Effects of lockdowns on neurobiological and psychometric parameters in unipolar depression during the COVID-19 pandemic.

Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.

Effects of bilateral sequential theta-burst stimulation on 5-HT1A receptors in the dorsolateral prefrontal cortex in treatment-resistant depression: a proof-of-concept trial.

Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT1A) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [carbonyl-11C]WAY-100635 including arterial blood sampling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation (n = 8 and n = 3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted of excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere, time, and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group, time, and HAMD on specific distribution volume (VS) of 5-HT1A receptor. While post-hoc comparisons showed no significant changes of 5-HT1A receptor VS in either group, higher 5-HT1A receptor VS after treatment correlated with greater difference in HAMD (r = -0.62). The results of this proof-of-concept trial hint towards potential effects of TBS on the distribution of the 5-HT1A receptor. Due to the small sample size, all results must, however, be regarded with caution.

Effects of bilateral sequential theta-burst stimulation on functional connectivity in treatment-resistant depression: First results.

BACKGROUND: Previous studies suggest that transcranial magnetic stimulation exerts antidepressant effects by altering functional connectivity (FC). However, knowledge about this mechanism is still limited. Here, we aimed to investigate the effect of bilateral sequential theta-burst stimulation (TBS) on FC in treatment-resistant depression (TRD) in a sham-controlled longitudinal study. METHODS: TRD patients (n = 20) underwent a three-week treatment of intermittent TBS of the left and continuous TBS of the right dorsolateral prefrontal cortex (DLPFC). Upon this trial's premature termination, 15 patients had received active TBS and five patients sham stimulation. Resting-state functional magnetic resonance imaging was performed at baseline and after treatment. FC (left and right DLPFC) was estimated for each participant, followed by group statistics (t-tests). Furthermore, depression scores were analyzed (linear mixed models analysis) and tested for correlation with FC. RESULTS: Both groups exhibited reductions of depression scores, however, there was no significant main effect of group, or group and time. Anticorrelations between DLPFC and the subgenual cingulate cortex (sgACC) were observed for baseline FC, corresponding to changes in depression severity. Treatment did not significantly change DLPFC-sgACC connectivity, but significantly reduced FC between the left stimulation target and bilateral anterior insula. CONCLUSIONS: Our data is compatible with previous reports on the relevance of anticorrelation between DLPFC and sgACC for treatment success. Furthermore, FC changes between left DLPFC and bilateral anterior insula highlight the effect of TBS on the salience network. LIMITATIONS: Due to the limited sample size, results should be interpreted with caution and are of exploratory nature.

Increased left dorsolateral prefrontal cortex density following escitalopram intake during relearning: a randomized, placebo-controlled trial in healthy humans.

Background: Serotonergic agents affect brain plasticity and reverse stress-induced dendritic atrophy in key fronto-limbic brain areas associated with learning and memory. Objectives: The aim of this study was to investigate effects of the antidepressant escitalopram on gray matter during relearning in healthy individuals to inform a model for depression and the neurobiological processes of recovery. Design: Randomized double blind placebo control, monocenter study. Methods: In all, 76 (44 females) healthy individuals performed daily an associative learning task with emotional or non-emotional content over a 3-week period. This was followed by a 3-week relearning period (randomly shuffled association within the content group) with concurrent daily selective serotonin reuptake inhibitor (i.e., 10 mg escitalopram) or placebo intake. Results: Via voxel-based morphometry and only in individuals that developed sufficient escitalopram blood levels over the 21-day relearing period, an increased density of the left dorsolateral prefrontal cortex was found. When investigating whether there was an interaction between relearning and drug intervention for all participants, regardless of escitalopram levels, no changes in gray matter were detected with either surfaced-based or voxel-based morphometry analyses. Conclusion: The left dorsolateral prefrontal cortex affects executive function and emotional processing, and is a critical mediator of symptoms and treatment outcomes of depression. In line, the findings suggest that escitalopram facilitates neuroplastic processes in this region if blood levels are sufficient. Contrary to our hypothesis, an effect of escitalopram on brain structure that is dependent of relearning content was not detected. However, this may have been a consequence of the intensity and duration of the interventions. Registration: ClinicalTrials.gov Identifier: NCT02753738; Trial Name: Enhancement of learning associated neural plasticity by Selective Serotonin Reuptake Inhibitors; URL: https://clinicaltrials.gov/ct2/show/NCT02753738.

The Impact of Theta-Burst Stimulation on Cortical GABA and Glutamate in Treatment-Resistant Depression: A Surface-Based MRSI Analysis Approach.

Background: Theta burst stimulation (TBS) belongs to one of the biological antidepressant treatment options. When applied bilaterally, excitatory intermittent TBS (iTBS) is commonly targeted to the left and inhibitory continuous TBS (cTBS) to the right dorsolateral prefrontal cortex. TBS was shown to influence neurotransmitter systems, while iTBS is thought to interfere with glutamatergic circuits and cTBS to mediate GABAergic neurotransmission. Objectives: We aimed to expand insights into the therapeutic effects of TBS on the GABAergic and glutamatergic system utilizing 3D-multivoxel magnetic resonance spectroscopy imaging (MRSI) in combination with a novel surface-based MRSI analysis approach to investigate changes of cortical neurotransmitter levels in patients with treatment-resistant depression (TRD). Methods: Twelve TRD patients (five females, mean age ± SD = 35 ± 11 years) completed paired MRSI measurements, using a GABA-edited 3D-multivoxel MEGA-LASER sequence, before and after 3 weeks of bilateral TBS treatment. Changes in cortical distributions of GABA+/tNAA (GABA+macromolecules relative to total N-acetylaspartate) and Glx/tNAA (Glx = mixed signal of glutamate and glutamine), were investigated in a surface-based region-of-interest (ROI) analysis approach. Results: ANCOVAs revealed a significant increase in Glx/tNAA ratios in the left caudal middle frontal area (p corr. = 0.046, F = 13.292), an area targeted by iTBS treatment. Whereas, contralateral treatment with cTBS evoked no alterations in glutamate or GABA concentrations. Conclusion: This study demonstrates surface-based adaptions in the stimulation area to the glutamate metabolism after excitatory iTBS but not after cTBS, using a novel surface-based analysis of 3D-MRSI data. The reported impact of facilitatory iTBS on glutamatergic neurotransmission provides further insight into the neurobiological effects of TBS in TRD.

Serotonergic modulation of effective connectivity in an associative relearning network during task and rest.

An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character-German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.

Intravenous esketamine leads to an increase in impulsive and suicidal behaviour in a patient with recurrent major depression and borderline personality disorder.

Objectives: As clinical studies demonstrated that ketamine possesses rapid-acting antidepressant and antisuicidal effects, it is increasingly used in affective disorders. The neuroplastic properties of ketamine are well described in preclinical and imaging studies, and are highly related to its antidepressive mechanism of action.Methods: Here, we report on a female patient with recurrent major depression and borderline personality disorder (BPD) who was treated with intravenous (i.v.) esketamine as rapid-acting augmentation therapy to improve severe and acute depressive symptoms and suicidal behaviour.Results: Esketamine led to an initial improvement of these symptoms. However, during the course of treatment, loosened and disinhibited behaviour and severe suicidal ideation occurred during and immediately after esketamine application. Hence, i.v. esketamine was discontinued, and she further received treatment as usual, which demonstrated to be beneficial.Conclusions: With current knowledge at hand, one cannot exclude esketamine's effects on the equilibrium of neural plasticity in brain networks, potentially initiating undesirable symptoms as impulsive behaviour and emotional dysregulation. Therefore, until investigations focus on efficacy and side effects profile of esketamine in depressed patients with (comorbid) BPD, treatment with this fast-acting medication should be considered with caution in this patient group.

Escitalopram modulates learning content-specific neuroplasticity of functional brain networks.

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.

Comparison and Reliability of Hippocampal Subfield Segmentations Within FreeSurfer Utilizing T1- and T2-Weighted Multispectral MRI Data.

The accurate segmentation of in vivo magnetic resonance imaging (MRI) data is a crucial prerequisite for the reliable assessment of disease progression, patient stratification or the establishment of putative imaging biomarkers. This is especially important for the hippocampal formation, a brain area involved in memory formation and often affected by neurodegenerative or psychiatric diseases. FreeSurfer, a widely used automated segmentation software, offers hippocampal subfield delineation with multiple input options. While a single T1-weighted (T1) sequence is regularly used by most studies, it is also possible and advised to use a high-resolution T2-weighted (T2H) sequence or multispectral information. In this investigation it was determined whether there are differences in volume estimations depending on the input images and which combination of these deliver the most reliable results in each hippocampal subfield. 41 healthy participants (age = 25.2 years ± 4.2 SD) underwent two structural MRIs at three Tesla (time between scans: 23 days ± 11 SD) using three different structural MRI sequences, to test five different input configurations (T1, T2, T2H, T1 and T2, and T1 and T2H). We compared the different processing pipelines in a cross-sectional manner and assessed reliability using test-retest variability (%TRV) and the dice coefficient. Our analyses showed pronounced significant differences and large effect sizes between the processing pipelines in several subfields, such as the molecular layer (head), CA1 (head), hippocampal fissure, CA3 (head and body), fimbria and CA4 (head). The longitudinal analysis revealed that T1 and multispectral analysis (T1 and T2H) showed overall higher reliability across all subfields than T2H alone. However, the specific subfields had a substantial influence on the performance of segmentation results, regardless of the processing pipeline. Although T1 showed good test-retest metrics, results must be interpreted with caution, as a standard T1 sequence relies heavily on prior information of the atlas and does not take the actual fine structures of the hippocampus into account. For the most accurate segmentation, we advise the use of multispectral information by using a combination of T1 and high-resolution T2-weighted sequences or a T2 high-resolution sequence alone.

Detached empathic experience of others' pain in remitted states of depression - An fMRI study.

BACKGROUND: Major depressive disorder is strongly associated with impairments and difficulties in social interactions. Deficits in empathy, a vital skill for social interactions, have been identified as a risk factor for relapse. However, research on empathy in remitted states of depression is scarce. We chose a social neuroscience approach to investigate potentially altered neural processes involved in sub-components of empathy in remitted states of depression. We expected aberrations in cognitive components of empathy, based on previous reports regarding their role as risk factors for relapse. METHODS: Employing functional magnetic resonance imaging and a pain empathy task (video clips of painful medical treatments), we compared behavioral and neural empathic responses of unmedicated remitted depressive patients (N = 32) to those of untreated acutely depressed patients (N = 29) and healthy controls (N = 35). Self-report ratings of pain evaluation and affect-sharing were obtained. RESULTS: Compared to controls and acutely depressed patients, remitted depressive patients reported higher pain evaluation and showed increased activity in the right temporo-parietal junction. This region, which is central to self-other distinction and which has been linked to adopting a detached perspective, also exhibited reduced connectivity to the anterior insula. Furthermore, we observed reduced activity in regions involved in emotion processing (amygdala) and perception of affective facial expressions (fusiform face area, posterior superior temporal sulcus). CONCLUSIONS: Remitted states of depression are associated with a detached empathic style in response to others' pain, characterized by increased self-other distinction, lowered affective processing, and reduced connectivity between empathy-related brain regions. Although this may prevent emotional harm in specific situations, it may reduce opportunities for positive experiences in social interactions in the long run.

Predicting Antidepressant Citalopram Treatment Response via Changes in Brain Functional Connectivity After Acute Intravenous Challenge.

Introduction: The early and therapy-specific prediction of treatment success in major depressive disorder is of paramount importance due to high lifetime prevalence, and heterogeneity of response to standard medication and symptom expression. Hence, this study assessed the predictability of long-term antidepressant effects of escitalopram based on the short-term influence of citalopram on functional connectivity. Methods: Twenty nine subjects suffering from major depression were scanned twice with resting-state functional magnetic resonance imaging under the influence of intravenous citalopram and placebo in a randomized, double-blinded cross-over fashion. Symptom factors were identified for the Hamilton depression rating scale (HAM-D) and Beck's depression inventory (BDI) taken before and after a median of seven weeks of escitalopram therapy. Predictors were calculated from whole-brain functional connectivity, fed into robust regression models, and cross-validated. Results: Significant predictive power could be demonstrated for one HAM-D factor describing insomnia and the total score (r = 0.45-0.55). Remission and response could furthermore be predicted with an area under the receiver operating characteristic curve of 0.73 and 0.68, respectively. Functional regions with high influence on the predictor were located especially in the ventral attention, fronto-parietal, and default mode networks. Conclusion: It was shown that medication-specific antidepressant symptom improvements can be predicted using functional connectivity measured during acute pharmacological challenge as an easily assessable imaging marker. The regions with high influence have previously been related to major depression as well as the response to selective serotonin reuptake inhibitors, corroborating the advantages of the current approach of focusing on treatment-specific symptom improvements.

Reconfiguration of functional brain networks and metabolic cost converge during task performance.

The ability to solve cognitive tasks depends upon adaptive changes in the organization of whole-brain functional networks. However, the link between task-induced network reconfigurations and their underlying energy demands is poorly understood. We address this by multimodal network analyses integrating functional and molecular neuroimaging acquired concurrently during a complex cognitive task. Task engagement elicited a marked increase in the association between glucose consumption and functional brain network reorganization. This convergence between metabolic and neural processes was specific to feedforward connections linking the visual and dorsal attention networks, in accordance with task requirements of visuo-spatial reasoning. Further increases in cognitive load above initial task engagement did not affect the relationship between metabolism and network reorganization but only modulated existing interactions. Our findings show how the upregulation of key computational mechanisms to support cognitive performance unveils the complex, interdependent changes in neural metabolism and neuro-vascular responses.

Hippocampal GABA levels correlate with retrieval performance in an associative learning paradigm.

Neural plasticity is a complex process dependent on neurochemical underpinnings. Next to the glutamatergic system which contributes to memory formation via long-term potentiation (LTP) and long-term depression (LTD), the main inhibitory neurotransmitter, GABA is crucially involved in neuroplastic processes. Hence, we investigated changes in glutamate and GABA levels in the brain in healthy participants performing an associative learning paradigm. Twenty healthy participants (10 female, 25 ±â€¯5 years) underwent paired multi-voxel magnetic resonance spectroscopy imaging before and after completing 21 days of a facial associative learning paradigm in a longitudinal study design. Changes of GABA and glutamate were compared to retrieval success in the hippocampus, insula and thalamus. No changes in GABA and glutamate concentration were found after 21 days of associative learning. However, baseline hippocampal GABA levels were significantly correlated with initial retrieval success (pcor = 0.013, r = 0.690). In contrast to the thalamus and insula (pcor>0.1), higher baseline GABA levels in the hippocampus were associated with better retrieval performance in an associative learning paradigm. Therefore, our findings support the importance of hippocampal GABA levels in memory formation in the human brain in vivo.

Changes in White Matter Microstructure After Electroconvulsive Therapy for Treatment-Resistant Depression.

BACKGROUND: Treatment-resistant depression is among the most debilitating conditions in psychiatry. Recent studies have associated alterations in white matter microstructure measured with magnetic resonance imaging with poor antidepressant response. Therefore, the extent to which electroconvulsive therapy, the most effective therapeutic option for treatment-resistant depression, affects white matter microstructure warrants investigation. METHODS: A total 13 patients suffering from severe unipolar treatment-resistant depression underwent magnetic resonance imaging with a diffusion tensor imaging sequence before and after undergoing a series of right unilateral electroconvulsive therapy. Diffusivity metrics were compared voxel-wise using tract-based spatial statistics and repeated-measures ANOVA. RESULTS: A total 12 patients responded to electroconvulsive therapy and 9 were classified as remitters. An increase in axial diffusivity was observed in the posterior limb of the internal capsule of the right hemisphere (PFWE ≤ .05). The increase in this area was higher in the right compared with the left hemisphere (P < .05). No correlation of this effect with treatment response could be found. CONCLUSIONS: The strong lateralization of effects to the hemisphere of electrical stimulation suggests an effect of electroconvulsive therapy on diffusivity metrics which is dependent of electrode placement. Investigation in controlled studies is necessary to reveal to what extent the effects of electroconvulsive therapy on white matter microstructure are related to clinical outcomes and electrode placement.

Correction: Epistasis of HTR1A and BDNF risk genes alters cortical 5-HT1A receptor binding: PET results link genotype to molecular phenotype in depression.

In the original Article, co-author Professor Andreas Hahn was not included in the author list. This has been corrected in the XML, PDF and HTML versions of this Article.

Association between dynamic resting-state functional connectivity and ketamine plasma levels in visual processing networks.

Numerous studies demonstrate ketamine's influence on resting-state functional connectivity (rsFC). Seed-based and static rsFC estimation methods may oversimplify FC. These limitations can be addressed with whole-brain, dynamic rsFC estimation methods. We assessed data from 27 healthy subjects who underwent two 3 T resting-state fMRI scans, once under subanesthetic, intravenous esketamine and once under placebo, in a randomized, cross-over manner. We aimed to isolate only highly robust effects of esketamine on dynamic rsFC by using eight complementary methodologies derived from two dynamic rsFC estimation methods, two functionally defined atlases and two statistical measures. All combinations revealed a negative influence of esketamine on dynamic rsFC within the left visual network and inter-hemispherically between visual networks (p < 0.05, corrected), hereby suggesting that esketamine's influence on dynamic rsFC is highly stable in visual processing networks. Our findings may be reflective of ketamine's role as a model for psychosis, a disorder associated with alterations to visual processing and impaired inter-hemispheric connectivity. Ketamine is a highly effective antidepressant and studies have shown changes to sensory processing in depression. Dynamic rsFC in sensory processing networks might be a promising target for future investigations of ketamine's antidepressant properties. Mechanistically, sensitivity of visual networks for esketamine's effects may result from their high expression of NMDA-receptors.

Serotonin Transporter Binding in the Human Brain After Pharmacological Challenge Measured Using PET and PET/MR.

Introduction: In-vivo quantification of the serotonin transporter (SERT) guided our understanding of many neuropsychiatric disorders. A recently introduced bolus plus constant infusion protocol has been shown to allow the reliable determination of SERT binding with reduced scan time. In this work, the outcomes of two methods, a bolus injection paradigm on a GE PET camera, and a bolus plus infusion paradigm on a combined Siemens PET/MR camera were compared. Methods: A total of seven healthy subjects underwent paired PET and paired PET/MR scans each with intravenous double-blind application of 7.5 mg citalopram or saline in a randomized cross-over study design. While PET scans were performed according to standard protocols and non-displaceable binding potentials (BPND) were calculated using the multi-linear reference tissue model, during PET/MR measurements [11C]DASB was applied as bolus plus constant infusion, and BPND was calculated using the steady state method and data acquired at tracer equilibrium. Occupancies were calculated as the relative decrease in BPND between saline and citalopram scans. Results: During placebo scans, a mean difference in BPND of -0.08 (-11.71%) across all ROIs was found between methods. PET/MR scans resulted in higher BPND estimates than PET scans in all ROIs except the midbrain. A mean difference of -0.19 (-109.40%) across all ROIs between methods was observed for citalopram scans. PET/MR scans resulted in higher BPND estimates than PET scans in all ROIs. For occupancy, a mean difference of 23.12% (21.91%) was observed across all ROIs. PET/MR scans resulted in lower occupancy compared to PET scans in all ROIs except the temporal cortex. While for placebo, BPND of high-binding regions (thalamus and striatum) exhibited moderate reliability (ICC = 0.66), during citalopram scans ICC decreased (0.36-0.46). However, reliability for occupancy remained high (0.57-0.82). Conclusion: Here, we demonstrated the feasibility of reliable and non-invasive SERT quantification using a [11C]DASB bolus plus constant infusion protocol at a hybrid PET/MR scanner, which might facilitate future pharmacological imaging studies. Highest agreement with established methods for quantification of occupancy and SERT BPND at baseline was observed in subcortical high-binding regions.

Antidepressant treatment, not depression, leads to reductions in behavioral and neural responses to pain empathy.

Major depressive disorder (MDD) has been hypothesized to lead to impairments in empathy. Previous cross-sectional studies did not disentangle effects of MDD itself and antidepressant treatment. In this first longitudinal neuroimaging study on empathy in depression, 29 patients with MDD participated in two functional magnetic resonance imaging (fMRI) sessions before and after 3 months of antidepressant therapy. We compared their responses to an empathy for pain task to a group of healthy controls (N = 35). All participants provided self-report ratings targeting cognitive (perspective taking) and affective (unpleasant affect) aspects of empathy. To control for general effects on processing of negative affective states, participants additionally underwent an electrical pain task. Before treatment, we found no differences in empathic responses between controls and patients with MDD. After treatment, patients showed significant decreases in both affective empathy and activity of three a priori selected brain regions associated with empathy for pain. Decreases in affective empathy were moreover correlated with symptom improvement. Moreover, functional connectivity during the empathy task between areas associated with affective (anterior insula) and cognitive (precuneus) empathy decreased between sessions in the MDD group. Neither cognitive empathy nor responses to painful electrical shocks were changed after treatment. These findings contradict previous cross-sectional reports of empathy deficits in acute MDD. Rather, they suggest that antidepressant treatment reduces the aversive responses triggered by exposure to the suffering of others. Importantly, this cannot be explained by a general blunting of negative affect, as treatment did not change self-experienced pain.

Hippocampal Subfields in Acute and Remitted Depression-an Ultra-High Field Magnetic Resonance Imaging Study.

BACKGROUND: Studies investigating hippocampal volume changes after treatment with serotonergic antidepressants in patients with major depressive disorder yielded inconsistent results, and effects on hippocampal subfields are unclear. METHODS: To detail treatment effects on total hippocampal and subfield volumes, we conducted an open-label study with escitalopram followed by venlafaxine upon nonresponse in 20 unmedicated patients with major depressive disorder. Before and after 12 weeks treatment, we measured total hippocampal formation volumes and subfield volumes with ultra-high field (7 Tesla), T1-weighted, structural magnetic resonance imaging, and FreeSurfer. Twenty-eight remitted patients and 22 healthy subjects were included as controls. We hypothesized to detect increased volumes after treatment in major depressive disorder. RESULTS: We did not detect treatment-related changes of total hippocampal or subfield volumes in patients with major depressive disorder. Secondary results indicated that the control group of untreated, stable remitted patients, compared with healthy controls, had larger volumes of the right hippocampal-amygdaloid transition area and right fissure at both measurement time points. Depressed patients exhibited larger volumes of the right subiculum compared with healthy controls at MRI-2. Exploratory data analyses indicated lower baseline volumes in the subgroup of remitting (n = 10) vs nonremitting (n = 10) acute patients. CONCLUSIONS: The results demonstrate that monoaminergic antidepressant treatment in major depressive disorder patients was not associated with volume changes in hippocampal subfields. Studies with larger sample sizes to detect smaller effects as well as other imaging modalities are needed to further assess the impact of antidepressant treatment on hippocampal subfields.