A growing body of evidence suggests that, during decision-making, BOLD signal in the ventromedial prefrontal cortex (VMPFC) correlates both with motivational variables - such as incentives and expected values - and metacognitive variables - such as confidence judgments - which reflect the subjective probability of being correct. At the behavioral level, we recently demonstrated that the value of monetary stakes bias confidence judgments, with gain (respectively loss) prospects increasing (respectively decreasing) confidence judgments, even for similar levels of difficulty and performance. If and how this value-confidence interaction is reflected in the VMPFC remains unknown. Here, we used an incentivized perceptual decision-making fMRI task that dissociates key decision-making variables, thereby allowing to test several hypotheses about the role of the VMPFC in the value-confidence interaction. While our initial analyses seemingly indicate that the VMPFC combines incentives and confidence to form an expected value signal, we falsified this conclusion with a meticulous dissection of qualitative activation patterns. Rather, our results show that strong VMPFC confidence signals observed in trials with gain prospects are disrupted in trials with no - or negative (loss) - monetary prospects. Deciphering how decision variables are represented and interact at finer scales seems necessary to better understand biased (meta)cognition.

Distance to white matter trajectories is associated with treatment response to internal capsule deep brain stimulation in treatment-refractory depression.

BACKGROUND: Deep brain stimulation (DBS) is an innovative treatment for treatment-refractory depression. DBS is usually targeted at specific anatomical landmarks, with patients responding to DBS in approximately 50% of cases. Attention has recently shifted to white matter tracts to explain DBS response, with initial open-label trials targeting white matter tracts yielding much higher response rates (>70%). OBJECTIVE/HYPOTHESIS: Our aim was to associate distance to individual white matter tracts around the stimulation target in the ventral anterior limb of the internal capsule to treatment response. METHODS: We performed diffusion magnetic resonance tractography of the superolateral branch of the medial forebrain bundle and the anterior thalamic radiation in fourteen patients that participated in our randomized clinical trial. We combined the tract reconstructions with the postoperative images to identify the DBS leads and estimated the distance between tracts and leads, which we subsequently associated with treatment response. RESULTS: Stimulation closer to both tracts was significantly correlated to a larger symptom decrease (r = 0.61, p = 0.02), suggesting that stimulation more proximal to the tracts was beneficial. Biophysical modelling indicated that 37.5% of tracts were even outside the volume of activated tissue. There was no difference in lead placement with respect to anatomical landmarks, which could mean that differences in treatment response were driven by individual differences in white matter anatomy. CONCLUSIONS: Our results suggest that deep brain stimulation of the ventral anterior limb of the internal capsule could benefit from targeting white matter bundles. We recommend acquiring diffusion magnetic resonance data for each individual patient.

Abnormalities of confidence in psychiatry: an overview and future perspectives.

Our behavior is constantly accompanied by a sense of confidence and its' precision is critical for adequate adaptation and survival. Importantly, abnormal confidence judgments that do not reflect reality may play a crucial role in pathological decision-making typically seen in psychiatric disorders. In this review, we propose abnormalities of confidence as a new model of interpreting psychiatric symptoms. We hypothesize a dysfunction of confidence at the root of psychiatric symptoms either expressed subclinically in the general population or clinically in the patient population. Our review reveals a robust association between confidence abnormalities and psychiatric symptomatology. Confidence abnormalities are present in subclinical/prodromal phases of psychiatric disorders, show a positive relationship with symptom severity, and appear to normalize after recovery. In the reviewed literature, the strongest evidence was found for a decline in confidence in (sub)clinical OCD, and for a decrease in confidence discrimination in (sub)clinical schizophrenia. We found suggestive evidence for increased/decreased confidence in addiction and depression/anxiety, respectively. Confidence abnormalities may help to understand underlying psychopathological substrates across disorders, and should thus be considered transdiagnostically. This review provides clear evidence for confidence abnormalities in different psychiatric disorders, identifies current knowledge gaps and supplies suggestions for future avenues. As such, it may guide future translational research into the underlying processes governing these abnormalities, as well as future interventions to restore them.

Two sides of the same coin: Monetary incentives concurrently improve and bias confidence judgments.

Decisions are accompanied by a feeling of confidence, that is, a belief about the decision being correct. Confidence accuracy is critical, notably in high-stakes situations such as medical or financial decision-making. We investigated how incentive motivation influences confidence accuracy by combining a perceptual task with a confidence incentivization mechanism. By varying the magnitude and valence (gains or losses) of monetary incentives, we orthogonalized their motivational and affective components. Corroborating theories of rational decision-making and motivation, our results first reveal that the motivational value of incentives improves aspects of confidence accuracy. However, in line with a value-confidence interaction hypothesis, we further show that the affective value of incentives concurrently biases confidence reports, thus degrading confidence accuracy. Finally, we demonstrate that the motivational and affective effects of incentives differentially affect how confidence builds on perceptual evidence. Together, these findings may provide new hints about confidence miscalibration in healthy or pathological contexts.

Compulsive perseveration: empirical criticism on the mood-as-input model.

It has been proposed that the "Mood as Input" model provides an explanation of the perseverative nature of Obsessive Compulsive (OC) behaviour (MacDonald, B. C., & Davey, G. C. L. (2005). A mood-as-input account of perseverative checking: The relationship between stop rules, mood and confidence in having checked successfully. Behaviour Research and Therapy, 43, 69-91). The model implies that task perseveration occurs when individuals (a) experience a bad mood and (b) ask themselves "did I do as much as I can?" In two earlier experiments with healthy participants (MacDonald, B. C., & Davey, G. C. L. (2005). A mood-as-input account of perseverative checking: The relationship between stop rules, mood and confidence in having checked successfully. Behaviour Research and Therapy, 43, 69-91) it was found that when the allegedly critical conditions were met (negative mood and "did I as much as I can?" stop rule) perseveration occurred on a complex text-correction task. This finding was held to support a "mood as input" explanation of compulsive perseveration. It is important to note, however, that perseveration in clinical samples occurs for very simple "tasks" (e.g. closing a door or washing ones hands) and perseveration does not increase efficacy of performance. In the present study we compared the effects of the original task to effects of text correction tasks that were simpler and more OCD-like. The original effects were replicated: the combination of negative mood and the "did I do as much as I can" stop rule provoked perseveration. Meanwhile, "perseveration" was highly functional: the more "perseveration" the more text-errors were detected. Secondly, to the degree that tasks became simpler and more OCD-like, less checking occurred and the effects of the "did I do as much as I can?" stop rule on detection of errors became smaller. The findings raise questions about the validity of the paradigm as a model of OC perseveration.

Compulsivity in obsessive-compulsive disorder and addictions.

Compulsive behaviors are driven by repetitive urges and typically involve the experience of limited voluntary control over these urges, a diminished ability to delay or inhibit these behaviors, and a tendency to perform repetitive acts in a habitual or stereotyped manner. Compulsivity is not only a central characteristic of obsessive-compulsive disorder (OCD) but is also crucial to addiction. Based on this analogy, OCD has been proposed to be part of the concept of behavioral addiction along with other non-drug-related disorders that share compulsivity, such as pathological gambling, skin-picking, trichotillomania and compulsive eating. In this review, we investigate the neurobiological overlap between compulsivity in substance-use disorders, OCD and behavioral addictions as a validation for the construct of compulsivity that could be adopted in the Research Domain Criteria (RDoC). The reviewed data suggest that compulsivity in OCD and addictions is related to impaired reward and punishment processing with attenuated dopamine release in the ventral striatum, negative reinforcement in limbic systems, cognitive and behavioral inflexibility with diminished serotonergic prefrontal control, and habitual responding with imbalances between ventral and dorsal frontostriatal recruitment. Frontostriatal abnormalities of compulsivity are promising targets for neuromodulation and other interventions for OCD and addictions. We conclude that compulsivity encompasses many of the RDoC constructs in a trans-diagnostic fashion with a common brain circuit dysfunction that can help identifying appropriate prevention and treatment targets.

The Desire for Amputation or Paralyzation: Evidence for Structural Brain Anomalies in Body Integrity Identity Disorder (BIID).

BACKGROUND: Body Integrity Identity Disorder (BIID) is a condition in which individuals perceive a mismatch between their internal body scheme and physical body shape, resulting in an absolute desire to be either amputated or paralyzed. The condition is hypothesized to be of congenital nature, but evidence for a neuro-anatomical basis is sparse. METHODS: We collected T1-weighted structural magnetic resonance imaging scans on a 3T scanner in eight individuals with BIID and 24 matched healthy controls, and analyzed the data using voxel-based morphometry. RESULTS: The results showed reduced grey matter volume in the left dorsal and ventral premotor cortices and larger grey matter volume in the cerebellum (lobule VIIa) in individuals with BIID compared to controls. CONCLUSION: The premotor cortex and cerebellum are thought to be crucial for the experience of body-ownership and the integration of multisensory information. Our results suggest that BIID is associated with structural brain anomalies and might result from a dysfunction in the integration of multisensory information, leading to the feeling of disunity between the mental and physical body shape.

Doubt in the Insula: Risk Processing in Obsessive-Compulsive Disorder.

Extensive cleaning or checking of patients with obsessive-compulsive disorder (OCD) are often interpreted as strategies to avoid harm and as an expression of the widespread belief that OCD patients are more risk-averse. However, despite its clinical significance, the neural basis of risk attitude in OCD is unknown. Here, we investigated neural activity during risk processing using functional magnetic resonance imaging and simultaneously assessed risk attitude using a separate behavioral paradigm in OCD patients with different symptoms versus healthy controls (HCs). We found opposite insula responses to high versus low risk in OCD patients compared to HCs: a positive correlation between insula activity and risk-aversion in patients versus a negative correlation in controls. Although OCD patients overall were not more risk-averse than controls, there were differences between subgroups of OCD patients: patients with doubt/checking symptoms were more risk-averse than other patients. Taken together, OCD patients show a reversed pattern of risk processing by the insula compared to HCs. Moreover, the data suggest that increased activation of the insula signals an abnormal urge to avoid risks in the subpopulation of OCD patients with doubt and checking symptoms. These results indicate a role for the insula in excessive risk-avoidance relevant to OCD.