Subgenual activation and the finger of blame: individual differences and depression vulnerability.

BACKGROUND: Subgenual cingulate cortex (SCC) responses to self-blaming emotion-evoking stimuli were previously found in individuals prone to self-blame with and without a history of major depressive disorder (MDD). This suggested SCC activation reflects self-blaming emotions such as guilt, which are central to models of MDD vulnerability. METHOD: Here, we re-examined these hypotheses in an independent larger sample. A total of 109 medication-free participants (70 with remitted MDD and 39 healthy controls) underwent fMRI whilst judging self- and other-blaming emotion-evoking statements. They also completed validated questionnaires of proneness to self-blaming emotions including those related to internal (autonomy) and external (sociotropy) evaluation, which were subjected to factor analysis. RESULTS: An interaction between group (remitted MDD v. Control) and condition (self- v. other-blame) was observed in the right SCC (BA24). This was due to higher SCC signal for self-blame in remitted MDD and higher other-blame-selective activation in Control participants. Across the whole sample, extracted SCC activation cluster averages for self- v. other-blame were predicted by a regression model which included the reliable components derived from our factor analysis of measures of proneness to self-blaming emotions. Interestingly, this prediction was solely driven by autonomy/self-criticism, and adaptive guilt factors, with no effect of sociotropy/dependency. CONCLUSIONS: Despite confirming the prediction of SCC activation in self-blame-prone individuals and those vulnerable to MDD, our results suggest that SCC activation reflects blame irrespective of where it is directed rather than selective for self. We speculate that self-critical individuals have more extended SCC representations for blame in the context of self-agency.

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence.

This corrects the article DOI: 10.1038/npp.2016.289.

Self-blame-Selective Hyperconnectivity Between Anterior Temporal and Subgenual Cortices and Prediction of Recurrent Depressive Episodes.

IMPORTANCE: Patients with remitted major depressive disorder (MDD) were previously found to display abnormal functional magnetic resonance imaging connectivity (fMRI) between the right superior anterior temporal lobe (RSATL) and the subgenual cingulate cortex and adjacent septal region (SCSR) when experiencing self-blaming emotions relative to emotions related to blaming others (eg, "indignation or anger toward others"). This finding provided the first neural signature of biases toward overgeneralized self-blaming emotions (eg, "feeling guilty for everything"), known to have a key role in cognitive vulnerability to MDD. It is unknown whether this neural signature predicts risk of recurrence, a crucial step in establishing its potential as a prognostic biomarker, which is urgently needed for stratification into pathophysiologically more homogeneous subgroups and for novel treatments. OBJECTIVE: To use fMRI in remitted MDD at baseline to test the hypothesis that RSATL-SCSR connectivity for self-blaming relative to other-blaming emotions predicts subsequent recurrence of depressive episodes. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study from June 16, 2011, to October 10, 2014, in a clinical research facility completed by 75 psychotropic medication-free patients with remitted MDD and no relevant comorbidity. In total, 31 remained in stable remission, and 25 developed a recurring episode over the 14 months of clinical follow-up and were included in the primary analysis. Thirty-nine control participants with no personal or family history of MDD were recruited for further comparison. MAIN OUTCOMES AND MEASURES: Between-group difference (recurring vs stable MDD) in RSATL connectivity, with an a priori SCSR region of interest for self-blaming vs other-blaming emotions. RESULTS: We corroborated our hypothesis that during the experience of self-blaming vs other-blaming emotions, RSATL-SCSR connectivity predicted risk of subsequent recurrence. The recurring MDD group showed higher connectivity than the stable MDD group (familywise error-corrected P < .05 over the a priori SCSR region of interest) and the control group. In addition, the recurring MDD group also exhibited RSATL hyperconnectivity with the right ventral putamen and claustrum and the temporoparietal junction. Together, these regions predicted recurrence with 75% accuracy. CONCLUSIONS AND RELEVANCE: To our knowledge, this study is the first to provide a robust demonstration of an fMRI signature of recurrence risk in remitted MDD. Additional studies are needed for its further optimization and validation as a prognostic biomarker.

Minocycline as an adjunct for treatment-resistant depressive symptoms: study protocol for a pilot randomised controlled trial.

BACKGROUND: Depression is one of the leading causes of disability worldwide. A high proportion of patients do not respond to standard drug treatments. Recent evidence has suggested that anti-inflammatory treatment may have beneficial effects in major depression. Minocycline is a tetracycline antibiotic with good CNS penetration that exerts effects on multiple interacting symptoms implicated in the pathophysiology of mood disorders. Open-label studies have suggested that minocycline is effective as an adjunct drug in improving depressive symptoms. METHODS/DESIGN: This is a multi-centre, 3-month, double-blind, placebo-controlled, pilot trial of minocycline added to treatment as usual for patients suffering from DSM-IV major depressive disorder. This will be a double-blind, randomised, controlled, two parallel-arm study with 20 participants in each arm, giving a total of 40 participants. There will be a screening visit, a randomization visit and four follow-up visits. Clinical assessments using the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ -9) and the Generalised Anxiety Disorder scale (GAD-7) will be carried out at every visit. Side effects checklists will also be undertaken at each visit. Biomarkers (inflammatory cytokines and CRP) will be measured at baseline and at the end of the treatment phase. Minocycline will be started at 100 mg once daily (OD) and will be increased to 200 mg at two weeks. DISCUSSION: Anti-inflammatory treatments have been shown to have some beneficial effects in the treatment of major depressive disorder. The aim of this pilot randomised controlled trial is to establish the degree of improvement in depressive symptoms with the addition of minocycline to treatment as usual. TRIAL REGISTRATION: ClinicalTrials.gov NCT02263872 registered 10 October 2014.

Machine learning algorithm accurately detects fMRI signature of vulnerability to major depression.

Standard functional magnetic resonance imaging (fMRI) analyses cannot assess the potential of a neuroimaging signature as a biomarker to predict individual vulnerability to major depression (MD). Here, we use machine learning for the first time to address this question. Using a recently identified neural signature of guilt-selective functional disconnection, the classification algorithm was able to distinguish remitted MD from control participants with 78.3% accuracy. This demonstrates the high potential of our fMRI signature as a biomarker of MD vulnerability.

Increased amygdala response to shame in remitted major depressive disorder.

Proneness to self-blaming moral emotions such as shame and guilt is increased in major depressive disorder (MDD), and may play an important role in vulnerability even after symptoms have subsided. Social psychologists have argued that shame-proneness is relevant for depression vulnerability and is distinct from guilt. Shame depends on the imagined critical perception of others, whereas guilt results from one's own judgement. The neuroanatomy of shame in MDD is unknown. Using fMRI, we compared 21 participants with MDD remitted from symptoms with no current co-morbid axis-I disorders, and 18 control participants with no personal or family history of MDD. The MDD group exhibited higher activation of the right amygdala and posterior insula for shame relative to guilt (SPM8). This neural difference was observed despite equal levels of rated negative emotional valence and frequencies of induced shame and guilt experience across groups. These same results were found in the medication-free MDD subgroup (N = 15). Increased amygdala and posterior insula activations, known to be related to sensory perception of emotional stimuli, distinguish shame from guilt responses in remitted MDD. People with MDD thus exhibit changes in the neural response to shame after symptoms have subsided. This supports the hypothesis that shame and guilt play at least partly distinct roles in vulnerability to MDD. Shame-induction may be a more sensitive probe of residual amygdala hypersensitivity in MDD compared with facial emotion-evoked responses previously found to normalize on remission.

Guilt-selective functional disconnection of anterior temporal and subgenual cortices in major depressive disorder.

CONTEXT: Proneness to overgeneralization of self-blame is a core part of cognitive vulnerability to major depressive disorder (MDD) and remains dormant after remission of symptoms. Current neuroanatomical models of MDD, however, assume general increases of negative emotions and are unable to explain biases toward emotions entailing self-blame (eg, guilt) relative to those associated with blaming others (eg, indignation). Recent functional magnetic resonance imaging (fMRI) studies in healthy participants have shown that moral feelings such as guilt activate representations of social meaning within the right superior anterior temporal lobe (ATL). Furthermore, this area was selectively coupled with the subgenual cingulate cortex and adjacent septal region (SCSR) during the experience of guilt compared with indignation. Despite its psychopathological importance, the functional neuroanatomy of guilt in MDD is unknown. OBJECTIVE: To use fMRI to test the hypothesis that, in comparison with control individuals, participants with remitted MDD exhibit guilt-selective SCSR-ATL decoupling as a marker of deficient functional integration. DESIGN: Case-control study from May 1, 2008, to June 1, 2010. SETTING: Clinical research facility. PARTICIPANTS: Twenty-five patients with remitted MDD (no medication in 16 patients) with no current comorbid Axis I disorders and 22 controls with no personal or family history of MDD. MAIN OUTCOME MEASURES: Between-group difference of ATL coupling with a priori SCSR region of interest for guilt vs indignation. RESULTS: We corroborated the prediction of a guilt-selective reduction in ATL-SCSR coupling in MDD vs controls (familywise error-corrected P=.001 over the region of interest) and revealed additional medial frontopolar, right hippocampal, and lateral hypothalamic areas of decoupling while controlling for medication status and intensity of negative emotions. Lower levels of ATL-SCSR coupling were associated with higher scores on a validated measure of overgeneralized self-blame (67-item Interpersonal Guilt Questionnaire). CONCLUSIONS: Vulnerability to MDD is associated with temporofrontolimbic decoupling that is selective for self-blaming feelings. This provides the first neural mechanism ofMDD vulnerability that accounts for self-blaming biases.

Significant association between the C(-1019)G functional polymorphism of the HTR1A gene and impulsivity.

Serotonin-1A (5-HT(1A)) receptors are known to play a role in impulsivity-related behavior. The C(-1019)G functional polymorphism (rs6295) has been suggested to regulate the 5-HT(1A) receptor gene (HTR(1A)) expression in presynaptic raphe neurons, namely, increased receptor concentration and reduced neuronal firing could be associated with the G allele. Previous studies indicate that this polymorphism is associated with aggression, suicide, and several psychiatric disorders, yet its association with impulsivity has rarely been investigated. We studied the relationship between impulsivity and the C(-1019)G polymorphism of the HTR(1A) in a population sample of 725 volunteers using the Impulsiveness subscale (IVE-I) of the Eysenck Impulsiveness, Venturesomeness, and Empathy scale and also the Barratt Impulsiveness Scale (BIS-11). Data were analyzed using analysis of variance with age and gender as covariates and Tukey's HSD post-hoc test. Post-hoc analysis revealed that the study had 0.958 power to detect 0.15 effect size. Significant differences between the C(-1019)G genotype groups (GG vs. GC vs. CC) were found. Subjects carrying GG genotype showed significantly higher impulsiveness scores compared to GC or CC carriers for the IVE-I scale (P = 0.014), for the Motor (P = 0.021), Cognitive Impulsiveness (P = 0.002), and for the BIS total score (P = 0.008) but not for the Nonplanning Impulsiveness (P = 0.520) subscale of the BIS-11. Our results suggest the involvement of the HTR(1A) in the continuum phenotype of impulsivity.

A voxel-based morphometric MRI study in men with borderline personality disorder: preliminary findings.

OBJECTIVE: There is increasing evidence for subtle changes in brain morphology and function in patients with borderline personality disorder (BPD). Structural brain imaging studies show lower volume in frontal, temporal and parietal brain regions than in healthy controls. The aim of our preliminary study of men with BPD was to investigate structural brain changes and their relationship with a measure of impulsivity. METHODS: We examined seven male patients with BPD and six control men using voxel-based morphometry. Analysis of covariance was carried out to assess regionally specific differences in grey and white matter (WM) volumes. Correlations between trait impulsivity as measured using the Impulsiveness-Venturesomeness-Empathy scale and brain volumes were studied. RESULTS: Compared with healthy men, men with BPD had similar WM volumes but smaller grey matter (GM) volumes in frontal, temporal and parietal cortices. The latter were negatively correlated with trait impulsivity. CONCLUSIONS: Our findings fit with previous reports of smaller regional GM volumes reported in women with BPD, and suggest that in men there may be an association between smaller GM volumes and impulsivity.

The NR1 N-methyl-D-aspartate subunit and brain-derived neurotrophic factor in temporal lobe epilepsy hippocampus: a comparison of patients with and without coexisting psychiatric symptoms.

PURPOSE: The glutamate N-methyl-D-aspartate (NMDA) receptor and the neurotrophin brain-derived neurotrophic factor have been implicated in the pathophysiology of schizophrenia and depression. Since these psychiatric disorders are common in temporal lobe epilepsy (TLE), a comparison of TLE patients with and without coexisting psychiatric symptoms may be useful to unravel pathophysiologic mechanisms for psychosis or depression. METHODS: We used immunoautoradiography to assess the NR1 NMDA receptor subunit and brain-derived neurotrophic factor in resected TLE hippocampus. RESULTS: No changes relative to comparison controls were found for TLE patients with schizophrenia-like psychosis or depression. Increased NR1 was found in the dentate molecular layer in the dysphoria group and unmedicated depressed patients. CONCLUSIONS: An increase in NR1 protein in the dentate molecular layer suggests an upregulation of NMDA receptors in granule cells in TLE patients with dysphoria and depression. This finding is compatible with the theory that increased NMDA receptor function is involved in the pathogenesis of depression and that antidepressants may act by opposing this mechanism.

Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder.

Several theories of schizophrenia suggest dysfunction in glutamate neurotransmission in higher brain regions such as the prefrontal cortex (PFC). Previous studies have investigated whether astroglial abnormalities could give rise to glutamate dysfunction using glial fibrillary acidic protein (GFAP) immunocytochemistry. We have used quantitative immunoautoradiography to measure glutamine synthetase (GS), the glial enzyme which recycles synaptic glutamate, as a more direct test of glial mechanisms of abnormal glutamate function in schizophrenia. We compared GS with GFAP immunoautoradiography in dorsolateral (area 9) and orbitofrontal (area 11/47) cortex. Optical density measures from film autoradiographs revealed an increase in GFAP immunoreactivity in area 9 in schizophrenia and a decrease in area 11/47 in both schizophrenia and bipolar disorder. The increase in GFAP in area 9 significantly correlated with lifetime antipsychotic drug treatment, whereas the reduction in area 11/47 occurred despite this effect. There were no changes in GS immunoreactivity in any psychiatric disorder. Regional and antigen-specific down-regulation of GFAP protein in OFC in schizophrenia and bipolar disorder may relate to disease mechanisms of psychosis.

Neuronal correlates of theory of mind and empathy: a functional magnetic resonance imaging study in a nonverbal task.

Theory of Mind (ToM), the ability to attribute mental states to others, and empathy, the ability to infer emotional experiences, are important processes in social cognition. Brain imaging studies in healthy subjects have described a brain system involving medial prefrontal cortex, superior temporal sulcus and temporal pole in ToM processing. Studies investigating networks associated with empathic responding also suggest involvement of temporal and frontal lobe regions. In this fMRI study, we used a cartoon task derived from Sarfati et al. (1997) [Sarfati, Y., Hardy-Bayle, M.C., Besche, C., Widlocher, D. 1997. Attribution of intentions to others in people with schizophrenia: a non-verbal exploration with comic strips. Schizophrenia Research 25, 199-209.]with both ToM and empathy stimuli in order to allow comparison of brain activations in these two processes. Results of 13 right-handed, healthy, male volunteers were included. Functional images were acquired using a 1.5 T Phillips Gyroscan. Our results confirmed that ToM and empathy stimuli are associated with overlapping but distinct neuronal networks. Common areas of activation included the medial prefrontal cortex, temporoparietal junction and temporal poles. Compared to the empathy condition, ToM stimuli revealed increased activations in lateral orbitofrontal cortex, middle frontal gyrus, cuneus and superior temporal gyrus. Empathy, on the other hand, was associated with enhanced activations of paracingulate, anterior and posterior cingulate and amygdala. We therefore suggest that ToM and empathy both rely on networks associated with making inferences about mental states of others. However, empathic responding requires the additional recruitment of networks involved in emotional processing. These results have implications for our understanding of disorders characterized by impairments of social cognition, such as autism and psychopathy.

Interictal SPECT in patients with mesial temporal lobe epilepsy and psychosis: a case-control study.

Psychosis is commonly observed in patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS). Interictal single photon emission computed tomography (SPECT) was performed to compare regional cerebral blood flow (rCBF) pattern of MTLE-HS patients with psychosis of epilepsy (POE) comorbidity and MTLE-HS patients without any psychiatric disorders (Control group). For this, 21 patients with POE and 23 Control patients were matched by educational level, clinical, demographic, electrophysiological, and MRI data. SPECT scans were acquired using (99m)Tc and interpreted with a semiquantitative method. We analyzed brain regions of interest (ROI) of frontal, temporal, and parietal cortex, in addition to subcortical structures. There were no significant statistical differences of ROI between the POE group and the Control group after Bonferroni adjustment. However, we observed a trend for rCBF increase of right posterior cingulate in the POE Group. This increase would be in accordance with recent findings of cingulate abnormalities in schizophrenia, suggesting that abnormal function in this region might be associated with the psychotic phenomena.

Gender differences and the effects of ketamine in healthy volunteers.

We present a critical perspective of the impact of gender differences on a widely accepted model of ketamine psychosis in healthy volunteers. Male and female patients with schizophrenia present with different symptomatology, disease course and response to pharmacological intervention. Accordingly, it is expected that ketamine psychosis in healthy volunteers fulfils this face validity. Pre-clinical studies in rats indicate a gender difference in response to ketamine administration. However, a review of the literature to date indicates that studies carried out in healthy volunteers have used all male or mixed samples, indicating the need for further studies comparing the psychopathological effects of ketamine in males and females.

Olanzapine for recurrent aggression in a patient with temporal lobe epilepsy who had temporal lobectomy.

We report the case of a patient with epilepsy who had interictal severe affective aggression, and whose epilepsy significantly improved (but not aggression) after successful temporal lobectomy. Olanzapine significantly improved these aggressive episodes refractory to neurosurgery and previous pharmacological treatments including antipsychotics, anticonvulsants/mood stabilizers and benzodiazepines.