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

Unresolved-Disorganized Attachment Associated With Smaller Hippocampus and Increased Functional Connectivity Beyond Psychopathology

Loss and abuse in children can lead to unresolved–disorganized (UD) attachment. How this condition relates to brain structure and functional connectivity (FC) is unknown. We therefore aimed to investigate gray matter volume (GMV) and resting state functional connectivity (RSFC) correlates of UD attachment in adolescents. Based on previous neuroimaging studies of trauma effects, we hypothesized that the structure of the amygdala and hippocampus and the FC of the latter would be linked to UD attachment. Anatomical and RSFC data were collected from a mixed group of adolescents (N = 74) with symptoms of posttraumatic stress disorder (PTSD) related to childhood sexual abuse (CSA), anxiety/depressive symptoms, and without psychiatric disorder as part of the Emotional Pathways’ Imaging Study in Clinical Adolescents (EPISCA). Bilateral volumes of the amygdala and hippocampus were measured using the FMRIB Software Library, and RSFC of the hippocampus was assessed using seed-based correlation. UD attachment was measured using the Adult Attachment Interview. Hierarchical regression and correlation were used to assess the associations between UD status (continuous and categorical), brain structure, and FC, adjusting for a general psychopathology factor, puberty stage, gender, age, and IQ. UD attachment was associated with a smaller left hippocampal volume, R2 =.23, and a higher level of FC between the hippocampus and the middle temporal gyrus and lateral occipital cortex. The associations among UD attachment, specific brain structure, and FC across psychopathological classifications shows promise for dimensional complements to the dominant classificatory approach in clinical research and practice

Toward identifying reproducible brain signatures of obsessive-compulsive profiles: rationale and methods for a new global initiative

Background Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2–3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. Methods We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. Discussion Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it

Toward identifying reproducible brain signatures of obsessive-compulsive profiles: rationale and methods for a new global initiative

Background Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2–3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. Methods We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. Discussion Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it

Unresolved-disorganized attachment associated with smaller hippocampus and increased functional connectivity beyond psychopathology

Loss and abuse in children can lead to unresolved-disorganized (UD) attachment. How this condition relates to brain structure and functional connectivity (FC) is unknown. We therefore aimed to investigate gray matter volume (GMV) and resting state functional connectivity (RSFC) correlates of UD attachment in adolescents. Based on previous neuroimaging studies of trauma effects, we hypothesized that the structure of the amygdala and hippocampus and the FC of the latter would be linked to UD attachment. Anatomical and RSFC data were collected from a mixed group of adolescents (N = 74) with symptoms of posttraumatic stress disorder (PTSD) related to childhood sexual abuse (CSA), anxiety/depressive symptoms, and without psychiatric disorder as part of the Emotional Pathways' Imaging Study in Clinical Adolescents (EPISCA). Bilateral volumes of the amygdala and hippocampus were measured using the FMRIB Software Library, and RSFC of the hippocampus was assessed using seed-based correlation. UD attachment was measured using the Adult Attachment Interview. Hierarchical regression and correlation were used to assess the associations between UD status (continuous and categorical), brain structure, and FC, adjusting for a general psychopathology factor, puberty stage, gender, age, and IQ. UD attachment was associated with a smaller left hippocampal volume, R2 = .23, and a higher level of FC between the hippocampus and the middle temporal gyrus and lateral occipital cortex. The associations among UD attachment, specific brain structure, and FC across psychopathological classifications shows promise for dimensional complements to the dominant classificatory approach in clinical research and practice

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

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

Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder

Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric comorbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in graymatter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multisite imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples. An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients (n = 174) and healthy control (HC)-participants (n = 213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium

Aberrant limbic and salience network resting-state functional connectivity in panic disorder without comorbidity

<p>Background: Panic disorder (PD) is a prevalent and debilitating disorder but its neurobiology is still poorly understood. We investigated resting-state functional connectivity (RSFC) in PD without comorbidity in three networks that have been linked to PD before. This could provide new insights in how functional integration of brain regions involved in fear and panic might relate to the symptomatology of PD.</p><p>Methods: Eleven PD patients without comorbidity and eleven pair-wise matched healthy controls underwent resting-state fMRI. We used seed regions-of-interest in the bilateral amygdala (limbic network), the bilateral dorsal anterior cingulate cortex (dACC) (salience network), and the bilateral posterior cingulate cortex (default mode network). RSFC of these areas was assessed using seed-based correlations. All results were cluster corrected for multiple comparisons (Z > 2.3, p <.05).</p><p>Results: Abnormalities were identified in the limbic network with increased RSFC between the right amygdala and the bilateral precuneus in PD patients. In the salience network the dACC demonstrated altered connectivity with frontal, parietal and occipital areas.</p><p>Limitations: The small sample size and hypothesis-driven approach could restrict finding additional group differences that may exist. Other caveats are reflected in the use of medication by two participants and the acquisition of the resting-state scan at the end of a fixed imaging protocol.</p><p>Conclusion: We found altered RSFC in PD between areas involved in emotion regulation and emotional and somatosensory stimulus processing, as well as an area engaged in self-referential processing, not implicated in models for PD before. These findings extend existing functional neuroanatomical models of PD, as the altered RSFC may underlie increased sensitivity for bodily symptoms. (C) 2012 Elsevier B.V. All rights reserved.</p>