Theta burst stimulation for depression: a systematic review and network and pairwise meta-analysis.

In clinical practice, theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial magnetic stimulation (rTMS), as it allows for the delivery of more stimuli in less time and at similar intensities. To date, accelerated treatment plans according to various continuous (cTBS) and intermittent TBS (iTBS) protocols for depression have been proposed. To investigate which of the TBS protocols provided a favorable risk-benefit balance for individuals with depression, this systematic review and random-effects model network meta-analysis was conducted. The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence of switch to mania, and incidence of headache/discomfort at treatment site. In this meta-analysis, a total of 23 randomized controlled trials (n = 960, mean age = 41.88 years, with 60.78% females) were included. Approximately 69.57% of the trials included individuals with an exclusive diagnosis of major depressive disorder. The following six TBS protocols (target) were evaluated: cTBS (right-dorsolateral prefrontal cortex [R-DLPFC]), cTBS (R-DLPFC) + iTBS (left-DLPFC [L-DLPFC]), iTBS (L-DLPFC), iTBS (L-DLPFC) + iTBS (R-DLPFC), iTBS (left-dorsomedial prefrontal cortex) + iTBS (right-dorsomedial prefrontal cortex), and iTBS (occipital lobe). Compared to sham, cTBS (R-DLPFC) + iTBS (L-DLPFC), iTBS (L-DLPFC), and iTBS (occipital lobe) had a higher response rate (k = 23); cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) dominated in the depression symptom improvement (k = 23); and iTBS (L-DLPFC) had a higher remission rate (k = 15). No significant differences were found for all-cause discontinuation rate (k = 17), incidence of switch to mania (k = 7), and incidence of headache/discomfort at treatment site (k = 10) between any TBS protocols and sham. Thus, cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) demonstrate favorable risk-benefit balance for the treatment of depression.

Neural response during prefrontal theta burst stimulation: Interleaved TMS-fMRI of full iTBS protocols.

BACKGROUND: Left prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. OBJECTIVE/HYPOTHESIS: In our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. METHODS: Concurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. RESULTS: Concurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. CONCLUSIONS: Full iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.

Chronometric TMS-fMRI of personalized left dorsolateral prefrontal target reveals state-dependency of subgenual anterior cingulate cortex effects.

Transcranial magnetic stimulation (TMS) applied to a left dorsolateral prefrontal cortex (DLPFC) area with a specific connectivity profile to the subgenual anterior cingulate cortex (sgACC) has emerged as a highly effective non-invasive treatment option for depression. However, antidepressant outcomes demonstrate significant variability among therapy plans and individuals. One overlooked contributing factor is the individual brain state at the time of treatment. In this study we used interleaved TMS-fMRI to investigate the influence of brain state on acute TMS effects, both locally and remotely. TMS was performed during rest and during different phases of cognitive task processing. Twenty healthy participants were included in this study. In the first session, imaging data for TMS targeting were acquired, allowing for identification of individualized targets in the left DLPFC based on highest anti-correlation with the sgACC. The second session involved chronometric interleaved TMS-fMRI measurements, with 10 Hz triplets of TMS administered during rest and at distinct timings during an N-back task. Consistent with prior findings, interleaved TMS-fMRI revealed significant BOLD activation changes in the targeted network. The precise timing of TMS relative to the cognitive states during the task demonstrated distinct BOLD response in clinically relevant brain regions, including the sgACC. Employing a standardized timing approach for TMS using a task revealed more consistent modulation of the sgACC at the group level compared to stimulation during rest. In conclusion, our findings strongly suggest that acute local and remote effects of TMS are influenced by brain state during stimulation. This study establishes a basis for considering brain state as a significant factor in designing treatment protocols, possibly improving TMS treatment outcomes.

Citizen science approach to assessing patient perception of MRI with flexible radiofrequency coils.

Magnetic Resonance Imaging (MRI) is a major medical imaging modality, which is non-invasive and provides unique soft tissue contrast without ionizing radiation. The successful completion of MRI exams critically depends on patient compliance, and, thus patient comfort. The design, appearance and usability of local MRI radiofrequency (RF) coils potentially influences the patients' perception of the exam. However, systematic investigations and empirical evidence for these aspects are missing. A questionnaire specifically evaluating the impact of RF coils on patient comfort in MRI would be a valuable addition to clinical studies comparing the performance of novel flexible RF coils with standard rigid coils. This paper describes the development of such a questionnaire in the scope of a citizen science (CS) initiative conducted with a group of students at the upper secondary school level. In this work, the CS initiative is presented in the format of a case report and its impact on scientific projects and the students' education is outlined. The resulting questionnaire is made available in German and English so as to be directly applicable by researchers working on the clinical evaluation of novel RF coils or the comfort evaluation of specific hardware setups in general.

Accelerated Theta Burst Stimulation: Safety, Efficacy, and Future Advancements.

Theta burst stimulation (TBS) is a noninvasive brain stimulation technique that can be used to modulate neural networks underlying psychiatric and neurological disorders. TBS can be delivered intermittently or continuously. The conventional intermittent TBS protocol is approved by the U.S. Food and Drug Administration to treat otherwise treatment-resistant depression, but the 6-week duration limits the applicability of this therapy. Accelerated TBS protocols present an opportunity to deliver higher pulse doses in shorter periods of time, thus resulting in faster and potentially more clinically effective treatment. However, the acceleration of TBS delivery raises questions regarding the relative safety, efficacy, and durability compared with conventional TBS protocols. In this review paper, we present the data from accelerated TBS trials to date that support the safety and effectiveness of accelerated protocols while acknowledging the need for more durability data. We discuss the stimulation parameters that seem to be important for the efficacy of accelerated TBS protocols and possible avenues for further optimization.

Effectiveness of rTMS and tDCS treatment for chronic TBI symptoms: A systematic review and meta-analysis.

INTRODUCTION: Traumatic brain injury (TBI) is a major cause of long-term disability with conventional treatments frequently falling short to restore a good quality-of-life. Non-invasive brain stimulation (NIBS) techniques have shown potential as therapeutic options for neuropsychiatric conditions, including TBI sequelae. This study aims at providing a systematic review and meta-analysis on the effectiveness of repetitive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) on post-TBI symptoms. METHODS: Fifteen randomized controlled trials (RCTs) on adult TBI patients that examined the effects of multiple treatment sessions of NIBS techniques were selected from five databases. Symptoms were clustered into four categories: depression, anxiety, headache and cognitive dysfunctions. Meta-analysis was performed using correlated and hierarchical effects models. RESULTS: There were only few and heterogeneous studies with generally small sample sizes. Most studies targeted the dorsolateral prefrontal cortex (dlPFC). Overall, the effects of NIBS were small. However, there was a significant effect for overall symptoms (0.404, p = 0.031). Moreover, subgroup analyses revealed significant overall effects for anxiety (0.195, p = 0.020) and headache (0.354, p = 0.040). CONCLUSIONS: To date, there is limited evidence supporting the effectiveness of NIBS concerning treatment for TBI sequelae. The observed effect sizes were modest, suggesting subtle improvements rather than drastic changes. While NIBS techniques remain promising for treating neuropsychiatric conditions, larger RCT studies with longer follow-ups, optimized stimulation parameters and standardized methodology are required to establish their efficacy in addressing TBI sequelae.

Concurrent TMS/fMRI reveals individual DLPFC dose-response pattern.

BACKGROUND: TMS is a valuable tool in both research and clinical settings, playing a crucial role in understanding brain-behavior relationships and providing treatment for various neurological and psychiatric conditions. Importantly, TMS over left DLPFC is an FDA approved treatment for MDD. Despite its potential, response variability to TMS remains a challenge, with stimulation parameters, particularly the stimulation intensity, being a primary contributor to these differences. OBJECTIVE: The objective of this study was to establish dose-response relationships of TMS stimulation in DLPFC by means of concurrent TMS/fMRI. METHODS: Here, we stimulated 15 subjects at different stimulation intensities of 80, 90, 100 and 110 % relative to the motor threshold during concurrent TMS/fMRI. The experiment comprised two sessions: one session to collect anatomical data in order to perform neuronavigation and one session dedicated to dose-response mapping. We calculated GLMs for each intensity level and each subject, as well as at a group-level per intensity. RESULTS: On a group level, we show that the strongest BOLD-response was at 100 % stimulation. However, investigating individual dose response-relationships showed differences in response patterns across the group: subjects that responded to subthreshold stimulation, subjects that required above threshold stimulation in order to show a significant BOLD-response and atypical responders. CONCLUSIONS: We observed qualitative inter-subject variability in terms of dose-response relationship to TMS over left DLPFC, which hints towards the motor threshold not being directly transferable to the excitability of the DLPFC. Concurrent TMS/fMRI might have the potential to improve response rates to rTMS applications. As such, it may be valuable in the future to consider implementing this approach prior to clinical TMS or validating more cost-effective methods to determine dose and target with respect to changes in clinical symptoms.

Functional connectivity explains how neuronavigated TMS of posterior temporal subregions differentially affect language processing.

BACKGROUND: "Wernicke's area" is most often used to describe the posterior superior temporal gyrus (STG) and refers to a region traditionally thought to support language comprehension. However, the posterior STG additionally plays a critical role in language production. The purpose of the current study was to determine to what extent regions within the posterior STG are selectively recruited during language production. METHODS: 23 healthy right-handed participants completed an auditory fMRI localizer task, resting-state fMRI and underwent neuronavigated TMS language mapping. We applied repetitive TMS bursts during a picture naming paradigm to probe speech disruptions of different categories (anomia, speech arrest, semantic paraphasia and phonological paraphasia). We combined an in-house built high precision stimulation software suite with E-field modeling to map the naming errors to cortical regions and revealed a dissociation of language functions within the temporal gyrus. Resting state fMRI was used to explain how E-field peaks of different categories differentially affected language production. RESULTS: Peaks for phonological and semantic errors were found in the STG while those for anomia and speech arrest were located in the MTG. Seed-based connectivity analysis revealed a local connectivity pattern for phonological and semantic errors, while anomia and speech arrest seeds resulted in a larger network between IFG and posterior MTG. CONCLUSIONS: Our study provides important insights into the functional neuroanatomy of language production and might help to increase the current understanding of specific language production difficulties on a causal level.

Improved brain stimulation targeting by optimising image acquisition parameters.

Functional connectivity analysis from rs-fMRI data has been used for determining cortical targets in therapeutic applications of non-invasive brain stimulation using transcranial magnetic stimulation (TMS). Reliable connectivity measures are therefore essential for every rs-fMRI-based TMS targeting approach. Here, we examine the effect of echo time (TE) on the reproducibility and spatial variability of resting-state connectivity measures. We acquired multiple runs of single-echo fMRI data with either short (TE = 30 ms) or long (TE = 38 ms) echo time to investigate inter-run spatial reproducibility of a clinically relevant functional connectivity map, i.e., originating from the sgACC. We find that connectivity maps obtained from TE = 38 ms rs-fMRI data are significantly more reliable than those obtained from TE = 30 ms data sets. Our results clearly show that optimizing sequence parameters can be beneficial for ensuring high-reliability resting-state acquisition protocols to be used for TMS targeting. The differences between reliability in connectivity measures for different TEs could inform future clinical research in optimising MR sequences.

Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future.

Repetitive transcranial magnetic stimulation (rTMS) is an effective and evidence-based therapy for treatment-resistant major depressive disorder. A conventional course of rTMS applies 20-30 daily sessions over 4-6 weeks. The schedule of rTMS delivery can be accelerated by applying multiple stimulation sessions per day, which reduces the duration of a treatment course with a predefined number of sessions. Accelerated rTMS reduces time demands, improves clinical efficiency, and potentially induces faster onset of antidepressant effects. However, considerable heterogeneity exists across study designs. Stimulation protocols vary in parameters such as the stimulation target, frequency, intensity, number of pulses applied per session or over a course of treatment, and duration of intersession intervals. In this article, clinician-researchers and neuroscientists who have extensive research experience in accelerated rTMS synthesize a consensus based on two decades of investigation and development, from early studies ("Past") to contemporaneous theta burst stimulation, a time-efficient form of rTMS gaining acceptance in clinical settings ("Present"). We propose descriptive nomenclature for accelerated rTMS, recommend avenues to optimize therapeutic and efficiency potential, and suggest using neuroimaging and electrophysiological biomarkers to individualize treatment protocols ("Future"). Overall, empirical studies show that accelerated rTMS protocols are well tolerated and not associated with serious adverse effects. Importantly, the antidepressant efficacy of accelerated rTMS appears comparable to conventional, once daily rTMS protocols. Whether accelerated rTMS induces antidepressant effects more quickly remains uncertain. On present evidence, treatment protocols incorporating high pulse dose and multiple treatments per day show promise and improved efficacy.

Concurrent TMS-fMRI: Technical Challenges, Developments, and Overview of Previous Studies.

Transcranial magnetic stimulation (TMS) is a promising treatment modality for psychiatric and neurological disorders. Repetitive TMS (rTMS) is widely used for the treatment of psychiatric and neurological diseases, such as depression, motor stroke, and neuropathic pain. However, the underlying mechanisms of rTMS-mediated neuronal modulation are not fully understood. In this respect, concurrent or simultaneous TMS-fMRI, in which TMS is applied during functional magnetic resonance imaging (fMRI), is a viable tool to gain insights, as it enables an investigation of the immediate effects of TMS. Concurrent application of TMS during neuroimaging usually causes severe artifacts due to magnetic field inhomogeneities induced by TMS. However, by carefully interleaving the TMS pulses with MR signal acquisition in the way that these are far enough apart, we can avoid any image distortions. While the very first feasibility studies date back to the 1990s, recent developments in coil hardware and acquisition techniques have boosted the number of TMS-fMRI applications. As such, a concurrent application requires expertise in both TMS and MRI mechanisms and sequencing, and the hurdle of initial technical set up and maintenance remains high. This review gives a comprehensive overview of concurrent TMS-fMRI techniques by collecting (1) basic information, (2) technical challenges and developments, (3) an overview of findings reported so far using concurrent TMS-fMRI, and (4) current limitations and our suggestions for improvement. By sharing this review, we hope to attract the interest of researchers from various backgrounds and create an educational knowledge base.

Dynamic Causal Modeling of the Prefrontal/Amygdala Network During Processing of Emotional Faces.

Introduction: The importance of the amygdala/medial orbitofrontal cortex (OFC) network during processing of emotional stimuli, emotional faces in particular, is well established. This premise is supported by converging evidence from animal models, human neuroanatomical results, and neuroimaging studies. However, there is missing evidence from human brain connectivity studies that the OFC and no other prefrontal brain areas such as the dorsolateral prefrontal cortex (DLPFC) or ventrolateral prefrontal cortex (VLPFC) are responsible for amygdala regulation in the functional context of emotional face stimuli. Methods: Dynamic causal modeling of ultrahigh-field functional magnetic resonance imaging data acquired at 7 Tesla in 38 healthy subjects and a well-established paradigm for emotional face processing were used to assess the central role of the OFC to provide empirical validation for the assumed network architecture. Results: Using Bayesian model selection, it is demonstrated that indeed the OFC, and not the VLPFC and the DLPFC, downregulates amygdala activation during the emotion discrimination task. In addition, Bayesian model averaging group results were rigorously tested using bootstrapping, further corroborating these findings and providing an estimator for robustness and optimal sample sizes. Discussion: While it is true that VLPFC and DLPFC are relevant for the processing of emotional faces and are connected to the OFC, the OFC appears to be a central hub for the prefrontal/amygdala interaction. Impact statement Using dynamic causal modeling (DCM), abnormal effective connectivity in the orbitofrontal cortex (OFC)/amygdala network has been repeatedly observed in the pathophysiology of psychiatric disorders. However, it has to be considered that these findings are all based on the a priori assumption of the OFC being the central area for prefrontal control regulating amygdala activation. This is particularly important, as DCM results conditionally depend on the underlying model space used for model selection. Using Bayesian model comparison methods, it is shown that the OFC (and not the dorsolateral prefrontal cortex or ventrolateral prefrontal cortex) engages in amygdala downregulation in the context emotional face processing.

Intrasession and Intersession Reproducibility of Artificial Scotoma pRF Mapping Results at Ultra-High Fields.

Functional magnetic resonance imaging (fMRI) combined with population receptive field (pRF) mapping allows for associating positions on the visual cortex to areas on the visual field. Apart from applications in healthy subjects, this method can also be used to examine dysfunctions in patients suffering from partial visual field losses. While such objective measurement of visual deficits (scotoma) is of great importance for, e.g., longitudinal studies addressing treatment effects, it requires a thorough assessment of accuracy and reproducibility of the results obtained. In this study, we quantified the reproducibility of pRF mapping results within and across sessions in case of central visual field loss in a group of 15 human subjects. We simulated scotoma by masking a central area of 2° radius from stimulation to establish ground-truth conditions. This study was performed on a 7T ultra-high field MRI scanner for increased sensitivity. We found excellent intrasession and intersession reproducibility for the pRF center position (Spearman correlation coefficients for x, y: >0.95; eccentricity: >0.87; polar angle: >0.98), but only modest reproducibility for pRF size (Spearman correlation coefficients around 0.4). We further examined the scotoma detection performance using an automated method based on a reference dataset acquired with full-field stimulation. For the 2° artificial scotoma, the group-averaged scotoma sizes were estimated at between 1.92° and 2.19° for different sessions. We conclude that pRF mapping of visual field losses yields robust, reproducible measures of retinal function and suggest the use of pRF mapping as an objective method for monitoring visual deficits during therapeutic interventions or disease progression.

Give me a pain that I am used to: distinct habituation patterns to painful and non-painful stimulation.

Pain habituation is associated with a decrease of activation in brain areas related to pain perception. However, little is known about the specificity of these decreases to pain, as habituation has also been described for other responses like spinal reflexes and other sensory responses. Thus, it might be hypothesized that previously reported reductions in activation are not specifically related to pain habituation. For this reason, we performed a 3 T fMRI study using either painful or non-painful electrical stimulation via an electrode attached to the back of the left hand. Contrasting painful vs. non-painful stimulation revealed significant activation clusters in regions well-known to be related to pain processing, such as bilateral anterior and posterior insula, primary/secondary sensory cortices (S1/S2) and anterior midcingulate cortex (aMCC). Importantly, our results show distinct habituation patterns for painful (in aMCC) and non-painful (contralateral claustrum) stimulation, while similar habituation for both types of stimulation was identified in bilateral inferior frontal gyrus (IFG) and contralateral S2. Our findings thus distinguish a general habituation in somatosensory processing (S2) and reduced attention (IFG) from specific pain and non-pain related habituation effects where pain-specific habituation effects within the aMCC highlight a change in affective pain perception.

Combining stimulus types for improved coverage in population receptive field mapping.

Retinotopy experiments using population receptive field (pRF) mapping are ideal for assigning regions in the visual field to cortical brain areas. While various designs for visual stimulation were suggested in the literature, all have specific shortcomings regarding visual field coverage. Here we acquired high-resolution 7 Tesla fMRI data to compare pRF-based coverage maps obtained with the two most commonly used stimulus variants: moving bars; rotating wedges and expanding rings. We find that stimulus selection biases the spatial distribution of pRF centres. In addition, eccentricity values and pRF sizes obtained from wedge/ring or bar stimulation runs show systematic differences. Wedge/ring stimulation results show lower eccentricity values and strongly reduced pRF sizes compared to bar stimulation runs. Statistical comparison shows significantly higher pRF centre numbers in the foveal 2° region of the visual field for wedge/ring compared to bar stimuli. We suggest and evaluate approaches for combining pRF data from different visual stimulus patterns to obtain improved mapping results.

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.

Technical Note: Human tissue-equivalent MRI phantom preparation for 3 and 7 Tesla.

PURPOSE: While test objects (phantoms) in magnetic resonance imaging (MRI) are crucial for sequence development, protocol validation, and quality control, studies on the preparation of phantoms have been scarce, particularly at fields exceeding 3 Tesla. Here, we present a framework for the preparation of phantoms with well-defined T1 and T2 times at 3 and 7 Tesla. METHODS: Phantoms with varying concentrations of agarose and Gd-DTPA were prepared and measured at 3 and 7 Tesla using T1 and T2 mapping techniques. An empirical, polynomial model was constructed that best represents the data at both field strengths, enabling the preparation of new phantoms with specified combinations of both T1 and T2 . Instructions for three different tissue types (brain gray matter, brain white matter, and renal cortex) are presented and validated. RESULTS: T1 times in the samples ranged from 698 to 2820 ms and from 695 to 2906 ms, whereas T2 times ranged from 39 to 227 ms and from 34 to 235 ms for 3 and 7 Tesla scans, respectively. Models for both relaxation times used six parameters to represent the data with an adjusted R² of 0.998 and 0.997 for T1 and T2 , respectively. CONCLUSION: Based on the equations derived from the current study, it is now possible to obtain accurate weight specifications for a test object with desired T1 and T2 relaxation times. This will spare researchers the laborious task of trail-and-error approaches in test object preparation attempts.

Reproducibility of amygdala activation in facial emotion processing at 7T.

Despite its importance as the prime method for non-invasive assessment of human brain function, functional MRI (fMRI) was repeatedly challenged with regards to the validity of the fMRI-derived brain activation maps. Amygdala fMRI was particularly targeted, as the amygdala's anatomical position in the ventral brain combined with strong magnetic field inhomogeneities and proximity to large vessels pose considerable obstacles for robust activation mapping. In this high-resolution study performed at ultra-high field (7T) fMRI, we aimed at (1) investigating systematic replicability of amygdala group-level activation in response to an established emotion processing task by varying task instruction and acquisition parameters and (2) testing for intra- and intersession reliability. At group-level, our results show statistically significant activation in bilateral amygdala and fusiform gyrus for each of the runs acquired. In addition, while fusiform gyrus activations are consistent across runs and sessions, amygdala activation levels show habituation effects across runs. This amygdala habituation effect is replicated in a session repeated two weeks later. Varying task instruction between matching emotions and matching persons does not change amygdala activation strength. Also, comparing two acquisition protocols with repetition times of either 700 â€‹ms or 1400 â€‹ms did not result in statistically significant differences of activation levels. Regarding within-subject reliability of amygdala activation, despite considerable variance in individual habituation patterns, we report fair to good inter-session reliability for the first run and excellent reliability for averages over runs. We conclude that high-resolution fMRI at 7T allows for robust mapping of amygdala activation in a broad range of variations. Our results of amygdala 7T fMRI are suitable to inform methodology and may encourage future studies to continue using emotion discrimination paradigms in clinical and non-clinical applications.

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.