Longitudinal Changes in Structural Connectivity in Young People at High Genetic Risk for Bipolar Disorder.

OBJECTIVE: Recent studies of patients with bipolar disorder or at high genetic risk reveal structural dysconnections among key brain networks supporting cognitive and affective processes. Understanding the longitudinal trajectories of these networks across the peak age range of bipolar disorder onset could inform mechanisms of illness onset or resilience. METHODS: Longitudinal diffusion-weighted MRI and phenotypic data were acquired at baseline and after 2 years in 183 individuals ages 12-30 years in two cohorts: 97 unaffected individuals with a first-degree relative with bipolar disorder (the high-risk group) and 86 individuals with no family history of mental illness (the control group). Whole-brain structural networks were derived using tractography, and longitudinal changes in these networks were studied using network-based statistics and mixed linear models. RESULTS: Both groups showed widespread longitudinal changes, comprising both increases and decreases in structural connectivity, consistent with a shared neurodevelopmental process. On top of these shared changes, high-risk participants showed weakening of connectivity in a network encompassing the left inferior and middle frontal areas, left striatal and thalamic structures, the left fusiform, and right parietal and occipital regions. Connections among these regions strengthened in the control group, whereas they weakened in the high-risk group, shifting toward a cohort with established bipolar disorder. There was marginal evidence for even greater network weakening in those who had their first manic or hypomanic episode before follow-up. CONCLUSIONS: Neurodevelopment from adolescence into early adulthood is associated with a substantial reorganization of structural brain networks. Differences in these maturational processes occur in a multisystem network in individuals at high genetic risk of bipolar disorder. This may represent a novel candidate to understand resilience and predict conversion to bipolar disorder.

Aberrant intrinsic functional connectivity in thalamo-cortical networks in major depressive disorder.

OBJECTIVE: Growing evidence has implicated dysfunction of the thalamus and its projection cortical targets in depression. However, the anatomical specificity of thalamo-cortical connectivity in major depressive disorder (MDD) remains unknown due to the regional heterogeneity of the thalamus and limited methods to examine this. METHODS: Resting-state fMRI was collected on 70 MDD patients and 70 healthy controls. The thalamus was parcellated based on connectivity with six predefined cortical regions of interest (ROIs). The segmented thalamic nuclei were used as seeds to map connectivity with the rest of the whole brain. The cortical-to-thalamus connectivity values and thalamus-based connectivity maps were compared between groups. RESULTS: The cortical ROIs demonstrated correlations with spatially distinct zones within the thalamus. We found a trend toward reduced parietal ROI-to-thalamus connectivity in MDD. Importantly, MDD patients demonstrated reduced connectivity between prefrontal and parietal thalamus ROIs and bilateral middle frontal gyrus (MFG) and the right posterior default mode network (DMN) and between the prefrontal and motor thalamus ROIs and lateral temporal regions. Conversely, increased connectivity emerged between the motor thalamus ROI and right MFG and right medial frontal gyrus/anterior cingulate; between motor/somatosensory thalamus ROIs and right posterior DMN; between prefrontal/somatosensory thalamus ROIs and cerebellum; and between the parietal thalamus ROI and left insula. CONCLUSIONS: This study is the first to examine the anatomical specificity of thalamo-cortical connectivity disturbances in MDD. Subjects with MDD demonstrated altered thalamo-cortical connectivity characterized by a complex pattern of region-dependent hypo- or hyperconnectivity. We therefore speculate that selectively modulating the connectivity of thalamo-cortical circuitry may be a potential novel therapeutic mechanism for MDD.

Augmenting transcranial direct current stimulation with (D)-cycloserine for depression: a pilot study.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that causes changes in cortical excitability. Recent double-blind placebo-controlled clinical trials suggest that tDCS may be efficacious in the treatment of depression. Pharmacological agents that prolong the effects of tDCS could lead to greater cumulative changes in cortical excitability, producing greater and more prolonged efficacy. One agent shown to prolong the excitability-enhancing effects of tDCS in healthy subjects is D-Cycloserine, a partial agonist at the glycine-binding site of N-methyl-D-aspartate receptors. We investigated whether combining prefrontal tDCS with D-Cycloserine could enhance and/or prolong the antidepressant effect of tDCS. METHODS: Five depressed subjects who had relapsed or failed to achieve remission after receiving a previous course of prefrontal tDCS were recruited. In this open-label pilot study, subjects ingested 100-mg D-Cycloserine 2 hours before tDCS sessions. Subjects received 20 minutes of tDCS at 2 mA on consecutive weekdays for a total of 20 sessions. The anode was placed at pF3 and the cathode at F8 (10/20 system). Clinical response was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: The change in Montgomery-Åsberg Depression Rating Scale scores was not greater with the combination of D-Cycloserine and tDCS than had previously been produced by tDCS alone. No significant additional adverse effects were reported. CONCLUSIONS: This pilot open-label study found that pretreatment with 100-mg D-Cycloserine 2 hours before tDCS was well tolerated but did not enhance the antidepressant efficacy of anodal prefrontal tDCS.

Exploring culture-specific differences in beliefs about causes, kinship and the heritability of major depressive disorder: the views of Anglo-Celtic and Chinese-Australians.

The aim of this study was to explore cultural differences in causal attributions and beliefs about heritability of major depressive disorder (MDD). Face-to-face interviews with Anglo-Celtic- and Chinese-Australians community members with a family history of MDD were conducted and subjected to a rigorous qualitative analysis, using the computer software NVivo. Sixteen Anglo-Celtic-Australians and 16 Chinese-Australians were interviewed. Both groups believed that a combination of genetic and environmental factors contributed to MDD, that stress was an important cause of MDD, and that coping factors were significant moderators of the impact of stress on MDD. Both cultural groups believed that the causes of MDD affecting multiple family members included a shared family environment and a "contagion effect", in addition to genetics. Unique to the Chinese-Australian group was the beliefs that parental pressures to exceed academically contributed to MDD; this cultural group also reported beliefs that depression was due to God's will or alternatively fate, which in turn was related to attributions to feng shui and auspicious dates. This study documented key culture-specific differences in beliefs about causes and inheritance of MDD; such differences have major implications for clinician-patient communication about genetic risk associated with having a family history of MDD.

The association between meditation practice and treatment outcome in Mindfulness-based Cognitive Therapy for bipolar disorder.

This study aimed to examine the impact of quantity of mindfulness meditation practice on the outcome of psychiatric symptoms following Mindfulness-based Cognitive Therapy (MBCT) for those diagnosed with bipolar disorder. Meditation homework was collected at the beginning of each session for the MBCT program to assess quantity of meditation practice. Clinician-administered measures of hypo/mania and depression along with self-report anxiety, depression and stress symptom questionnaires were administered pre-, post-treatment and at 12-month follow-up. A significant correlation was found between a greater number of days meditated throughout the 8-week trial and clinician-rated depression scores on the Montgomery-Åsberg Depression Rating Scale at 12-month follow-up. There were significant differences found between those who meditated for 3 days a week or more and those who meditated less often on trait anxiety post-treatment and clinician-rated depression at 12-month follow-up whilst trends were noted for self-reported depression. A greater number of days meditated during the 8-week MBCT program was related to lower depression scores at 12-month follow-up, and there was evidence to suggest that mindfulness meditation practice was associated with improvements in depression and anxiety symptoms if a certain minimum amount (3 times a week or more) was practiced weekly throughout the 8-week MBCT program.

Transcranial direct current stimulation (tDCS) for depression: analysis of response using a three-factor structure of the Montgomery-Åsberg depression rating scale.

BACKGROUND: There is growing evidence that transcranial direct current stimulation (tDCS) may be an effective treatment for depression. However, no study to date has profiled the antidepressant effects of tDCS using items or factors on depression symptom severity rating scales. This could potentially provide information about the mechanisms by which tDCS achieves its antidepressant effects and also identify clinical predictors of response. METHODS: The present study analysed scores on the Montgomery-Åsberg depression rating scale (MADRS) from a randomised, sham-controlled trial of tDCS (Loo et al., 2012. British Journal of Psychiatry. 200, 52-59) using a three-factor model of MADRS items (Suzuki et al., 2005. Depression and Anxiety. 21, 95-97) encompassing dysphoria, retardation and vegetative symptoms. RESULTS: Participants in the active tDCS treatment group showed significant improvement in dysphoria while participants in the sham treatment group did not. While both groups showed improvement in retardation symptoms, improvement was significantly greater in the active tDCS group. Both groups also showed improvement in vegetative symptoms but there were no between-group differences. LIMITATIONS: Further studies with larger sample sizes are warranted to investigate the generalisability of results and whether the MADRS factor structure may change as a result of the specific treatment used. CONCLUSIONS: tDCS appears to be particularly effective in treating dysphoria and retardation, but not vegetative symptoms of depression. This may have implications for selection of types of depression most likely to respond to this treatment.

Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial.

BACKGROUND: Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy. AIMS: To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230). METHOD: Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed. RESULTS: There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3-6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS. CONCLUSIONS: Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.

Oxytocin as a moderator of hypnotizability.

Since hypnosis was popularly recognized in the nineteenth century, the phenomenon of hypnotizability has remained poorly understood. The capacity to increase hypnotizability has important implications because it may increase the number of people who can benefit from hypnotic interventions for psychological and medical conditions. Current theories emphasize that rapport between hypnotist and subject is pivotal to motivate the respondent to engage in strategies that allows them to suspend reality and respond to suggestions. The neuropeptide oxytocin is implicated in social bonding, and enhances a range of social behaviors in animals and humans. This study tested the proposal that oxytocin administration, which enhances social bonding in humans, may enhance hypnotic responding by administering intranasal spray of oxytocin or placebo prior to hypnosis in 40 low hypnotizable male subjects. When low hypnotizable individuals were administered oxytocin via nasal spray, their level of hypnotic responding increased significantly compared to hypnotic responding levels prior to oxytocin administration. This is the first demonstration of a neurochemical basis for hypnotic responding, and points to a potential neural mechanism to explain hypnotizability.

Fronto-extracephalic transcranial direct current stimulation as a treatment for major depression: an open-label pilot study.

BACKGROUND: Several recent trials have reported transcranial direct current stimulation (tDCS) to be effective in treating depression, though the relative benefits of different electrode montages remain unexplored. Whereas all recent studies have used a bifrontal (BF) electrode montage, studies published in the 1960s and 1970s placed one electrode in an extracephalic position, with some positive reports of efficacy. This study investigated the efficacy and safety of tDCS given with a fronto-extracephalic (F-EX) montage. METHODS: 2 mA tDCS was administered for 20 min every weekday over four weeks in 11 participants with a Major Depressive Episode who had previously shown inadequate response to, or relapsed following, a course of BF tDCS. For F-EX tDCS the anode was placed on the left dorsolateral prefrontal cortex and the cathode on the right upper arm. Depression severity and neuropsychological function were assessed before and after the treatment course. Antidepressant response was compared across an equivalent treatment period for both montages. RESULTS: F-EX tDCS was shown to be safe and well tolerated. Depression ratings improved after acute treatment on the Montgomery Åsberg Depression Rating Scale (p < 0.001). Participants showed greater initial treatment response with F-EX tDCS than with BF tDCS (p < 0.001). LIMITATIONS: This was an open label pilot study. The two comparison treatments were applied consecutively. CONCLUSION: F-EX tDCS appears to be safe and to have antidepressant effects, and may lead to more rapid improvement than tDCS given with a BF montage.

Mindfulness, response styles and dysfunctional attitudes in bipolar disorder.

BACKGROUND: This study aimed to examine differences between mindfulness, dysfunctional attitudes and response styles in subjects with bipolar disorder, major depressive disorder and controls. METHOD: A total of 192 participants were included in this study: 90 with bipolar disorder, 36 with remitted major depressive disorder and 66 subjects without a current or past history of a mood disorder. RESULTS: After controlling for current mood state and co-morbid anxiety disorders, the groups did not differ on mindfulness or response styles scores, however, those with bipolar disorder scored significantly higher on the Dependency and Achievement subscales of the Dysfunctional Attitudes Scale than the other two groups. LIMITATIONS: Sample sizes were relatively small for the control and remitted major depressive disorder groups making it difficult to draw definitive conclusions. CONCLUSIONS: Participants with bipolar disorder appear to significantly differ from remitted depressives and controls on certain cognitive styles such as Dependency and Achievement on the Dysfunctional Attitudes Scale. Further research may help to understand how these cognitive domains impact on the course and outcome of bipolar disorder.

Hypomania induction in a patient with bipolar II disorder by transcranial direct current stimulation (tDCS).

OBJECTIVES: To report a case of hypomania induced by transcranial direct current stimulation (tDCS) given with an extracephalic reference electrode. Transcranial direct current stimulation is a noninvasive brain stimulation technique in which a weak current is applied through the scalp to produce changes in neuronal excitability in the underlying cerebral tissue. Recent clinical trials have shown promising results with left anodal prefrontal tDCS in treating depression. When the reference cathodal electrode in tDCS is moved from the cranium to an extracephalic position, larger areas of both cerebral hemispheres are stimulated, with potential implications for both efficacy and safety. METHODS: We report the case of a 33-year-old female with bipolar II disorder, on mood stabilizer medication, who had previously participated in a clinical trial of tDCS given with a bifrontal electrode montage for the treatment of major depression without incident, but became hypomanic when she received a later course of tDCS given with a frontoextracephalic configuration. Factors contributing to the development of hypomania in the second course of tDCS are examined. RESULTS: No substantial differences were found in the patient's clinical presentation between the 2 tDCS courses to explain the emergence of hypomania only after the second course. The different montage used in the second course appeared to be the main contributory factor in the induction of hypomania. CONCLUSIONS: The reported case suggests that frontoextracephalic tDCS has antidepressant properties and the potential to induce hypomanic symptoms. In particular, it raises the question of whether frontoextracephalic tDCS requires additional precautions when administered to bipolar patients compared to bifrontal tDCS.

Physical treatments for bipolar disorder: a review of electroconvulsive therapy, stereotactic surgery and other brain stimulation techniques.

BACKGROUND: Despite pharmacological advances, bipolar disorder continues to be difficult to treat. This article reviews the evidence base for the use of electroconvulsive therapy (ECT) and other brain stimulation therapies in bipolar disorder. METHODS: The evidence base for the efficacy of ECT and transcranial magnetic stimulation in the treatment of mania, bipolar depression and mixed affective states was reviewed. Reports on the use of vagus nerve stimulation, stereotaxic surgery, deep brain stimulation, magnetic seizure therapy and transcranial direct current stimulation in treating depression, as well as bipolar disorder were also reviewed. Studies were identified from Medline and Embase database searches. RESULTS: There are a few randomized controlled trials of ECT in mania and bipolar depression, and none in mixed affective states. Nevertheless, such studies consistently reported clinically meaningful efficacy, with a majority of pharmacotherapy resistant patients responding to ECT. Evidence for the use of other brain stimulation therapies in treating bipolar mood states is preliminary and limited. CONCLUSIONS: ECT is an effective treatment for acute mania, bipolar depression and mixed affective states and has useful efficacy even in pharmacotherapy-resistant patients. Other brain stimulation techniques may have potential for the treatment of bipolar disorder and should be further researched.

Repetitive transcranial magnetic stimulation for the treatment of obsessive compulsive disorder: a double-blind controlled investigation.

BACKGROUND: To determine the efficacy and tolerability of repetitive transcranial magnetic stimulation (rTMS) as a treatment for obsessive compulsive disorder (OCD) in a double-blind placebo-controlled study. METHOD: Subjects with treatment-resistant OCD were randomized to rTMS (n = 10) or sham rTMS (n = 8) for 10 sessions of daily stimulation over the left dorsolateral prefrontal cortex (DLPFC), with subjects and raters being blind to the treatment. Subjects were offered an open extension of up to 20 sessions of rTMS. RESULTS: The two groups did not differ on change in Yale-Brown Obsessive Compulsive Scale (YBOCS) or Maudsley Obsessive-Compulsive Inventory scores over 10 sessions, with or without correction for depression ratings. Over 20 sessions, there was a significant reduction in total YBOCS scores, but not after controlling for depression. rTMS over 20 sessions was well tolerated. CONCLUSION: Two weeks of rTMS over the left DLPFC is ineffective for treatment-resistant OCD.