Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms.

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other 'psychedelics' yet were related to clinical outcomes. A 'reset' therapeutic mechanism is proposed.

Anterior cingulate cortex grey matter volume abnormalities in adolescents with PTSD after childhood sexual abuse.

Adverse childhood experiences (ACE) substantially increase the risk of later psychiatric and somatic pathology. While neurobiological factors are likely to play a mediating role, specific insights are lacking. The scarce neuroimaging studies in traumatised pediatric populations have provided inconsistent results, potentially due to the inclusion of different types of trauma. To further improve our understanding of the neurobiology of pediatric psychotrauma, this study seeks to investigate abnormalities in grey matter volume (GMV) in a homogeneous group of adolescents with posttraumatic stress disorder (PTSD) due to childhood sexual abuse (CSA) and the relationship between GMV and symptom severity. We performed a voxel based morphometry (VBM) analysis in 21 adolescents with CSA-related PTSD and 25 matched non-traumatised, non-clinical adolescents. Hippocampus, amygdala, anterior cingulate cortex (ACC), medial PFC (mPFC) and superior temporal gyrus (STG) were chosen as regions of interest (ROIs). Trauma symptomatology was measured with the Trauma Symptom Checklist for Children (TSCC) and dissociation symptoms with the Adolescent Dissociative Experiences Scale (A-DES). The ROI analysis showed that the CSA-related PTSD group had significant smaller volumes of the dorsal ACC as compared to healthy controls. However, no correlations were found between GMV and scores on the TSCC and A-DES. The smaller ACC volume is partly in line with previous studies in traumatised youth and is a consistent finding in traumatised adults. Taken together our results suggest that the dorsal ACC is implicated in the neurobiological sequelae of CSA, potentially associated with an altered evaluative processing of emotion, but not directly with PTSD severity.

Altered neural processing of emotional faces in remitted Cushing's disease.

Patients with long-term remission of Cushing's disease (CD) demonstrate residual psychological complaints. At present, it is not known how previous exposure to hypercortisolism affects psychological functioning in the long-term. Earlier magnetic resonance imaging (MRI) studies demonstrated abnormalities of brain structure and resting-state connectivity in patients with long-term remission of CD, but no data are available on functional alterations in the brain during the performance of emotional or cognitive tasks in these patients. We performed a cross-sectional functional MRI study, investigating brain activation during emotion processing in patients with long-term remission of CD. Processing of emotional faces versus a non-emotional control condition was examined in 21 patients and 21 matched healthy controls. Analyses focused on activation and connectivity of two a priori determined regions of interest: the amygdala and the medial prefrontal-orbitofrontal cortex (mPFC-OFC). We also assessed psychological functioning, cognitive failure, and clinical disease severity. Patients showed less mPFC activation during processing of emotional faces compared to controls, whereas no differences were found in amygdala activation. An exploratory psychophysiological interaction analysis demonstrated decreased functional coupling between the ventromedial PFC and posterior cingulate cortex (a region structurally connected to the PFC) in CD-patients. The present study is the first to show alterations in brain function and task-related functional coupling in patients with long-term remission of CD relative to matched healthy controls. These alterations may, together with abnormalities in brain structure, be related to the persisting psychological morbidity in patients with CD after long-term remission.

Resting-State Functional Connectivity in Patients with Long-Term Remission of Cushing's Disease.

Glucocorticoid disturbance can be a cause of psychiatric symptoms. Cushing's disease represents a unique model for examining the effects of prolonged exposure to high levels of endogenous cortisol on the human brain as well as for examining the relation between these effects and psychiatric symptomatology. This study aimed to investigate resting-state functional connectivity (RSFC) of the limbic network, the default mode network (DMN), and the executive control network in patients with long-term remission of Cushing's disease. RSFC of these three networks of interest was compared between patients in remission of Cushing's disease (n=24; 4 male, mean age=44.96 years) and matched healthy controls (n=24; 4 male, mean age=46.5 years), using probabilistic independent component analysis to extract the networks and a dual regression method to compare both groups. Psychological and cognitive functioning was assessed with validated questionnaires and interviews. In comparison with controls, patients with remission of Cushing's disease showed an increased RSFC between the limbic network and the subgenual subregion of the anterior cingulate cortex (ACC) as well as an increased RSFC of the DMN in the left lateral occipital cortex. However, these findings were not associated with psychiatric symptoms in the patient group. Our data indicate that previous exposure to hypercortisolism is related to persisting changes in brain function.

Smaller grey matter volumes in the anterior cingulate cortex and greater cerebellar volumes in patients with long-term remission of Cushing's disease: a case-control study.

OBJECTIVE: Patients with long-term remission of Cushing's disease (CD) have persistent psychological and cognitive impairments. It is unknown whether, and to what extent, these impairments are accompanied by structural abnormalities in the brain. We aim to investigate structural changes in the brain in patients with predominantly long-term remission of CD and to examine whether these changes are associated with psychological and cognitive dysfunction and clinical severity. DESIGN: A cross-sectional, case-control study. METHODS: In 25 patients with predominantly long-term remission of CD and 25 matched healthy controls, grey matter volumes in the regions of interest (hippocampus, amygdala, and anterior cingulate cortex (ACC)) and in the whole brain were examined, using 3T magnetic resonance imaging and a voxel-based morphometry approach. Psychological and cognitive functioning were assessed using validated questionnaires and clinical severity was assessed using the Cushing's syndrome severity index. RESULTS: Compared with controls, patients had smaller grey matter volumes of areas in the ACC (on average 14%, P<0.05) and greater volume of the left posterior lobe of the cerebellum (on average 34%, P<0.05). As expected, patients with remitted CD reported more depressive symptoms (P=0.005), more anxiety (P=0.003), more social phobia (P=0.034), more apathy (P=0.002), and more cognitive failure (P=0.023) compared with controls, but the differences in grey matter volumes were not associated with psychological or cognitive measures, nor with clinical severity. CONCLUSION: Patients with predominantly long-term remission of CD showed specific structural brain abnormalities, in the presence of psychological dysfunction. Our data form a basis for future work aimed at elucidating the relation of the structural brain abnormalities and the sustained psychological deficits after long-term exposure to high cortisol levels.

Resilience to childhood maltreatment is associated with increased resting-state functional connectivity of the salience network with the lingual gyrus.

The experience of childhood maltreatment is related to an increased risk of developing a variety of psychiatric disorders, as well as a change in the structure of the brain. However, not much is known about the neurobiological basis of resilience to childhood maltreatment. This study aims to identify resting-state functional connectivity (RSFC) patterns specific for resilience to childhood maltreatment, focusing on the default mode and salience network and networks seeded from the amygdala and left dorsomedial prefrontal cortex. Resting-state functional MRI scans were obtained in 33 individuals. Seeds in the bilateral amygdala, the dorsal anterior cingulate cortex (dACC), the posterior cingulate cortex and the left dorsomedial prefrontal cortex were defined and used to examine whether resilient individuals differed from vulnerable individuals and healthy controls in RSFC with other brain regions. Within the salience network, the resilient group was associated with increased RSFC between the left dACC and a region containing the bilateral lingual gyrus and the occipital fusiform gyrus compared to both the vulnerable group and the healthy controls. In this study, we found RSFC patterns specific for resilient individuals. Regions that are implicated are related on a functional level to declarative memory and the processing of emotional stimuli.

Neuroimaging of resilience to stress: current state of affairs.

Resilience is defined as a dynamic, multidimensional process encompassing positive adaptation within the context of significant adversity. The complex nature of this construct makes it a difficult topic to study in neuroimaging research; however, in this article, we propose ways to operationalize resilience. The limited amount of structural and functional neuroimaging studies specifically designed to examine resilience have mainly focused on investigating alterations in regions of the brain involved in emotion and stress regulation circuitry. In the future, neuroimaging of resilience is expected to benefit from functional and structural connectivity approaches and the use of novel imaging task paradigms.

Resting-state functional connectivity abnormalities in limbic and salience networks in social anxiety disorder without comorbidity.

The neurobiology of social anxiety disorder (SAD) is not yet fully understood. Structural and functional neuroimaging studies in SAD have identified abnormalities in various brain areas, particularly the amygdala and elements of the salience network. This study is the first to examine resting-state functional brain connectivity in a drug-naive sample of SAD patients without psychiatric comorbidity and healthy controls, using seed regions of interest in bilateral amygdala, in bilateral dorsal anterior cingulate cortex for the salience network, and in bilateral posterior cingulate cortex for the default mode network. Twelve drug-naive SAD patients and pair-wise matched healthy controls, all drawn from the Netherlands Study of Depression and Anxiety sample, underwent resting-state fMRI. Group differences were assessed with voxel-wise gray matter density as nuisance regressor. All results were cluster corrected for multiple comparisons (Z>2.3, p<.05). Relative to control subjects, drug-naive SAD patients demonstrated increased negative right amygdala connectivity with the left middle temporal gyrus, left supramarginal gyrus and left lateral occipital cortex. In the salience network patients showed increased positive bilateral dorsal anterior cingulate connectivity with the left precuneus and left lateral occipital cortex. Default mode network connectivity was not different between groups. These data demonstrate that drug-naive SAD patients without comorbidity show differences in functional connectivity of the amygdala, and of areas involved in self-awareness, some of which have not been implicated in SAD before.