An analysis of self-referential processing and other aspects of emotional processing in healthy subjects and patients with affective disorders using functional magnetic resonance imaging

Emotionale Verarbeitung ist ein multidimensionaler Prozess, dessen kognitive Teilaspekte und entsprechende neuronale Korrelate mittels funktioneller agnetresonanztomographie (fMRT) dissoziiert werden können. In Studie 1 wird die angenommene enge Verknüpfung von selbstreferenzieller Verarbeitung (SRV) und episodischem Gedächtnisabruf (EGA) sowie deren gemeinsame und exklusive neuronale Repräsentation untersucht. Standardexperimentalaufgaben für SRV und EGA wurden in einem Experiment vereint und 29 Probanden mittels fMRT untersucht, so dass die Effekte von SRV und EGA kontrastiert und deren neuronale Korrelate dargestellt werden konnten. Bilder, die als selbstreferenziell eingestuft wurden, führten zu Anstiegen in den Blutsauerstoffgehalt-abhängigen (BOLD) Signalen (im Folgenden als „Aktivierungen“ bezeichnet) insbesondere im posterioren Cingulum (PCC), dem anterioren Praecuneus, dem medialen präfrontalen Cortex (MPFC) und inferioren Anteilen des Lobulus parietalis inferior. Im Gegensatz dazu waren bei der EGA Aktivierungen im posterioren Praecuneus, dem anterioren präfrontalen Cortex (aPFC), sowie superioren Anteilen des Lobulus parietalis inferior nachweisbar. Gemeinsame Aktivierungen von SRV und EGA fanden sich zwischen den zuvor erwähnten Regionen im Praecuneus und im inferioren Parietallappen, nicht jedoch im präfrontalen Cortex (PFC). Neben einem gemeinsam durch SRV und EGA aktivierten neuronalen Netzwerk im medialen und lateralen Parietallappen konnten durch Studie 1 drei funktionelle Unterteilungen im Vergleich SRV gegenüber EGA gezeigt werden: 1. eine anterior-posterior Unterteilung im medialen parietalen Cortex, 2. eine medial-anterolateral Unterteilung im PFC sowie 3. eine inferior-superior Unterteilung im lateralen parietalen Cortex. Studie 2 untersucht den Zusammenhang zwischen Aktivierung der Amygdala und Valenz der dargebotenen Stimuli bei hypomanischen und manischen bipolaren Patienten vor dem Hintergrund eines postulierten stimmungskongruenten Verarbeitungsbias bei der Manie. Die BOLD- Signale von 10 Patienten und 10 gesunden Kontrollpersonen bei der Betrachtung emotionaler Bilder wurden verglichen. Danach wurden die Bilder hinsichtlich ihrer Valenz und Intensität bewertet. Im Gegensatz zu gesunden Kontrollpersonen zeigten die Patienten nicht nur eine höhere Valenzbewertung positiver Bilder, sondern auch eine Mehraktivierung der linken Amygdala, die wiederum mit den Ergebnissen der „Young-Mania-Rating-Scale“ (YMRS) der Patienten korrelierte. Diese höheren Valenzbewertungen und gesteigerten Aktivierungen der Amygdala bei Betrachtung positiver emotionaler Bilder sind möglicherweise Ausdruck des postulierten positiven Verarbeitungsbias. Studie 3 untersucht die Aufmerksamkeitsmodulation bei der Verarbeitung emotionaler Bilder von Patienten mit Depression im Vergleich zu gesunden Kontrollprobanden, wobei im Rahmen der Depression eine verminderte Fähigkeit zur emotionalen Modulation angenommen wird. In einem fMRT-Experiment wurden Patienten und gesunden Kontrollpersonen emotionale Bilder mit und ohne Erwartungshinweis gezeigt. Während gesunde Probanden bei erwarteten im Gegensatz zu unerwarteten emotionalen Bildern eine Modulation mit herabgesetzter Aktivierung im dorsolateralen PFC (DLPFC) und gesteigerter Aktivierung im dorsomedialen PFC (DMPFC) zeigten, blieb diese bei Patienten mit Depression aus. Diese veränderte präfrontale Modulation könnte bei der Depression zur klinisch beobachtbaren verminderten emotionalen Modulationsfähigkeit beitragen.Emotional processing can be dissociated with functional magnetic resonance imaging (fMRI) into various cognitive functions and their corresponding neural correlates. Study 1 examines the functional overlap and dissociability of self-referential processing (SRP) and episodic memory retrieval (EMR). Standard tasks für SRP and EMR were combined into a single fMRI experiment involving 29 healthy subjects. The contrast of SRP- and EMR-related blood oxygen level dependent (BOLD) effects allowed a functional delineation of these processes. Stimuli judged as self-referential specifically activated the posterior cingulate/anterior precuneus, the medial prefrontal cortex and an inferior divison of the inferior parietal lobule while EMR specifically activated the posterior precuneus, the anterior prefrontal cortex and a superior division of the inferior parietal lobule. Overlapping activations were situated in the intermediate zones of the precuneus, the inferior parietal lobule, but not in the prefrontal cortex. Apart from common neuronal networks of SRP and EMR in the medial and lateral parietal cortex, three functional differentiations were observed: (1) an anterior-posterior differentiation in the medial parietal cortex, (2) a medial-anterolateral differentiation within the prefrontal cortex, (3) an inferior-superior differentiation within the lateral parietal cortex. Study 2 examines the relationship between amygdala activation and valence of the pictures presented in hypomanic and manic patients with fMRI. BOLD effects of 10 patients and 10 healthy control subjects viewing emotional pictures were contrasted. Following fMRI emotional valence and intensity were rated in a seperate session. Compared to healthy control subjects patients showed higher valence ratings in positive pictures and associated larger BOLD responses in the left amygdala that correlated with the patients Young Mania Rating Scale scores. Increased valence ratings and amygdala responses associated with positive picture viewing may reflect a postulated positive processing bias in mania. Study 3 examines the attentional modulation of patients with major depression compared to healthy control subjects in processing emotional pictures, postulating a reduced ability for emotional modulation in depression. fMRI BOLD effects of emotional picture viewing with and without emotional expectancy cue were contrasted. A modulation with reduced activation in the dorsolateral prefrontal cortex and enhanced activation in the dorsomedial prefrontal cortex was observed in healthy controls but not in patients with major depression. Altered prefrontal modulation may contribute to the impaired emotional modulation in major depression

There’s more to the picture than meets the eye

Background!#!Watertight closure of the dura mater is fundamental in neurosurgery. Besides the classical suturing techniques, a variety of biomaterials have been proposed as sealants. Platelet rich fibrin (PRF) is an autologous biomaterial which can readily be obtained through low-speed centrifugation of patient's own blood. It is rich in fibrin, growth factors, leucocytes and cytokines and has shown adhesive properties while promoting the physiological wound healing process. In this study, we investigated the effect of applying PRF in reinforcing the watertight dura mater closure.!##!Methods!#!We created an in vitro testing device, where the watertight dura mater closure could be hydrostatically assessed. On 26 fresh harvested bovine dura maters, a standardised 20-mm incision was closed with a running suture, and the leak pressure was measured first without (primary leak pressure) and then with PRF augmentation (secondary leak pressure). The two groups of measurements have been statistically analysed with the Student's paired t test.!##!Results!#!The 'running suture only group' had a leak pressure of 10.5 ± 1.2 cmH2O (mean ± SD) while the 'PRF-augmented group' had a leak pressure of 47.2 ± 2.6 cm H2O. This difference was statistically significant (p < 0.001; paired t test).!##!Conclusions!#!Autologous platelet rich fibrin augmentation reliably reinforced watertight closure of the dura mater to a > 4-fold increased leak pressure after failure of the initial standard running suture technique

A detailed analysis of anatomical plausibility of crossed and uncrossed streamline rendition of the dentato-rubro-thalamic tract (DRT(T)) in a commercial stereotactic planning system

Background!#!An increasing number of neurosurgeons use display of the dentato-rubro-thalamic tract (DRT) based on diffusion weighted imaging (dMRI) as basis for their routine planning of stimulation or lesioning approaches in stereotactic tremor surgery. An evaluation of the anatomical validity of the display of the DRT with respect to modern stereotactic planning systems and across different tracking environments has not been performed.!##!Methods!#!Distinct dMRI and anatomical magnetic resonance imaging (MRI) data of high and low quality from 9 subjects were used. Six subjects had repeated MRI scans and therefore entered the analysis twice. Standardized DICOM structure templates for volume of interest definition were applied in native space for all investigations. For tracking BrainLab Elements (BrainLab, Munich, Germany), two tensor deterministic tracking (FT2), MRtrix IFOD2 ( https://www.mrtrix.org ), and a global tracking (GT) approach were used to compare the display of the uncrossed (DRTu) and crossed (DRTx) fiber structure after transformation into MNI space. The resulting streamlines were investigated for congruence, reproducibility, anatomical validity, and penetration of anatomical way point structures.!##!Results!#!In general, the DRTu can be depicted with good quality (as judged by waypoints). FT2 (surgical) and GT (neuroscientific) show high congruence. While GT shows partly reproducible results for DRTx, the crossed pathway cannot be reliably reconstructed with the other (iFOD2 and FT2) algorithms.!##!Conclusion!#!Since a direct anatomical comparison is difficult in the individual subjects, we chose a comparison with two research tracking environments as the best possible 'ground truth.' FT2 is useful especially because of its manual editing possibilities of cutting erroneous fibers on the single subject level. An uncertainty of 2 mm as mean displacement of DRTu is expectable and should be respected when using this approach for surgical planning. Tractographic renditions of the DRTx on the single subject level seem to be still illusive

The dentato-rubro-thalamic tract as the potential common deep brain stimulation target for tremor of various origin: an observational case series

Introduction!#!Deep brain stimulation alleviates tremor of various origins. The dentato-rubro-thalamic tract (DRT) has been suspected as a common tremor-reducing structure. Statistical evidence has not been obtained. We here report the results of an uncontrolled case series of patients with refractory tremor who underwent deep brain stimulation under tractographic assistance.!##!Methods!#!A total of 36 patients were enrolled (essential tremor (17), Parkinson's tremor (8), multiple sclerosis (7), dystonic head tremor (3), tardive dystonia (1)) and received 62 DBS electrodes (26 bilateral; 10 unilateral). Preoperatively, diffusion tensor magnetic resonance imaging sequences were acquired together with high-resolution anatomical T1W and T2W sequences. The DRT was individually tracked and used as a direct thalamic or subthalamic target. Intraoperative tremor reduction was graded on a 4-point scale (0 = no tremor reduction to 3 = full tremor control) and recorded together with the current amplitude, respectively. Stimulation point coordinates were recorded and compared to DRT. The relation of the current amplitude needed to reduce tremor was expressed as TiCR (tremor improvement per current ratio).!##!Results!#!Stimulation points of 241 were available for analysis. A total of 68 trajectories were tested (62 dB leads, 1.1 trajectories tested per implanted lead). Tremor improvement was significantly decreasing (p < 0.01) if the distance to both the border and the center of the DRT was increasing. On the initial trajectory, 56 leads (90.3%) were finally placed. Long-term outcomes were not part of this analysis.!##!Discussion!#!Tremor of various origins was acutely alleviated at different points along the DRT fiber tract (above and below the MCP plane) despite different tremor diseases. DRT is potentially a common tremor-reducing structure. Individual targeting helps to reduce brain penetrating tracts. TiCR characterizes stimulation efficacy and might help to identify an optimal stimulation point

“The Heart Asks Pleasure First”—Conceptualizing Psychiatric Diseases as MAINTENANCE Network Dysfunctions through Insights from slMFB DBS in Depression and Obsessive–Compulsive Disorder

More than a decade ago, deep brain stimulation (DBS) of the superolateral medial forebrain bundle (slMFB), as part of the greater MFB system, had been proposed as a putative yet experimental treatment strategy for therapy refractory depression (TRD) and later for obsessive–compulsive disorders (OCD). Antidepressant and anti-OCD efficacy have been shown in open case series and smaller trials and were independently replicated. The MFB is anato-physiologically confluent with the SEEKING system promoting euphoric drive, reward anticipation and reward; functions realized through the mesocorticolimbic dopaminergic system. Growing clinical experience concerning surgical and stimulation aspects from a larger number of patients shows an MFB functionality beyond SEEKING and now re-informs the scientific rationale concerning the MFB’s (patho-) physiology. In this white paper, we combine observations from more than 75 cases of slMFB DBS. We integrate these observations with a selected literature review to provide a new neuroethological view on the MFB. We here formulate a re-interpretation of the MFB as the main structure of an integrated SEEKING/MAINTENANCE circuitry, allowing for individual homeostasis and well-being through emotional arousal, basic and higher affect valence, bodily reactions, motor programing, vigor and flexible behavior, as the basis for the antidepressant and anti-OCD efficacy

Tomographic tract tracing and data driven approaches to unravel complex 3D fiber anatomy of DBS relevant prefrontal projections to the diencephalic-mesencephalic junction in the marmoset

Background: Understanding prefrontal cortex projections to diencephalic-mesencephalic junction (DMJ), especially to subthalamic nucleus (STN) and ventral mesencephalic tegmentum (VMT) helps our comprehension of Deep Brain Stimulation (DBS) in major depression (MD) and obsessive-compulsive disorder (OCD). Fiber routes are complex and tract tracing studies in non-human primate species (NHP) have yielded conflicting results. The superolateral medial forebrain bundle (slMFB) is a promising target for DBS in MD and OCD. It has become a focus of criticism owing to its name and its diffusion weighted-imaging based primary description. Objective: To investigate DMJ connectivity in NHP with a special focus on slMFB and the limbic hyperdirect pathway utilizing three-dimensional and data driven techniques. Methods: We performed left prefrontal adeno-associated virus - tracer based injections in the common marmoset monkey (n = 52). Histology and two-photon microscopy were integrated into a common space. Manual and data driven cluster analyses of DMJ, subthalamic nucleus and VMT together, followed by anterior tract tracing streamline (ATTS) tractography were deployed. Results: Typical pre- and supplementary motor hyperdirect connectivity was confirmed. The advanced tract tracing unraveled the complex connectivity to the DMJ. Limbic prefrontal territories directly projected to the VMT but not STN. Discussion: Intricate results of tract tracing studies warrant the application of advanced three-dimensional analyses to understand complex fiber-anatomical routes. The applied three-dimensional techniques can enhance anatomical understanding also in other regions with complex fiber anatomy. Conclusion: Our work confirms slMFB anatomy and enfeebles previous misconceptions. The rigorous NHP approach strengthens the role of the slMFB as a target structure for DBS predominantly in psychiatric indications like MD and OCD

Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression

Background: Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) emerges as a - yet experimental - treatment for major depressive disorder (MDD) and other treatment refractory psychiatric diseases. First experiences have been reported from two open label pilot trials in major depression (MDD) and long-term effectiveness for MDD (50 months) has been reported. Objective: To give a detailed description of the surgical technique for DBS of the superolateral branch of the medial forebrain bundle (slMFB) in MDD. Methods: Surgical experience from bilateral implantation procedures in n = 24 patients with MDD is reported. The detailed procedure of tractography-assisted targeting together with detailed electrophysiology in 144 trajectories in the target region (recording and stimulation) is described. Achieved electrode positions were evaluated based on postoperative helical CT and fused to preoperative high resolution anatomical magnetic resonance imaging (MRI; Philips Medical Systems, Best, Netherlands), including the pre-operative diffusion tensor imaging (DTI) tractographic information (StealthViz DTI, Medtronic, USA; Framelink 5.0, Medtronic, USA). Midcommissural point (MCP) coordinates of effective contact (EC) location, together with angles of entry into the target region were evaluated. To investigate incidental stimulation of surrounding nuclei (subthalamic nucleus, STN; substantia nigra, SNr; and red nucleus, RN) as a possible mechanism, a therapeutic triangle (TT) was defined, located between these structures (based on MRI criteria in T2) and evaluated with respect to EC locations. Results: Bilateral slMFB DBS was performed in all patients. We identified an electrophysiological environment (defined by autonomic reaction, passive microelectrode recording, acute effects and oculomotor effects) that helps to identify the proper target site on the operation table. Postoperative MCP-evaluation of effective contacts (EC) shows a significant variability with respect to localization. Evaluation of the TT shows that responders will typically have their active contacts inside the triangle and that surrounding nuclei (STN, SNr, RN) are not directly hit by EC, indicating a predominant white matter stimulation. The individual EC position within the triangle cannot be predicted and is based on individual slMFB (tractography) geometry. There was one intracranial bleeding (FORESEE I study) during a first implantation attempt in a patient who later received full bilateral implantation. Typical oculomotor side effects are idiosyncratic for the target region and at inferior contacts. Conclusion: The detailed surgical procedure of slMFB DBS implantation has not been described before. The slMFB emerges as an interesting region for the treatment of major depression (and other psychiatric diseases) with DBS. So far it has only been successfully researched in open label clinical case series and in 15 patients published. Stimulation probably achieves its effect through direct white-matter modulation of slMFB fibers. The surgical implantation comprises a standardized protocol combining tractographic imaging based on DTI, targeting and electrophysiological evaluation of the target region. To this end, slMFB DBS surgery is in technical aspects comparable to typical movement disorder surgery. In our view, slMFB DBS should only be performed under tractographic assistance. Keywords: Deep brain stimulation, Depression, Diffusion tensor imaging, Fiber tracking, Medial forebrain bundle, OCD, slMFB, Stereotactic surgery, Tractograph

Rebound Tremor Frequency as a Potential Diagnostic Marker for Delayed Therapy Escape after Thalamic Deep Brain Stimulation for Essential Tremor—Insights from a Cross-Sectional Study

Delayed therapy escape (DTE) is frequent after thalamic deep brain stimulation for essential tremor, leading to reduced quality of life, often with ataxic symptoms, and early recognition is challenging. Our goal was to examine whether a low-frequency rebound tremor of the left hand after switching off stimulation is useful as a diagnostic marker for DTE. In this cross-sectional study with additional retrospective analysis, we examined 31 patients with bilateral thalamic DBS ≥ 12 months for essential tremor, using quantitative assessments including video-based motion capture, Fahn–Tolosa–Marin Tremor Rating Scale (FTMTRS), and scale for the assessment and rating of ataxia (SARA). If available, preoperative (preOP) and 12-month postoperative assessments were included in the analysis. Evaluations occurred with DBS activated (ON) and deactivated (OFF). A higher ratio FTMTRS nowON/preOP indicated DTE. Preoperative FTMTRS scores were available for 16 patients, including 5 patients with DTE. The receiver operating characteristic analysis found an area under the curve of 0.86 (p = 0.024) for identification of DTE by low-frequency rebound tremor (i.e., OFF) on the left. In conclusion, it could serve as a potential diagnostic marker

Disbalanced recruitment of crossed and uncrossed cerebello-thalamic pathways during deep brain stimulation is predictive of delayed therapy escape in essential tremor

Background: Thalamic deep brain stimulation (DBS) is an efficacious treatment for drug-resistant essential tremor (ET) and the dentato-rubro-thalamic tract (DRT) constitutes an important target structure. However, up to 40% of patients habituate and lose treatment efficacy over time, frequently accompanied by a stimulation-induced cerebellar syndrome. The phenomenon termed delayed therapy escape (DTE) is insufficiently understood. Our previous work showed that DTE clinically is pronounced on the non-dominant side and suggested that differential involvement of crossed versus uncrossed DRT (DRTx/DRTu) might play a role in DTE development. Methods: We retrospectively enrolled right-handed patients under bilateral thalamic DBS >12 months for ET from a cross-sectional study. They were characterized with the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) and Scale for the Assessment and Rating of Ataxia (SARA) scores at different timepoints. Normative fiber tractographic evaluations of crossed and uncrossed cerebellothalamic pathways and volume of activated tissue (VAT) studies together with [18F]Fluorodeoxyglucose positron emission tomography were applied. Results: A total of 29 patients met the inclusion criteria. Favoring DRTu over DRTx in the non-dominant VAT was associated with DTE (R2 = 0.4463, p < 0.01) and ataxia (R2 = 0.2319, p < 0.01). Moreover, increasing VAT size on the right (non-dominant) side was associated at trend level with more asymmetric glucose metabolism shifting towards the right (dominant) dentate nucleus. Conclusion: Our results suggest that a disbalanced recruitment of DRTu in the non-dominant VAT induces detrimental stimulation effects on the dominant cerebellar outflow (together with contralateral stimulation) leading to DTE and thus hampering the overall treatment efficacy