Establishing connectivity through microdissections of midbrain stimulation-related neural circuits.

Comprehensive understanding of the neural circuits involving the ventral tegmental area is essential for elucidating the anatomo-functional mechanisms governing human behaviour as well as the therapeutic and adverse effects of deep brain stimulation for neuropsychiatric diseases. While the ventral tegmental area has been successfully targeted with deep brain stimulation for different neuropsychiatric diseases, the axonal connectivity of the region has not been fully understood. Here using fiber micro-dissections in human cadaveric hemispheres, population-based high-definition fiber tractography, and previously reported deep brain stimulation hotspots, we find that the ventral tegmental area participates in an intricate network involving the serotonergic pontine nuclei, basal ganglia, limbic system, basal forebrain, and prefrontal cortex, which is implicated in the treatment of obsessive-compulsive disorder, major depressive disorder, Alzheimer's disease, cluster headaches, and aggressive behaviors.

Advanced therapies in Parkinson's disease: an individualized approach to their indication.

Device aided therapies (DAT) comprising the intrajejunal administration of levodopa/carbidopa intestinal gel (LCIG) and levodopa/carbidopa/entacapone intestinal gel (LECIG), the continuous subcutaneous application of foslevodopa/foscarbidopa or apomorphine infusion (CSAI) and deep brain stimulation (DBS) are used to treat Parkinson's disease with insufficient symptom alleviation under intensified pharmacotherapy. These DAT significantly differ in their efficacy profiles, indication, invasiveness, contraindications, and potential side effects. Usually, the evaluation of all these procedures is conducted simultaneously at the same point in time. However, as disease progression and symptom burden is extremely heterogeneous, clinical experience shows that patients reach the individual milestones for a certain therapy at different points in their disease course. Therefore, advocating for an individualized therapy evaluation for each DAT, requiring an ongoing evaluation. This necessitates that, during each consultation, the current symptomatology should be analyzed, and the potential suitability for a DAT be assessed. This work represents a critical interdisciplinary appraisal of these therapies in terms of their individual profiles and compares these DAT regarding contraindications, periprocedural considerations as well as their efficacy regarding motor- and non-motor deficits, supporting a personalized approach.

Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

Technical note: preliminary surgical experience with a new implantable epicranial stimulation device for chronic focal cortex stimulation in drug-resistant epilepsy.

PURPOSE: This study is to report some preliminary surgical considerations and outcomes after the first implantations of a new and commercially available implantable epicranial stimulation device for focal epilepsy. METHODS: We retrospectively analyzed data from clinical notes. Outcome parameters were as follows: wound healing, surgery time, and adverse events. RESULTS: Five patients were included (17-52 y/o; 3 female). Epicranial systems were uneventfully implanted under neuronavigation guidance. Some minor adverse events occurred. Wound healing in primary intention was seen in all patients. Out of these surgeries, certain concepts were developed: Skin incisions had to be significantly larger than expected. S-shaped incisions appeared to be a good choice in typical locations behind the hairline. Preoperative discussions between neurologist and neurosurgeon are mandatory in order to allow for the optimal coverage of the epileptogenic zone with the electrode geometry. CONCLUSION: In this first small series, we were able to show safe implantation of this new epicranial stimulation device. The use of neuronavigation is strongly recommended. The procedure is simple but not trivial and ideally belongs in the hands of a neurosurgeon.

Where Position Matters-Deep-Learning-Driven Normalization and Coregistration of Computed Tomography in the Postoperative Analysis of Deep Brain Stimulation.

INTRODUCTION: Recent developments in the postoperative evaluation of deep brain stimulation surgery on the group level warrant the detection of achieved electrode positions based on postoperative imaging. Computed tomography (CT) is a frequently used imaging modality, but because of its idiosyncrasies (high spatial accuracy at low soft tissue resolution), it has not been sufficient for the parallel determination of electrode position and details of the surrounding brain anatomy (nuclei). The common solution is rigid fusion of CT images and magnetic resonance (MR) images, which have much better soft tissue contrast and allow accurate normalization into template spaces. Here, we explored a deep-learning approach to directly relate positions (usually the lead position) in postoperative CT images to the native anatomy of the midbrain and group space. MATERIALS AND METHODS: Deep learning is used to create derived tissue contrasts (white matter, gray matter, cerebrospinal fluid, brainstem nuclei) based on the CT image; that is, a convolution neural network (CNN) takes solely the raw CT image as input and outputs several tissue probability maps. The ground truth is based on coregistrations with MR contrasts. The tissue probability maps are then used to either rigidly coregister or normalize the CT image in a deformable way to group space. The CNN was trained in 220 patients and tested in a set of 80 patients. RESULTS: Rigorous validation of such an approach is difficult because of the lack of ground truth. We examined the agreements between the classical and proposed approaches and considered the spread of implantation locations across a group of identically implanted subjects, which serves as an indicator of the accuracy of the lead localization procedure. The proposed procedure agrees well with current magnetic resonance imaging-based techniques, and the spread is comparable or even lower. CONCLUSIONS: Postoperative CT imaging alone is sufficient for accurate localization of the midbrain nuclei and normalization to the group space. In the context of group analysis, it seems sufficient to have a single postoperative CT image of good quality for inclusion. The proposed approach will allow researchers and clinicians to include cases that were not previously suitable for analysis.

Optogenetic stimulation of ventral tegmental area dopaminergic neurons in a female rodent model of depression: The effect of different stimulation patterns.

Major depressive disorder is one of the most common mental disorders, and more than 300 million of people suffer from depression worldwide. Recent clinical trials indicate that deep brain stimulation of the superolateral medial forebrain bundle (mfb) can have rapid and long-term antidepressant effects in patients with treatment-resistant depression. However, the mechanisms of action are elusive. In this study, using female rats, we demonstrate the antidepressant effects of selective optogenetic stimulation of the ventral tegmental area's dopaminergic (DA) neurons passing through the mfb and compare different stimulation patterns. Chronic mild unpredictable stress (CMUS) induced depressive-like, but not anxiety-like phenotype. Short-term and long-term stimulation demonstrated antidepressant effect (OSST) and improved anxiolytic effect (EPM), while long-term stimulation during CMUS induction prevented depressive-like behavior (OSST and USV) and improved anxiolytic effect (EPM). The results highlight that long-term accumulative stimulation on DA pathways is required for antidepressant and anxiolytic effect.

Deep brain stimulation for refractory obsessive-compulsive disorder (OCD): emerging or established therapy?

A consensus has yet to emerge whether deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) can be considered an established therapy. In 2014, the World Society for Stereotactic and Functional Neurosurgery (WSSFN) published consensus guidelines stating that a therapy becomes established when "at least two blinded randomized controlled clinical trials from two different groups of researchers are published, both reporting an acceptable risk-benefit ratio, at least comparable with other existing therapies. The clinical trials should be on the same brain area for the same psychiatric indication." The authors have now compiled the available evidence to make a clear statement on whether DBS for OCD is established therapy. Two blinded randomized controlled trials have been published, one with level I evidence (Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score improved 37% during stimulation on), the other with level II evidence (25% improvement). A clinical cohort study (N = 70) showed 40% Y-BOCS score improvement during DBS, and a prospective international multi-center study 42% improvement (N = 30). The WSSFN states that electrical stimulation for otherwise treatment refractory OCD using a multipolar electrode implanted in the ventral anterior capsule region (including bed nucleus of stria terminalis and nucleus accumbens) remains investigational. It represents an emerging, but not yet established therapy. A multidisciplinary team involving psychiatrists and neurosurgeons is a prerequisite for such therapy, and the future of surgical treatment of psychiatric patients remains in the realm of the psychiatrist.

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.

Robust intra-individual estimation of structural connectivity by Principal Component Analysis.

Fiber tractography based on diffusion-weighted MRI provides a non-invasive characterization of the structural connectivity of the human brain at the macroscopic level. Quantification of structural connectivity strength is challenging and mainly reduced to "streamline counting" methods. These are however highly dependent on the topology of the connectome and the particular specifications for seeding and filtering, which limits their intra-subject reproducibility across repeated measurements and, in consequence, also confines their validity. Here we propose a novel method for increasing the intra-subject reproducibility of quantitative estimates of structural connectivity strength. To this end, the connectome is described by a large matrix in positional-orientational space and reduced by Principal Component Analysis to obtain the main connectivity "modes". It was found that the proposed method is quite robust to structural variability of the data.

Neuromodulation in Psychiatric disorders: Experimental and Clinical evidence for reward and motivation network Deep Brain Stimulation: Focus on the medial forebrain bundle.

Deep brain stimulation (DBS) in psychiatric illnesses has been clinically tested over the past 20 years. The clinical application of DBS to the superolateral branch of the medial forebrain bundle in treatment-resistant depressed patients-one of several targets under investigation-has shown to be promising in a number of uncontrolled open label trials. However, there are remain numerous questions that need to be investigated to understand and optimize the clinical use of DBS in depression, including, for example, the relationship between the symptoms, the biological substrates/projections and the stimulation itself. In the context of precision and customized medicine, the current paper focuses on clinical and experimental research of medial forebrain bundle DBS in depression or in animal models of depression, demonstrating how clinical and scientific progress can work in tandem to test the therapeutic value and investigate the mechanisms of this experimental treatment. As one of the hypotheses is that depression engenders changes in the reward and motivational networks, the review looks at how stimulation of the medial forebrain bundle impacts the dopaminergic system.

SPECTRE-A novel dMRI visualization technique for the display of cerebral connectivity.

The visualization of diffusion MRI related properties in a comprehensive way is still a challenging problem. We propose a simple visualization technique to give neuroradiologists and neurosurgeons a more direct and personalized view of relevant connectivity patterns estimated from clinically feasible diffusion MRI. The approach, named SPECTRE (Subject sPEcific brain Connectivity display in the Target REgion), is based on tract-weighted imaging, where diffusion MRI streamlines are used to aggregate information from a different MRI contrast. Instead of using native MRI contrasts, we propose to use continuous template information as the underlying contrast for aggregation. In this respect, the SPECTRE approach is complementary to normative approaches where connectivity information is warped from the group level to subject space by anatomical registration. For the purpose of demonstration, we focus the presentation of the SPECTRE approach on the visualization of connectivity patterns in the midbrain regions at the level of subthalamic nucleus due to its importance for deep brain stimulation. The proposed SPECTRE maps are investigated with respect to plausibility, robustness, and test-retest reproducibility. Clear dependencies of reliability measures with respect to the underlying tracking algorithms are observed.

Navigated Deep Brain Stimulation Surgery: Evaluating the Combined Use of a Frame-Based Stereotactic System and a Navigation System.

Deep brain stimulation (DBS) is a complex surgical procedure that requires detailed anatomical knowledge. In many fields of neurosurgery navigation systems are used to display anatomical structures during an operation to aid performing these surgeries. In frame-based DBS, the advantage of visualization has not yet been evaluated during the procedure itself. In this study, we added live visualization to a frame-based DBS system, using a standard navigation system and investigated its accuracy and potential use in DBS surgery. As a first step, a phantom study was conducted to investigate the accuracy of the navigation system in conjunction with a frame-based approach. As a second step, 5 DBS surgeries were performed with this combined approach. Afterwards, 3 neurosurgeons and 2 neurologists with different levels of experience evaluated the potential use of the system with a questionnaire. Moreover, the additional personnel, costs and required set up time were noted and compared to 5 consecutive standard procedures. In the phantom study, the navigation system showed an inaccuracy of 2.1 mm (mean SD 0.69 mm). In the questionnaire, a mean of 9.4/10 points was awarded for the use of the combined approach as a teaching tool, a mean of 8.4/10 for its advantage in creating a 3-dimensional (3-D) map and a mean of 8/10 points for facilitating group discussions. Especially neurosurgeons and neurologists in training found it useful to better interpret clinical results and side effects (mean 9/10 points) and neurosurgeons appreciated its use to better interpret microelectrode recordings (mean 9/10 points). A mean of 6/10 points was awarded when asked if the benefits were worth the additional efforts. Initially 2 persons, then one additional person was required to set up the system with no relevant added time or costs. Using a navigation system for live visualization during frame-based DBS surgery can improve the understanding of the complex 3-D anatomy and many aspects of the procedure itself. For now, we would regard it as an excellent teaching tool rather than a necessity to perform DBS surgeries.

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.

Impact of Stereotactic Ventriculocisternostomy on Delayed Cerebral Infarction and Outcome After Subarachnoid Hemorrhage.

Background and Purpose- Delayed cerebral infarction (DCI) is an important cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Stereotactic catheter ventriculocisternostomy (STX-VCS) and fibrinolytic/spasmolytic lavage is a new method for DCI prevention. Here, we assess the effects of implementing STX-VCS in an unselected aSAH patient population of a tertiary referral center. Methods- Retrospective cohort study of all consecutive aSAH patients admitted to a neurosurgical referral center during a 7-year period (April 2012 to April 2019). Midterm STX-VCS was introduced and offered to patients at high risk for DCI. We compared the incidence and burden of DCI, neurological outcome, and the use of induced hypertension and endovascular rescue therapy in this consecutive aSAH population 3.5 years before versus 3.5 years after STX-VCS became available. Results- Four hundred thirty-six consecutive patients were included: 222 BEFORE and 214 AFTER. Fifty-seven of 214 (27%) patients received STX-VCS. Stereotactic procedures resulted in one (2%) subdural hematoma. Favorable neurological outcome at 6 months occurred in 118 (53%) patients BEFORE and 139 (65%) patients AFTER (relative risk, 0.79 [95% CI, 0.66-0.95]). DCI occurred in 40 (18.0%) patients BEFORE and 17 (7.9%) patients AFTER (relative risk, 0.68 [95% CI, 0.57-0.86]), and total DCI volumes were 8933 (100%) and 3329 mL (36%), respectively. Induced hypertension was used in 97 (44%) and 30 (15%) patients, respectively (relative risk, 0.55 [95% CI, 0.46-0.65]). Thirty (13.5%) patients BEFORE versus 5 (2.3%) patients AFTER underwent endovascular rescue therapies (relative risk, 0.17 [95% CI, 0.07-0.42]). Conclusions- Selecting high-risk patients for STX-VCS reduced the DCI incidence, burden, and related mortality in a consecutive aSAH patient population. This was associated with an improved neurological outcome.

Neuroimaging and electrophysiology meet invasive neurostimulation for causal interrogations and modulations of brain states.

Deep brain stimulation (DBS) has developed over the last twenty years into a highly effective evidenced-based treatment option for neuropsychiatric disorders. Moreover, it has become a fascinating tool to provide illustrative insights into the functioning of brain networks. New anatomical and pathophysiological models of DBS action have accelerated our understanding of neurological and psychiatric disorders and brain functioning. The description of the brain networks arose through the unique ability to illustrate long-range interactions between interconnected brain regions as derived from state-of-the-art neuroimaging (structural, diffusion, and functional MRI) and the opportunity to record local and large-scale brain activity at millisecond temporal resolution (microelectrode recordings, local field potential, electroencephalography, and magnetoencephalography). In the first part of this review, we describe how neuroimaging techniques have led to current understanding of DBS effects, by identifying and refining the DBS targets and illustrate the actual view on the relationships between electrode locations and clinical effects. One step further, we discuss how neuroimaging has shifted the view of localized DBS effects to a modulation of specific brain circuits, which has been possible from the combination of electrode location reconstructions with recently introduced network imaging methods. We highlight how these findings relate to clinical effects, thus postulating neuroimaging as a key factor to understand the mechanisms of DBS action on behavior and clinical effects. In the second part, we show how invasive electrophysiology techniques have been efficiently integrated into the DBS set-up to precisely localize the neuroanatomical targets of DBS based on distinct region-specific patterns of neural activity. Next, we show how multi-site electrophysiological recordings have granted a real-time window into the aberrant brain circuits within and beyond DBS targets to quantify and map the dynamic properties of rhythmic oscillations. We also discuss how DBS alters the transient synchrony states of oscillatory networks in temporal and spatial domains during resting, task-based and motion conditions, and how this modulation of brain states ultimately shapes the functional response. Finally, we show how a successful decoding and management of electrophysiological proxies (beta bursts, phase-amplitude coupling) of aberrant brain circuits was translated into adaptive DBS stimulation paradigms for a targeted and state-dependent invasive electrical neuromodulation.

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.

Deep Brain Stimulation of the Medial Forebrain Bundle in a Rodent Model of Depression: Exploring Dopaminergic Mechanisms with Raclopride and Micro-PET.

BACKGROUND: Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) can reverse depressive-like symptoms clinically and in experimental models of depression, but the mechanisms of action are unknown. OBJECTIVES: This study investigated the role of dopaminergic mechanisms in MFB stimulation-mediated behavior changes, in conjunction with raclopride administration and micropositron emission tomography (micro-PET). METHODS: Flinders Sensitive Line (FSL) rats were allocated into 4 groups: FSL (no treatment), FSL+ (DBS), FSL.R (FSL with raclopride), and FSL.R+ (FSL with raclopride and DBS). Animals were implanted with bilateral electrodes targeting the MFB and given 11 days access to raclopride in the drinking water with or without concurrent continuous bilateral DBS over the last 10 days. Behavioral testing was conducted after stimulation. A PET scan using [18F]desmethoxyfallypride was performed to determine D2 receptor availability before and after raclopride treatment. Changes in gene expression in the nucleus accumbens and the hippocampus were assessed using quantitative polymerase chain reaction. RESULTS: Micro-PET imaging showed that raclopride administration blocked 36% of the D2 receptor in the striatum, but the relative level of blockade was reduced/modulated by stimulation. Raclopride treatment enhanced depressive-like symptoms in several tasks, and the MFB DBS partially reversed the depressive-like phenotype. The raclopride-treated MFB DBS animals had increased levels of mRNA coding for dopamine receptor D1 and D2 suggestive of a stimulation-mediated increase in dopamine receptors. CONCLUSION: Data suggest that chronic and continuous MFB DBS could act via the modulation of the midbrain dopaminergic transmission, including impacting on the postsynaptic dopamine receptor profile.

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.

The dynamics of error processing in the human brain as reflected by high-gamma activity in noninvasive and intracranial EEG.

Error detection in motor behavior is a fundamental cognitive function heavily relying on local cortical information processing. Neural activity in the high-gamma frequency band (HGB) closely reflects such local cortical processing, but little is known about its role in error processing, particularly in the healthy human brain. Here we characterize the error-related response of the human brain based on data obtained with noninvasive EEG optimized for HGB mapping in 31 healthy subjects (15 females, 16 males), and additional intracranial EEG data from 9 epilepsy patients (4 females, 5 males). Our findings reveal a multiscale picture of the global and local dynamics of error-related HGB activity in the human brain. On the global level as reflected in the noninvasive EEG, the error-related response started with an early component dominated by anterior brain regions, followed by a shift to parietal regions, and a subsequent phase characterized by sustained parietal HGB activity. This phase lasted for more than 1 s after the error onset. On the local level reflected in the intracranial EEG, a cascade of both transient and sustained error-related responses involved an even more extended network, spanning beyond frontal and parietal regions to the insula and the hippocampus. HGB mapping appeared especially well suited to investigate late, sustained components of the error response, possibly linked to downstream functional stages such as error-related learning and behavioral adaptation. Our findings establish the basic spatio-temporal properties of HGB activity as a neural correlate of error processing, complementing traditional error-related potential studies.