Linking major depression and the neural substrates of associative processing.

It has been proposed that mood correlates with the breadth of associative thinking. Here we set this hypothesis to the test in healthy and depressed individuals. Generating contextual associations engages a network of cortical regions including the parahippocampal cortex (PHC), retrosplenial complex, and medial prefrontal cortex. The link between mood, associative processing, and its underlying cortical infrastructure provides a promising avenue for elucidating the mechanisms underlying the cognitive impairments in major depressive disorder (MDD). The participants included 15 nonmedicated individuals with acute major depressive episodes and 15 healthy matched controls. In an fMRI experiment, participants viewed images of objects that were either strongly or weakly associated with a specific context (e.g., a beach chair vs. a water bottle) while rating the commonality of each object. Analyses were performed to examine the brain activation and structural differences between the groups. Consistent with our hypothesis, controls showed greater activation of the contextual associations network than did depressed participants. In addition, PHC structural volume was correlated with ruminative tendencies, and the volumes of the hippocampal subfields were significantly smaller in depressed participants. Surprisingly, depressed participants showed increased activity in the entorhinal cortex (ERC), as compared with controls. We integrated these findings within a mechanistic account linking mood and associative thinking and suggest directions for the future.

Constricted semantic relations in acute depression.

BACKGROUND: It has been suggested that mood influences the breadth of associated information available for retrieval, with positive mood broadening and negative mood constricting the scope of associations. In this study, we asked whether this mood-associations connection is related to controlled processes which were linked to clinical symptoms in depression. METHODS: We used the semantic priming paradigm, which allows the dissociation of automatic and controlled processes by using short and long intervals between prime and target words. We further examined whether the strength of semantic relations (weak or strong) influence the priming effects in both neurotypical and depressed individuals. RESULTS: Experiment 1, testing neurotypical individuals, showed priming effects for strong semantically-related words regardless of interval length, but priming effects for weak semantically-related words were smaller in short intervals than in long intervals. Experiment 2, testing depressed individuals in long intervals, showed smaller priming effects for weak semantically-related words than shown by neurotypicals, but priming effects for strong semantically-related words which were comparable between the groups. LIMITATIONS: This study cannot determine the source for the differences in priming effects between depressed individuals and neurotypicals, and further studies are needed. CONCLUSIONS: This is the first study to show priming impairments in depressed individuals. We discuss our results in light of leading theories concerning cognitive impairment in depression, as well as the newly emerged field of digital psychiatry.

Impaired sense of agency and associated confidence in psychosis.

The Sense of Agency (SoA), our sensation of control over our actions, is a fundamental mechanism for delineating the Self from the environment and others. SoA arises from implicit processing of sensorimotor signals as well as explicit higher-level judgments. Psychosis patients suffer from difficulties in the sense of control over their actions and accurate demarcation of the Self. Moreover, it is unclear if they have metacognitive insight into their aberrant abilities. In this pre-registered study, we examined SoA and its associated confidence judgments using an embodied virtual reality paradigm in psychosis patients and controls. Our results show that psychosis patients not only have a severely reduced ability for discriminating their actions but they also do not show proper metacognitive insight into this deficit. Furthermore, an exploratory analysis revealed that the SoA capacities allow for high levels of accuracy in clinical classification of psychosis. These results indicate that SoA and its metacognition are core aspects of the psychotic state and provide possible venues for understanding the underlying mechanisms of psychosis, that may be leveraged for novel clinical purposes.

Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: a feasibility study.

Treatment for negative symptoms and cognitive deficits, core elements of schizophrenia, remains inadequate. Stimulation of the prefrontal cortex via transcranial magnetic stimulation (TMS) yields only moderate results, possibly due to limited stimulation depth. Deep-TMS enables deeper and wider stimulation than before. This preliminary study is the first to examine deep-TMS as a possible add-on treatment for negative symptoms and cognitive deficits of schizophrenia. The effect of 20 daily deep-TMS sessions (20 Hz, 120% motor threshold) over the prefrontal cortex of 15 patients indicated improvement in cognition and negative symptoms that was maintained at 2-wk post-treatment follow-up.

Ruminative Tendency Relates to Ventral Striatum Functionality: Evidence From Task and Resting-State fMRI.

BACKGROUND: Ruminative responding involves repetitive and passive thinking about one's negative affect. This tendency interferes with initiation of goal-directed rewarding strategies, which could alleviate depressive states. Such reward-directed response selection has been shown to be mediated by ventral striatum/nucleus accumbens (VS/NAcc) function. However, to date, no study has examined whether trait rumination relates to VS/NAcc functionality. Here, we tested whether rumination moderates VS/NAcc function both in response to reward and during a ruminative state. METHODS: Trait rumination was considered dimensionally using Rumination Response Scale (RRS) scores. Our sample (N = 80) consisted of individuals from a community sample and from patients diagnosed with major depressive disorder, providing a broad range of RRS scores. Participants underwent fMRI to assess two modes of VS/NAcc functionality: 1) in response to reward, and 2) during resting-state, as a proxy for ruminative state. We then tested for associations between RRS scores and VS/NAcc functional profiles, statistically controlling for overall depressive symptom severity. RESULTS: RRS scores correlated positively with VS/NAcc response to reward. Furthermore, we noted that higher RRS scores were associated with increased ruminative-dependent resting-state functional connectivity of the VS/NAcc with the left orbitofrontal cortex. CONCLUSIONS: These findings suggest that ruminative tendencies manifest in VS/NAcc reward- and rumination-related functions, providing support for a theoretical-clinical perspective of rumination as a habitual impairment in selection of rewarding, adaptive coping strategies.

Effectiveness and safety of adjunctive antidepressants in the treatment of bipolar depression: a review.

The treatment of the depressed phase of Bipolar Disorder (BPD) is understudied and poses a widespread clinical dilemma. While the use of mood stabilizers in BPD is a common practice, the role of antidepressants in the depressive phase of the illness remains controversial. This paper reviews the available literature on the subject and highlights the factors essential for making clinical decisions for treating BPD. Most of the standard randomized controlled trials report the efficacy of antidepressants in the acute phase of BPD, but the data also indicate higher switch rates to mania and acceleration of mood cycle with their use. Nevertheless, a recent large effectiveness study (STEP-BD) found no superiority or risk of adjunct antidepressants to a mood stabilizer in the treatment of BPD. In light of the available data, future large clinical studies are essential for elucidating the role of antidepressants in the treatment of the depressed phase of BPD. Until then, factors such as history of severe manias, past depression severity and length and rapid cycling will continue to play a role in the decision of clinicians in prescribing antidepressants for BPD in different phases of the disorder.

A randomized controlled feasibility and safety study of deep transcranial magnetic stimulation.

OBJECTIVE: The H-coils are a new development in transcranial magnetic stimulation (TMS) research, allowing direct stimulation of deeper neuronal pathways than does standard TMS. This study assessed possible health risks, and some cognitive and emotional effects, of two H-coil versions designed to stimulate deep portions of the prefrontal cortex, using several stimulation frequencies. METHODS: Healthy volunteers (n=32) were randomly assigned to one of four groups: each of two H-coil designs (H1/H2), standard figure-8 coil, and sham-coil control. Subjects were tested in a pre-post design, during three increasing (single pulses, 10 Hz, and 20 Hz) stimulation sessions, as well as 24-36 h after the last stimulation. RESULTS: The major finding of the present study is that stimulation with the novel H-coils was well tolerated, with no adverse physical or neurological outcomes. Computerized cognitive tests found no deterioration in cognitive functions, except for a transient short-term effect of the H1-coil on spatial recognition memory on the first day of rTMS (but not in the following treatment days). On the other hand, spatial working memory was transiently improved by the H2-coil treatment. Finally, the questionnaires showed no significant emotional or mood alterations, except for reports on 'detachment' experienced by subjects treated with the H1-coil. CONCLUSIONS: This study provides additional evidence for the feasibility and safety of the two H-coil designs (H1/H2). SIGNIFICANCE: The H-coils offer a safe new tool with potential for both research and clinical applications for psychiatric and neurological disorders associated with dysfunctions of deep brain regions.

H-coil repetitive transcranial magnetic stimulation for treatment resistant major depressive disorder: An 18-week continuation safety and feasibility study.

OBJECTIVE: Evidence has shown that repetitive transcranial magnetic stimulation (rTMS) can be effective as an acute treatment for major depressive disorder (MDD). However, few studies have examined the safety and feasibility of rTMS as a long-term\continuation treatment. Deep-TMS is a novel tool enabling deeper stimulation than standard coils. The current study examined the safety and feasibility of repetitive deep-TMS continuation treatment for MDD over the course of 18 weeks, following 4 weeks of acute treatment. METHOD: A total of 29 MDD patients were enrolled in the study. rTMS sessions (20 Hz) were given for a total of 22 weeks, divided into: 4 weeks of acute daily treatments, followed by 18 weeks of continuation treatments. Clinical evaluations were performed weekly throughout the study. RESULTS: A significant decrease from baseline in Hamilton Depression Rating Scale (HDRS) score was found at the end of the acute phase, and maintained throughout the study (P < 0.0001). The Kaplan-Meier estimated probability of response was 46.15% (SE = 9.78%) at the end of the acute phase, and 81.12% (SE = 9.32%) at the end of the study (22 weeks). probability of remission at the end of the acute phase was 26.92% (SE = 8.70%) and 71.45% (SE = 10.99%) at the end of the study. Response in the acute phase was indicative of response in the continuation phases. The procedure was generally well tolerated and no adverse events were reported. CONCLUSION: The results suggest that H-coil deep-TMS administered continuation treatment can help maintain an antidepressant effect for 18 weeks, following 4 weeks of acute treatment.

H-coil repetitive transcranial magnetic stimulation for the treatment of bipolar depression: an add-on, safety and feasibility study.

OBJECTIVES: The H1-Coil is a novel transcranial magnetic stimulation (TMS) device capable of inducing a magnetic field with a deeper and wider distribution than standard coils. This pilot study evaluated the safety and feasibility of the H1-Coil as adjuvant treatment for bipolar depression (BPD). METHODS: Nineteen patients diagnosed as having BPD and under treatment with psychotropic medication were enrolled in the study. They received daily prefrontal repetitive TMS (rTMS: 20 Hz, 2 s on, 20 s off, totaling 1680 stimuli) every weekday for four consecutive weeks. The primary outcome measure was the change from baseline in the Hamilton Depression Rating Scale (HDRS-24) score a week after the last treatment session. RESULTS: A significant mean decrease of 12.9 points in the HDRS-24 scale (P< 0.001) was found. Response rate was 63.2% and remission rate was 52.6%. Treatment was well tolerated in terms of headache and overall discomfort, and there were no significant change in cognitive functioning or mood switches. One patient had a short induced generalized seizure without complications. CONCLUSIONS: An add-on H-coil rTMS treatment protocol in BPD subjects indicated improvement in bipolar depression symptoms. Sham-control studies to further determine the efficacy and safety of the H-Coil for BPD are warranted.