Resolving dyskinesias at sustained anti-OCD efficacy by steering of DBS away from the anteromedial STN to the mesencephalic ventral tegmentum - case report.

Here we describe therapeutic results in a female patient who underwent bilateral slMFB DBS for OCD. During a 35-month long course of stimulation, she suffered from stimulation-induced dyskinesia of her right leg which we interpreted as co-stimulation of the adjacent anteromedial subthalamic nucleus (amSTN). After reprogramming to steer the stimulation away from the amSTN medial into the direction of the mesencephalic ventral tegmentum (MVT which contains the ventral tegmental area, VTA), the dyskinesias disappeared. Remarkably, anti-OCD efficacy in the presented patient was preserved and achieved with a bilateral stimulation which by our imaging study fully avoided the amSTN.

"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.

The psychological burden of a two-stage exchange of infected total hip and knee arthroplasties.

Infection is one of the most challenging complications after total joint arthroplasties affecting up to 30,000 patients in the US per year. This study investigates the psycho-social burden induced by the two-stage intervention in infected hip or knee replacements. All patients were treated with a two-stage exchange and were assessed at three different timepoints regarding their psychological conditions. Our findings suggest that psychological sequelae after treatment of periprosthetic joint infection are clearly underestimated in the literature and psychological correlates and side effects should be further highlighted during the training process of young surgeons.

Diverging prefrontal cortex fiber connection routes to the subthalamic nucleus and the mesencephalic ventral tegmentum investigated with long range (normative) and short range (ex-vivo high resolution) 7T DTI.

Uncertainties concerning anatomy and function of cortico-subcortical projections have arisen during the recent years. A clear distinction between cortico-subthalamic (hyperdirect) and cortico-tegmental projections (superolateral medial forebrain bundle, slMFB) so far is elusive. Deep Brain Stimulation (DBS) of the slMFB (for major depression, MD and obsessive compulsive disorders, OCD) has on the one hand been interpreted as actually involving limbic (prefrontal) hyperdirect pathways. On the other hand slMFB's stimulation region in the mesencephalic ventral tegmentum is said to impact on other structures too, going beyond the antidepressant (or anti OCD) efficacy of sole modulation of the cortico-tegmental reward-associated pathways. We have here used a normative diffusion MRT template (HCP, n = 80) for long-range tractography and augmented this dataset with ex-vivo high resolution data (n = 1) in a stochastic brain space. We compared this data with histological information and used the high resolution ex-vivo data set to scrutinize the mesencephalic tegmentum for small fiber pathways present. Our work resolves an existing ambiguity between slMFB and prefrontal hyperdirect pathways which-for the first time-are described as co-existent. DBS of the slMFB does not appear to modulate prefrontal hyperdirect cortico-subthalamic but rather cortico-tegmental projections. Smaller fiber structures in the target region-as far as they can be discerned-appear not to be involved in slMFB DBS. Our work enfeebles previous anatomical criticism and strengthens the position of the slMFB DBS target for its use in MD and OCD.

Johann Bernhard Aloys von Gudden: The Unrecognized Role of the Psychiatrist and Neuroanatomist in Modern Stereotactic Neurosurgery.

Bernhard von Gudden was the founder of the famous school of psychiatry and neuroanatomy in Munich, Germany. Beyond his association with the mysterious death of King Ludwig II of Bavaria, not much is known about Bernhard von Gudden's work in neuroanatomy. He pioneered fiber tract mapping by studying the effects of neurodegeneration following brain lesions. His ideas and work lay the foundation for subsequent fiber tract mapping strategies including the latest method using diffusion tensor magnetic resonance. This paper describes and acknowledges his contribution to the field, now collectively known as connectomics, and describes how it has become an essential tool in modern stereotactic neurosurgery.

Tractographic description of major subcortical projection pathways passing the anterior limb of the internal capsule. Corticopetal organization of networks relevant for psychiatric disorders.

BACKGROUND: Major depression (MD) and obsessive-compulsive disorder (OCD) are psychiatric diseases with a huge impact on individual well-being. Despite optimal treatment regiments a subgroup of patients remains treatment resistant and stereotactic surgery (stereotactic lesion surgery, SLS or Deep Brain Stimulation, DBS) might be an option. Recent research has described four networks related to MD and OCD (affect, reward, cognitive control, default network) but only on a cortical and the adjacent sub-cortical level. Despite the enormous impact of comparative neuroanatomy, animal science and stereotactic approaches a holistic theory of subcortical and cortical network interactions is elusive. Because of the dominant hierarchical rank of the neocortex, corticofugal approaches have been used to identify connections in subcortical anatomy without anatomical priors and in part confusing results. We here propose a different corticopetal approach by identifying subcortical networks and search for neocortical convergences thereby following the principle of phylogenetic and ontogenetic network development. MATERIAL AND METHODS: This work used a diffusion tensor imaging data from a normative cohort (Human Connectome Project, HCP; n = 200) to describe eight subcortical fiber projection pathways (PPs) from subthalamic nucleus (STN), substantia nigra (SNR), red nucleus (RN), ventral tegmental area (VTA), ventrolateral thalamus (VLT) and mediodorsal thalamus (MDT) in a normative space (MNI). Subcortical and cortical convergences were described including an assignment of the specific pathways to MD/OCD-related networks. Volumes of activated tissue for different stereotactic stimulation sites and procedures were simulated to understand the role of the distinct networks, with respect to symptoms and treatment of OCD and MD. RESULTS: The detailed course of eight subcortical PPs (stnPP, snrPP, rnPP, vlATR, vlATRc, mdATR, mdATRc, vtaPP/slMFB) were described together with their subcortical and cortical convergences. The anterior limb of the internal capsule can be subdivided with respect to network occurrences in ventral-dorsal and medio-lateral gradients. Simulation of stereotactic procedures for OCD and MD showed dominant involvement of mdATR/mdATRc (affect network) and vtaPP/slMFB (reward network). DISCUSSION: Corticofugal search strategies for the evaluation of stereotactic approaches without anatomical priors often lead to confusing results which do not allow for a clear assignment of a procedure to an involved network. According to our simulation of stereotactic procedures in the treatment of OCD and MD, most of the target regions directly involve the reward (and affect) networks, while side-effects can in part be explained with a co-modulation of the control network. CONCLUSION: The here proposed corticopetal approach of a hierarchical description of 8 subcortical PPs with subcortical and cortical convergences represents a new systematics of networks found in all different evolutionary and distinct parts of the human brain.

Effects of magnetic seizure therapy on anterograde and retrograde amnesia in treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) is the gold standard for treatment-resistant depression (TRD). However, cognitive side effects, mainly anterograde and retrograde amnesia, frequently occur. Magnetic seizure therapy (MST) is tested using more focal seizure induction. However, the suggestion MST may be more beneficial than ECT because it causes fewer amnesia have not yet been comprehensively investigated using common neuropsychological testing specifically for ECT. We aimed to examine whether MST causes anterograde and retrograde amnesia. METHODS: Ten patients with TRD were treated with MST (8.9 [2] treatments) at 100% machine output, a frequency of 100 Hz and 657.4 (62) pulses per train. The short form of the Autobiographical Memory Inventory was administered to test retrograde amnesia. Furthermore, an extended neuropsychological test battery, including verbal and nonverbal recall as well as recognition tasks, was used. RESULTS: We observed changes in retrograde amnesia, although they were not clinically relevant (mean: -0.42 ± 0.14). Furthermore, no anterograde amnesia as well as no effects on global cognitive status, attention, language, and executive functions after MST were measured. CONCLUSIONS: The cognitive safety and efficacy of MST in patients with TRD were indicated. However, the main limitations of the present study were the small sample and as a consequence, the low statistical power to detect changes after treatment. Therefore, our findings require replication in further studies. In addition, a direct comparison between MST and ECT in a larger sample should be performed before MST can be discussed as an alternative treatment approach to ECT in clinical practice.

Frontal white matter architecture predicts efficacy of deep brain stimulation in major depression.

Major depression is a frequent and severe disorder, with a combination of psycho- and pharmacotherapy most patients can be treated. However, ~20% of all patients suffering from major depressive disorder remain treatment resistant; a subgroup might be treated with deep brain stimulation (DBS). We present two trials of DBS to the superolateral medial forebrain bundle (slMFB DBS; FORESEE I and II). The goal was to identify informed features that allow to predict treatment response. Data from N = 24 patients were analyzed. Preoperative imaging including anatomical sequences (T1 and T2) and diffusion tensor imaging (DTI) magnetic resonance imaging sequences were used together with postoperative helical CT scans (for DBS electrode position). Pathway activation modeling (PAM) as well as preoperative structural imaging and morphometry was used to understand the response behavior of patients (MADRS). A left fronto-polar and partly orbitofrontal region was identified that showed increased volume in preoperative anatomical scans. Further statistical analysis shows that the volume of this "HUB-region" is predictive for later MADRS response from DBS. The HUB region connects to typical fiber pathways that have been addressed before in therapeutic DBS in major depression. Left frontal volume growth might indicate intrinsic activity upon disconnection form the main emotional network. The results are significant since for the first time we found an informed feature that might allow to identify and phenotype future responders for slMFB DBS. This is a clear step into the direction of personalized treatments.

Machine learning-aided personalized DTI tractographic planning for deep brain stimulation of the superolateral medial forebrain bundle using HAMLET.

BACKGROUND: Growing interest exists for superolateral medial forebrain bundle (slMFB) deep brain stimulation (DBS) in psychiatric disorders. The surgical approach warrants tractographic rendition. Commercial stereotactic planning systems use deterministic tractography which suffers from inherent limitations, is dependent on manual interaction (ROI definition), and has to be regarded as subjective. We aimed to develop an objective but patient-specific tracking of the slMFB which at the same time allows the use of a commercial surgical planning system in the context of deep brain stimulation. METHODS: The HAMLET (Hierarchical Harmonic Filters for Learning Tracts from Diffusion MRI) machine learning approach was introduced into the standardized workflow of slMFB DBS tractographic planning on the basis of patient-specific dMRI. Rendition of the slMFB with HAMLET serves as an objective comparison for the refinement of the deterministic tracking procedure. Our application focuses on the tractographic planning of DBS (N = 8) for major depression and OCD. RESULTS: Previous results have shown that only fibers belonging to the ventral tegmental area to prefrontal/orbitofrontal axis should be targeted. With the proposed technique, the deterministic tracking approach, that serves as the surgical planning data, can be refined, over-sprouting fibers are eliminated, bundle thickness is reduced in the target region, and thereby probably a more accurate targeting is facilitated. The HAMLET-driven method is meant to achieve a more objective surgical fiber display of the slMFB with deterministic tractography. CONCLUSIONS: The approach allows overlying the results of patient-specific planning from two different approaches (manual deterministic and machine learning HAMLET). HAMLET shows the slMFB as a volume and thus serves as an objective tracking corridor. It helps to refine results from deterministic tracking in the surgical workspace without interfering with any part of the standard software solution. We have now included this workflow in our daily clinical experimental work on slMFB DBS for psychiatric indications.

Treatment resistance in major depression is correlated with increased plasma levels of neurofilament light protein reflecting axonal damage.

Treatment resistant major depression is accompanied with a sizable impact on quality of life with severe consequences for social integrity, individual health and socioeconomic state. In- and outpatient care of patients with treatment resistant major depression remains very challenging for both patients and the health system. One reason is the limited knowledge on the etiology of treatment resistance in major depression resulting difficulties developing efficient treatment strategies for this group of severe depressed patients. Therefore, new focuses on research are needed. Biomarkers reliably reflecting neuropathological processes could help to understand the actual mechanisms in treatment resistance. Neurofilament light protein might be a reliable biomarker of axonal damage in the brain. Due to accumulating evidence that major depression is associated with axonal damage, it is our hypothesis that treatment resistant major depression is correlated with persistent axonal damage within circuits processing affective responses. Axonal damage is reflected by increased levels of neurofilament light protein in plasma. To evaluate our hypothesis, neurofilament light protein will be measured in a group of patients with homogeneous symptomatology of treatment resistant major depression.

Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.

Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/- 4) at baseline to 12.9 (SD +/- 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.

Deep brain stimulation: current challenges and future directions.

The clinical use of deep brain stimulation (DBS) is among the most important advances in the clinical neurosciences in the past two decades. As a surgical tool, DBS can directly measure pathological brain activity and can deliver adjustable stimulation for therapeutic effect in neurological and psychiatric disorders correlated with dysfunctional circuitry. The development of DBS has opened new opportunities to access and interrogate malfunctioning brain circuits and to test the therapeutic potential of regulating the output of these circuits in a broad range of disorders. Despite the success and rapid adoption of DBS, crucial questions remain, including which brain areas should be targeted and in which patients. This Review considers how DBS has facilitated advances in our understanding of how circuit malfunction can lead to brain disorders and outlines the key unmet challenges and future directions in the DBS field. Determining the next steps in DBS science will help to define the future role of this technology in the development of novel therapeutics for the most challenging disorders affecting the human brain.

Clinical Predictors of Response to Magnetic Seizure Therapy in Depression: A Preliminary Report.

OBJECTIVES: Magnetic seizure therapy (MST) is a novel convulsive brain stimulation method in clinical testing, which is used as an alternative for electroconvulsive therapy in patients with treatment-resistant depression (TRD). Preliminary studies have suggested that MST leads to fewer cognitive adverse effects than electroconvulsive therapy but has similar efficacy. However, the clinical predictors of response to MST have not been evaluated yet. This study aimed to investigate whether these predictors can be identified in patients with TRD. METHODS: Thirty-eight patients with TRD were included. As clinical predictors for treatment response, we used the diagnosis, sex, age, family history, and severity of depression, as well as the melancholic, psychotic, anxiety, and atypical depression symptoms. A response was defined as an improvement higher than 50% on the 28-item Hamilton Rating Scale for Depression. The binary logistic regression, stepwise linear regression, and effect sizes were calculated. RESULTS: We found that 68.4% of the patients responded to MST. The responders had significantly fewer previous depressive episodes, less severe depression, and fewer melancholic (anhedonia) and anxiety symptoms than the nonresponders. In addition, responders were more likely to have a positive family history of depression than nonresponders. In particular, the number of previous episodes and a family history of depression were significant predictors of the response to MST. CONCLUSIONS: We demonstrate that the chronicity, severity, and family history of depression, as well as the presence of melancholic and anxiety symptoms, can serve as clinical predictors of the response to MST. Further research with a larger sample size will be required to verify these preliminary findings.

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.

Deep brain stimulation of the supero-lateral branch of the medial forebrain bundle does not lead to changes in personality in patients suffering from severe depression.

BACKGROUND: Reports of changes in patients' social behavior during deep brain stimulation (DBS) raised the question whether DBS induces changes in personality. This study explored if (1) DBS is associated with changes in personality in patients suffering from treatment-resistant depression (TRD), (2) how personality dimensions and depression are associated, and (3) if TRD patients' self-ratings of personality are valid. METHODS: TRD patients were assessed before DBS (n = 30), 6 months (t2, n = 21), 2 (t3, n = 17) and 5 years (t4, n = 11) after the initiation of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB-DBS). Personality was measured with the NEO-Five-Factor Inventory (NEO-FFI), depression severity with Hamilton (HDRS), and Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Personality dimensions did not change with slMFB-DBS compared with baseline. Extraversion was negatively correlated with HDRS28 (r = -0.48, p < 0.05) and MADRS (r = -0.45, p < 0.05) at t2. Inter-rater reliability was high for the NEO-FFI at baseline (Cronbach's α = 0.74) and at t4 (α = 0.65). Extraversion [t(29) = -5.20; p < 0.001] and openness to experience [t(29) = -6.96; p < 0.001] differed statistically significant from the normative sample, and did not predict the antidepressant response. CONCLUSIONS: slMFB-DBS was not associated with a change in personality. The severity of depression was associated with extraversion. Personality of TRD patients differed from the healthy population and did not change with response, indicating a possible scar effect. Self-ratings of personality seem valid to assess personality during TRD.

Autonomy in Depressive Patients Undergoing DBS-Treatment: Informed Consent, Freedom of Will and DBS' Potential to Restore It.

According to the World Health Organization, depression is one of the most common and most disabling psychiatric disorders, affecting at any given time approximately 325 million people worldwide. As there is strong evidence that depressive disorders are associated with a dynamic dysregulation of neural circuits involved in emotional processing, recently several attempts have been made to intervene directly in these circuits via deep brain stimulation (DBS) in patients with treatment-resistant major depressive disorder (MDD). Given the promising results of most of these studies, the rising medical interest in this new treatment correlates with a growing sensitivity to ethical questions. One of the most crucial concerns is that DBS might interfere with patients' ability to make autonomous decisions. Thus, the goal of this article is to evaluate the impact DBS presumably has on the capacity to decide and act autonomously in patients with MDD in the light of the autonomy-undermining effects depression has itself. Following the chronological order of the procedure, special attention will first be paid to depression's effects on patients' capacity to make use of their free will in giving valid Informed Consent. We suggest that while the majority of patients with MDD appear capable of autonomous choices, as it is required for Informed Consent, they might still be unable to effectively act according to their own will whenever acting includes significant personal effort. In reducing disabling depressive symptoms like anhedonia and decrease of energy, DBS for treatment resistant MDD thus rather seems to be an opportunity to substantially increase autonomy than a threat to it.