Targeting the affective brain-a randomized controlled trial of real-time fMRI neurofeedback in patients with depression.

Functional magnetic resonance imaging neurofeedback (fMRI-NF) training of areas involved in emotion processing can reduce depressive symptoms by over 40% on the Hamilton Depression Rating Scale (HDRS). However, it remains unclear if this efficacy is specific to feedback from emotion-regulating regions. We tested in a single-blind, randomized, controlled trial if upregulation of emotion areas (NFE) yields superior efficacy compared to upregulation of a control region activated by visual scenes (NFS). Forty-three moderately to severely depressed medicated patients were randomly assigned to five sessions augmentation treatment of either NFE or NFS training. At primary outcome (week 12) no significant group mean HDRS difference was found (B = -0.415 [95% CI -4.847 to 4.016], p = 0.848) for the 32 completers (16 per group). However, across groups depressive symptoms decreased by 43%, and 38% of patients remitted. These improvements lasted until follow-up (week 18). Both groups upregulated target regions to a similar extent. Further, clinical improvement was correlated with an increase in self-efficacy scores. However, the interpretation of clinical improvements remains limited due to lack of a sham-control group. We thus surveyed effects reported for accepted augmentation therapies in depression. Data indicated that our findings exceed expected regression to the mean and placebo effects that have been reported for drug trials and other sham-controlled high-technology interventions. Taken together, we suggest that the experience of successful self-regulation during fMRI-NF training may be therapeutic. We conclude that if fMRI-NF is effective for depression, self-regulation training of higher visual areas may provide an effective alternative.

Subgenual Cingulum Microstructure Supports Control of Emotional Conflict.

Major depressive disorder (MDD) is associated with specific difficulties in attentional disengagement from negatively valenced material. Diffusion MRI studies have demonstrated altered white matter microstructure in the subgenual cingulum bundle (CB) in individuals with MDD, though the functional significance of these alterations has not been examined formally. This study explored whether individual differences in selective attention to negatively valenced stimuli are related to interindividual differences in subgenual CB microstructure. Forty-six individuals (21 with remitted MDD, 25 never depressed) completed an emotional Stroop task, using happy and angry distractor faces overlaid by pleasant or unpleasant target words and a control gender-based Stroop task. CBs were reconstructed in 38 individuals using diffusion-weighted imaging and tractography, and mean fractional anisotropy (FA) computed for the subgenual, retrosplenial, and parahippocampal subdivisions. No significant correlations were found between FA and performance in the control gender-based Stroop task in any CB region. However, the degree of interference produced by angry face distractors on time to identify pleasant words (emotional conflict) correlated selectively with FA in the subgenual CB (r = -0.53; P = 0.01). Higher FA was associated with reduced interference, irrespective of a diagnosis of MDD, suggesting that subgenual CB microstructure is functionally relevant for regulating attentional bias toward negative interpersonal stimuli.

A review of white matter microstructure alterations of pathways of the reward circuit in depression.

BACKGROUND: Depressed mood, anhedonia, psychomotor retardation and alterations of circadian rhythm are core features of the depressive syndrome. Its neural correlates can be located within a frontal-striatal-tegmental neural network, commonly referred to as the reward circuit. It is the aim of this article to review literature on white matter microstructure alterations of the reward system in depression. METHOD: We searched for diffusion tensor imaging (DTI)-studies that have explored neural deficits within the cingulum bundle, the uncinate fasciculus and the supero-lateral medial forebrain bundle/anterior thalamic radiation - in adolescent and adult depression (acute and remitted), melancholic depression, treatment-resistant depression and those at familial risk of depression. The relevant diffusion MRI literature was identified using PUBMED. RESULTS: Thirty-five studies were included. In people at familial risk for depression the main finding was reduced fractional anisotropy (FA) in the cingulum bundle. Both increases and decreases of FA have been reported in the uncinate fasciculus in adolescents. Reductions of FA in the uncinate fasciculus and the anterior thalamic radiation/supero-lateral medial forebrain bundle during acute depressive episodes in adults were most consistently reported. LIMITATIONS: Non-quantitative approach. CONCLUSIONS: Altered cingulum bundle microstructure in unaffected relatives may either indicate resilience or vulnerability to depression. Uncinate fasciculus and supero-lateral medial forebrain bundle microstructure may be altered during depressive episodes in adult MDD. Future studies call for a careful clinical stratification of clinically meaningful subgroups.

Emerging drugs for bipolar depression: an update.

INTRODUCTION: The acute management of bipolar depression presents particular challenges. In most cases, it responds poorly to traditional antidepressants - chronicity and partial response are commonly observed. In a subset of patients, antidepressants provoke a switch into mania and/or cause rapid cycling over the long term. AREAS COVERED: The evidence supporting emerging and existing pharmacological treatments for bipolar depression, with particular reference to response and remission rates and risk of switching into mania, is reviewed. Novel modes of action and future pharmacological strategies are considered. EXPERT OPINION: Drugs with greater efficacy, tolerability and speed of action are required in the treatment of bipolar depression. Novel antidepressant agents, including NMDA antagonists, GABA-ergics, 5HT-7 and 5HT-2 antagonists and adjunctive dopaminergics, offer promise, perhaps with a low risk of switching. Newer dual-action antidepressants (e.g., milnacipran) may have good efficacy but the risk of switching is not known. More randomized controlled trials and naturalistic studies are required.

Integrative neuroimaging in mood disorders.

PURPOSE OF REVIEW: Neuroimaging has become a central technique of biological psychiatry and is uniquely suited to assess functional and structural brain changes in psychiatric patients in vivo. In this review, we highlight several recent developments that may enable the transition of psychiatric neuroimaging from laboratory to clinic. RECENT FINDINGS: We describe recent trends in refining imaging techniques for brain microstructure (diffusion imaging) and neurochemistry (magnetic resonance spectroscopy of neurotransmitters and metabolites) and their application to patients with mood disorders and individuals at risk, such as first-degree relatives. We also survey recent progress in imaging-guided deep brain stimulation (DBS), imaging-based (neurofeedback) therapies and studies looking at their convergent anatomical targets. These new interventional techniques, which aim to modulate brain circuits of emotion and motivation highlighted by functional imaging studies, have shown promising effects in several small studies. SUMMARY: The mapping of brain patterns associated with risk to develop mood disorders may pave the way for diagnostic/prognostic applications of neuroimaging. The neuromodulation techniques of DBS and neurofeedback, which target dysfunctional or compensatory circuits identified by functional imaging, may take neuroimaging into a new, therapeutic domain.

Marked reductions in visual evoked responses but not γ-aminobutyric acid concentrations or γ-band measures in remitted depression.

BACKGROUND: Magnetic resonance spectroscopy (MRS) studies have consistently demonstrated reduced cortical γ-aminobutyric acid (GABA) concentrations in individuals with major depression. However, evidence for a persistent deficit during remission, which would suggest that GABA dysfunction is a possible trait marker of depression, is equivocal. Although MRS measures total concentration of GABA, magneto-encephalography provides direct measures of neural activity, with cortical γ oscillations shaped by the activity of GABAergic inhibitory interneurons. In this study we investigated whether γ oscillations and GABA concentrations would differ in individuals with remitted depression (RD) compared with never depressed control subjects (ND). METHODS: Thirty-seven healthy, unmedicated female volunteers (n = 19 RD, and n = 18 ND) were recruited. The γ oscillation frequencies and amplitudes in the visual cortex, induced by simple grating stimuli, were quantified with time-frequency analyses. Distinct GABA/glutamate + glutamine MRS peaks were resolved from MEGA-PRESS difference spectra in prefrontal, occipital, and subcortical volumes. RESULTS: The RD and ND individuals did not differ in the frequency of subclinical depressive symptoms. The ND were slightly older (mean = 23 years vs. 21 years), but age did not correlate with dependent measures. There were no group differences in GABA levels or induced cortical γ measures, but RD individuals had markedly reduced M80 (C1) components of the pattern-onset evoked response (46% reduction, Cohen's d = 1.01, p = .006). CONCLUSIONS: Both MRS and magneto-encephalography measures of the GABA system are normal in RD. However, the early visual evoked response is a potential trait marker of the disorder.

Cingulum white matter in young women at risk of depression: the effect of family history and anhedonia.

BACKGROUND: Altered white matter microstructure in tracts integral to mood regulation networks could underlie vulnerability to major depressive disorder (MDD). Guided by functional magnetic resonance studies, we explored whether a positive family history of MDD (FH+) and anhedonia (reduced capacity for pleasure) were associated with altered white matter microstructure in the cingulum bundles and uncinate fasciculi. METHODS: Diffusion tensor magnetic resonance imaging data were acquired on 34 healthy female student volunteers (mean age 22 years). Exclusion criteria included other current or previous psychiatric disorder, current depression, and current psychotropic medication. Family history was determined using established criteria. Fiber tractography was performed for each individual for a priori tracts of interest and a comparison tract. Mean fractional anisotropy (FA), an index of microstructure, was calculated for each tract. RESULTS: Tracts were reconstructed in 18 FH+ individuals and 15 FH- individuals, who did not differ by age or subclinical depressive symptoms. FH+ subjects had 3% to 5% lower FA in the right and left cingulum bundles than FH- individuals (p = .012, p = .059, respectively). Post hoc analysis demonstrated 8% lower FA in the left subgenual cingulate (p = .007). Hedonic tone correlated positively with FA in the right and left cingulum bundles (r = .342, p = .052; r = .477, p = .005, respectively), and the left subgenual cingulum (r = .500, p = .003). CONCLUSIONS: Both family history of MDD and subclinical anhedonia are associated with reduced FA in the bilateral cingulum bundles, particularly in the left subgenual cingulum. Altered cingulum white matter architecture is implicated in the etiology of MDD.

Subgenual cingulate and visual cortex responses to sad faces predict clinical outcome during antidepressant treatment for depression.

BACKGROUND: Previous follow-up studies indicate that increased visual cortical, ventral cingulate and subcortical responses of depressed individuals to sad facial stimuli, but not happy stimuli could represent reversible markers of disease severity. We hypothesized that greater responses in these areas to sad stimuli, but not happy stimuli, would predict better subsequent clinical outcome. We also explored areas that would predict a poor outcome. METHODS: Twelve melancholically depressed individuals in the early stages of antidepressant treatment in a secondary care setting participated in two experiments comparing responses to varying intensities of sad and happy facial stimuli, respectively, using event related functional MRI. They repeated the experiments after a mean delay of 12 weeks of treatment. RESULTS: There was a variation in response to treatment. Greater right visual cortex and right subgenual cingulate (R-BA25) responses to sad stimuli, but not happy stimuli, in the early stages of treatment were associated with a good clinical outcome. Greater ventrolateral prefrontal cortex responses to either stimulus type were associated with a relatively poor outcome. LIMITATIONS: The sample size was modest and patients were taking a variety of antidepressants. CONCLUSIONS: Right subgenual cingulate and right visual cortical responses to sad stimuli predict good clinical outcome in the context of antidepressant treatment for severe depression in a naturalistic setting. Ventrolateral prefrontal cortex activity may indicate poor prognosis due to its relationship with negative rumination.

Wake-up call for British psychiatry.

The recent drive within the UK National Health Service to improve psychosocial care for people with mental illness is both understandable and welcome: evidence-based psychological and social interventions are extremely important in managing psychiatric illness. Nevertheless, the accompanying downgrading of medical aspects of care has resulted in services that often are better suited to offering non-specific psychosocial support, rather than thorough, broad-based diagnostic assessment leading to specific treatments to optimise well-being and functioning. In part, these changes have been politically driven, but they could not have occurred without the collusion, or at least the acquiescence, of psychiatrists. This creeping devaluation of medicine disadvantages patients and is very damaging to both the standing and the understanding of psychiatry in the minds of the public, fellow professionals and the medical students who will be responsible for the specialty's future. On the 200th birthday of psychiatry, it is fitting to reconsider the specialty's core values and renew efforts to use psychiatric skills for the maximum benefit of patients.

A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals.

BACKGROUND: The ventromedial prefrontal cortex (VMPFC) is a region implicated in the assessment of the rewarding potential of stimuli and may be dysfunctional in major depressive disorder (MDD). The few studies examining prefrontal cortical responses to emotive stimuli in MDD have indicated increased VMPFC responses to pleasant images but decreased responses to sad mood provocation when compared with healthy individuals. We wished to corroborate these results by examining neural responses to personally relevant happy and sad stimuli in MDD and healthy individuals within the same paradigm. METHODS: Neural responses to happy and sad emotional stimuli (autobiographical memory prompts and congruent facial expressions) were measured using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in MDD (n = 12) and healthy (n = 12) individuals. RESULTS: Increased and decreased responses in VMPFC were observed in MDD and healthy individuals, respectively, to happy stimuli, whereas the pattern was reversed for MDD and healthy individual responses to sad stimuli. These findings were not explained by medication effects in depressed individuals. CONCLUSIONS: These findings indicate a double dissociation of the pattern of VMPFC response to happy and sad stimuli in depressed and healthy individuals and suggest abnormal reward processing in MDD.

The neural correlates of anhedonia in major depressive disorder.

BACKGROUND: Anhedonia is a relative lack of pleasure in response to formerly rewarding stimuli. It is an important diagnostic feature of major depressive disorder (MDD), and predicts antidepressant efficacy. Understanding its neurobiological basis may help to target new treatments and predict treatment outcomes. Using a novel paradigm, we aimed to explore the correlations between anhedonia severity and magnitude of neural responses to happy and sad stimuli in regions previously implicated in studies of human reward processing and depressive anhedonia. METHODS: Neural responses to happy and sad emotional stimuli (autobiographical prompts and mood congruent facial expressions) were measured using blood oxygen level dependent (BOLD) functional magnetic resonance imaging in twelve MDD individuals with varying degrees of anhedonia. RESULTS: In response to happy stimuli, anhedonia, but not depression severity per se, was positively and negatively correlated with ventromedial prefrontal cortex (VMPFC) and amygdala/ventral striatal activity, respectively. State anxiety independently contributed to a VMPFC-subcortical dissociation of response to happy (but not sad) stimuli, which was similar, but different, to anhedonia. CONCLUSIONS: These findings suggest that anhedonia and state anxiety are associated with dysfunction within neural systems underlying the response to, and assessment of, the rewarding potential of emotive stimuli in MDD, and highlight the importance of employing a symptom-dimension-based approach in the examination of the neurobiology of depression.

A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder.

BACKGROUND: Accurate recognition of facial expressions is crucial for social functioning. In depressed individuals, implicit and explicit attentional biases away from happy and toward sad stimuli have been demonstrated. These may be associated with the negative cognitions in these individuals. METHODS: Using event-related functional magnetic resonance imaging (fMRI), neural responses to happy and sad facial expressions were measured in 14 healthy individuals and 16 individuals with major depressive disorder. RESULTS: Healthy but not depressed individuals demonstrated linear increases in response in bilateral fusiform gyri and right putamen to expressions of increasing happiness, while depressed individuals demonstrated linear increases in response in left putamen, left parahippocampal gyrus/amygdala, and right fusiform gyrus to expressions of increasing sadness. There was a negative correlation in depressed individuals between depression severity and magnitude of neural response within right fusiform gyrus to happy expressions. CONCLUSIONS: Our findings indicate preferential increases in neural response to sad but not happy facial expressions in neural regions involved in the processing of emotional stimuli in depressed individuals. These findings may be associated with the above pattern of implicit and explicit attentional biases in these individuals and suggest a potential neural basis for the negative cognitions and social dysfunction in major depression.

Information processing deficits in withdrawing alcoholics.

Prepulse inhibition (PPI) of the acoustic startle response (a reduction in response to an intense, startling stimulus (the pulse) if preceded by 30-150 ms by a weaker, non-startling stimulus) is an established model to index information processing deficits in thought-disordered schizophrenic patients. The present study aimed to investigate the influence of alcohol withdrawal on the PPI effect. Eight withdrawing alcoholic patients underwent testing for PPI of the acoustic startle response (defined as percentage reduction of the response over pulse-alone stimulus; prepulses 15 dB above the background) on three occasions (1, 3 and 7 days following the last drink). The results demonstrated remarkably low levels of PPI on days 1 and 3, with this being very robust in three patients who had a history of delirium tremens; there was a trend towards normalization of PPI on day 7. This study, although preliminary, suggests strongly that there is a deficit in the filtering of sensory information in alcohol-dependent patients undergoing alcohol withdrawal. This was most apparent in those with a history of delirium tremens. Further studies are needed to define the cause and chronicity of these deficits.

Salivary cortisol measurements during a medically assisted alcohol withdrawal.

Previous studies using plasma cortisol estimations have suggested that hypothalmo-pituitary-axis (HPA) activation occurs in alcohol-dependent patients during alcohol withdrawal. The present study set out to confirm this finding using salivary cortisol assays, which are a better indicator of plasma free cortisol, the fraction which exerts its physiological effects. Nine alcohol dependent patients provided four saliva samples (at 10 a.m., 2 p.m., 6 p.m. and 10 p.m.) on days 1, 3 and 7 of a medically assisted alcohol withdrawal (corresponding to 1, 3 and 7 days following the last drink, respectively).Withdrawal symptom severity, craving and mood disturbance were also measured. A group of non-alcohol-dependent individuals, without psychiatric or medical disorder, gave four samples at the same times on one day only. Mean daily cortisol levels in our alcohol-dependent population, as calculated by the area under the curve (AUC), decreased significantly over time (mean AUC (nmol/l/hour) on day 1 = 149, on day 7 = 85.7, p = 0.009) and were significantly higher than controls on each day (mean AUC in controls = 28.3, p = 0.001). The cortisol response showed a similar temporal trend to withdrawal symptom severity and mood disturbance. This is consistent with previous studies measuring plasma cortisol in alcohol withdrawal. However, the magnitude of the effect in our study was greater, and in contrast to some previous studies, levels were far from normal by day 7. The comparatively low cortisol response in our one mildly dependent patient suggests that there may be a relationship between dependence severity and the size of the cortisol response to withdrawal. Salivary cortisol sampling could prove to be a useful prognostic tool, with implications for subsequent withdrawal symptom severity, mood disturbances, risk of relapse and alcohol-related cognitive decline. There are implications for developing new treatments for alcohol withdrawal but more studies are needed.