Variability of white matter anatomy in the subcallosal cingulate area

The subcallosal cingulate (SCC) area is a putative hub in the brain network underlying depression. Deep brain stimulation (DBS) targeting a particular subregion of SCC, identified as the intersection of forceps minor (FM), uncinate fasciculus (UCF), cingulum and fronto‐striatal fiber bundles, may be critical to a therapeutic response in patients with severe, treatment‐resistant forms of major depressive disorder (MDD). The pattern and variability of the white matter anatomy and organization within SCC has not been extensively characterized across individuals. The goal of this study is to investigate the variability of white matter bundles within the SCC that structurally connect this region with critical nodes in the depression network. Structural and diffusion data from 100 healthy subjects from the Human Connectome Project database were analyzed. Anatomically defined SCC regions were used as seeds to perform probabilistic tractography and to estimate the connectivity from the SCC to subject‐specific target areas believed to be involved in the pathology of MDD including ventral striatum (VS), UCF, anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC). Four distinct areas of connectivity were identified within SCC across subjects: (a) postero‐lateral SCC connectivity to medial temporal regions via UCF, (b) postero‐medial connectivity to VS, (c) superior‐medial connectivity to ACC via cingulum bundle, and (d) antero‐lateral connectivity to mPFC regions via forceps minor. Assuming white matter connectivity is critical to therapeutic response, the improved anatomic understanding of SCC as well as an appreciation of the intersubject variability are critical to developing optimized therapeutic targeting for SCC DBS.     

Endovascular deep brain stimulation: Investigating the relationship between vascular structures and deep brain stimulation targets

BackgroundEndovascular delivery of current using ‘stentrodes’ – electrode bearing stents – constitutes a potential alternative to conventional deep brain stimulation (DBS). The precise neuroanatomical relationships between DBS targets and the vascular system, however, are poorly characterized to date.ObjectiveTo establish the relationships between cerebrovascular system and DBS targets and investigate the feasibility of endovascular stimulation as an alternative to DBS.MethodsNeuroanatomical targets as employed during deep brain stimulation (anterior limb of the internal capsule, dentatorubrothalamic tract, fornix, globus pallidus pars interna, medial forebrain bundle, nucleus accumbens, pedunculopontine nucleus, subcallosal cingulate cortex, subthalamic nucleus, and ventral intermediate nucleus) were superimposed onto probabilistic vascular atlases obtained from 42 healthy individuals. Euclidian distances between targets and associated vessels were measured. To determine the electrical currents necessary to encapsulate the predefined neurosurgical targets and identify potentially side-effect inducing substrates, a preliminary volume of tissue activated (VTA) analysis was performed.ResultsSix out of ten DBS targets were deemed suitable for endovascular stimulation: medial forebrain bundle (vascular site: P1 segment of posterior cerebral artery), nucleus accumbens (vascular site: A1 segment of anterior cerebral artery), dentatorubrothalamic tract (vascular site: s2 segment of superior cerebellar artery), fornix (vascular site: internal cerebral vein), pedunculopontine nucleus (vascular site: lateral mesencephalic vein), and subcallosal cingulate cortex (vascular site: A2 segment of anterior cerebral artery). While VTAs effectively encapsulated mfb and NA at current thresholds of 3.5 V and 4.5 V respectively, incremental amplitude increases were required to effectively cover fornix, PPN and SCC target (mean voltage: 8.2 ± 4.8 V, range: 3.0–17.0 V). The side-effect profile associated with endovascular stimulation seems to be comparable to conventional lead implantation. Tailoring of targets towards vascular sites, however, may allow to reduce adverse effects, while maintaining the efficacy of neural entrainment within the target tissue.ConclusionsWhile several challenges remain at present, endovascular stimulation of select DBS targets seems feasible offering novel and exciting opportunities in the neuromodulation armamentarium.     

Deep Brain Stimulation of the Subgenual Cingulate Cortex for the Treatment of Chronic Low Back Pain

ObjectivesDespite converging basic scientific and clinical evidence of the link between chronic pain and depression, existing therapies do not often take advantage of this overlap. Here, we provide a critical review of the literature that highlights the intersection in brain networks between chronic low back pain (CLBP) and depression and discuss findings from previous deep brain stimulation (DBS) studies for pain. Based on a multidimensional model of pain processing and the connectivity of the subgenual cingulate cortex (SCC) with areas that are implicated in both CLBP and depression, we propose a novel approach to the treatment of CLBP using DBS of the SCC.Materials and MethodsA narrative review with literature assessment.ResultsCLBP is associated with a shift away from somatosensory representation toward brain regions that mediate emotional processes. There is a high degree of overlap between these regions and those involved in depression, including the anterior cingulate cortex, medial prefrontal cortex, nucleus accumbens, and amygdala. Whereas target sites from previous DBS trials for pain were not anatomically positioned to engage these areas and their associated networks, the SCC is structurally connected to all of these regions as well as others involved in mediating sensory, cognitive, and affective processing in CLBP.ConclusionsCLBP and depression share a common underlying brain network interconnected by the SCC. Current data and novel technology provide an optimal opportunity to develop clinically effective trials of SCC DBS for CLBP.     

A connectomic analysis of deep brain stimulation for treatment-resistant depression

ObjectiveDeep brain stimulation (DBS) has been used as a treatment of last resort for treatment-resistant depression (TRD) for more than a decade. Many DBS targets have been proposed and tested clinically, but the underlying circuit mechanisms remain unclear. Uncovering white matter tracts (WMT) activated by DBS targets may provide crucial information about the circuit substrates mediating DBS efficacy in ameliorating TRD.MethodsWe performed probabilistic tractography using diffusion magnetic resonance imaging datas from 100 healthy volunteers in Human Connectome Project datasets to analyze the structural connectivity patterns of stimulation targeting currently-used DBS target for TRD. We generated mean and binary fiber distribution maps and calculated the numbers of WMT streamlines in the dataset.ResultsProbabilistic tracking results revealed that activation of distinct DBS targets demonstrated modulation of overlapping but considerably distinct pathways. DBS targets were categorized into 4 groups: Cortical, Striatal, Thalamic, and Medial Forebrain Bundle according to their main modulated WMT and brain areas. Our data also revealed that Brodmann area 10 and amygdala are hub structures that are associated with all DBS targets.ConclusionsOur results together suggest that the distinct mechanism of DBS targets implies individualized target selection and formulation in the future of DBS treatment for TRD. The modulation of Brodmann area 10 and amygdala may be critical for the efficacy of DBS-mediated treatment of TRD.     

Complex negative emotions induced by electrical stimulation of the human hypothalamus

BackgroundStimulation of the ventromedial hypothalamic region in animals has been reported to cause attack behavior labeled as sham-rage without offering information about the internal affective state of the animal being stimulated.ObjectiveTo examine the causal effect of electrical stimulation near the ventromedial region of the human hypothalamus on the human subjective experience and map the electrophysiological connectivity of the hypothalamus with other brain regions.MethodsWe examined a patient (Subject S20_150) with intracranial electrodes implanted across 170 brain regions, including the hypothalamus. We combined direct electrical stimulation with tractography, cortico-cortical evoked potentials (CCEP), and functional connectivity using resting state intracranial electroencephalography (EEG).ResultsRecordings in the hypothalamus did not reveal any epileptic abnormalities. Electrical stimulations near the ventromedial hypothalamus induced profound shame, sadness, and fear but not rage or anger. When repeated single-pulse stimulations were delivered to the hypothalamus, significant responses were evoked in the amygdala, hippocampus, ventromedial-prefrontal and orbitofrontal cortices, anterior cingulate, as well as ventral-anterior and dorsal-posterior insula. The time to first peak of these evoked responses varied and earliest propagations correlated best with the measures of resting-state EEG connectivity and structural connectivity.ConclusionThis patient's case offers details about the affective state induced by the stimulation of the human hypothalamus and provides causal evidence relevant to current theories of emotion. The complexity of affective state induced by the stimulation of the hypothalamus and the profile of hypothalamic electrophysiological connectivity suggest that the hypothalamus and its connected structures ought to be seen as causally important for human affective experience.     

Advanced Imaging in Psychiatric Neurosurgery: Toward Personalized Treatment

ObjectivesOur aim is to review several recent landmark studies discussing the application of advanced neuroimaging to guide target selection in deep brain stimulation (DBS) for psychiatric disorders.Materials and MethodsWe performed a PubMed literature search of articles related to psychiatric neurosurgery, DBS, diffusion tensor imaging, probabilistic tractography, functional magnetic resonance imaging (MRI), and blood oxygen level-dependent activation. Relevant articles were included in the review.ResultsRecent advances in neuroimaging, namely the use of diffusion tensor imaging, probabilistic tractography, functional MRI, and positron emission tomography have provided higher resolution depictions of structural and functional connectivity between regions of interest. Applying these imaging modalities to DBS has increased understanding of the mechanism of action of DBS from the single structure to network level, allowed for new DBS targets to be discovered, and allowed for individualized DBS targeting for psychiatric indications.ConclusionsAdvanced neuroimaging techniques may be especially important to guide personalized DBS targeting in psychiatric disorders such as treatment-resistant depression and obsessive–compulsive disorder where symptom profiles and underlying disordered circuitry are more heterogeneous. These articles suggest that advanced imaging can help to further individualize and optimize DBS, a promising next step in improving its efficacy.     

Personalized striatal targets for deep brain stimulation in obsessive-compulsive disorder

Background

Psychiatric conditions currently treated with deep brain stimulation (DBS), such as obsessive-compulsive disorder (OCD), are heterogeneous diseases with different symptomatic dimensions, indicating that fixed neuroanatomical DBS targets for all OCD cases may not be efficacious.

Bilateral Transcranial Direct Current Stimulation Over Dorsolateral Prefrontal Cortex Changes the Drug-cued Reactivity in the Anterior Cingulate Cortex of Crack-cocaine Addicts

BackgroundPatients addicted to crack-cocaine routinely have difficulty sustaining treatment, which could be related to dysfunctional cerebral activity that occurs in addiction.ObjectiveTo investigate the indirect electrophysiological effects of single transcranial direct current stimulation (tDCS) on cocaine-addicted brains.MethodsThe patients received either left cathodal/right anodal or sham stimulation over the DLPFC. The region of interest was the anterior cingulate cortex (ACC) during the N2 time window (200–350 ms). Event-related potentials in the ACC were measured during visual presentation of crack-related cues or neutral cues.ResultsLow-resolution brain electromagnetic tomography (LORETA) indicated that exposure to crack-related images led to increased activity in the ACC in the sham group, while the tDCS group showed decreased ACC activity after visualization of drug cues.ConclusionPrefrontal tDCS specifically modulated the ACC response during exposure to visual drug cues in crack-cocaine users.     

Connectivity Profile Predictive of Effective Deep Brain Stimulation in Obsessive-Compulsive Disorder

BackgroundDeep brain stimulation for obsessive-compulsive disorder is a rapidly developing treatment strategy for treatment-refractory patients. Both the exact target and impact on distributed brain networks remain a matter of debate. Here, we investigated which regions connected to stimulation sites contribute to clinical improvement effects and whether connectivity is able to predict outcomes.MethodsWe analyzed 22 patients (13 female) with treatment-refractory obsessive-compulsive disorder undergoing deep brain stimulation targeting the anterior limb of the internal capsule/nucleus accumbens. We calculated stimulation-dependent optimal connectivity separately for patient-specific connectivity data of 10 patients and for 12 additional patients using normative connectivity. Models of optimal connectivity were subsequently used to predict outcome in both an out-of-sample cross-validation and a leave-one-out cross-validation across the whole group.ResultsThe resulting models successfully cross-predicted clinical outcomes of the respective other sample, and a leave-one-out cross-validation across the whole group further demonstrated robustness of our findings (r = .630, p < .001). Specifically, the degree of connectivity between stimulation sites and medial and lateral prefrontal cortices significantly predicted clinical improvement. Finally, we delineated a frontothalamic pathway that is crucial to be modulated for beneficial outcome.ConclusionsSpecific connectivity profiles, encompassing frontothalamic streamlines, can predict clinical outcome of deep brain stimulation for obsessive-compulsive disorder. After further validation, our findings may be used to guide both deep brain stimulation targeting and programming and to inform noninvasive neuromodulation targets for obsessive-compulsive disorder.     

Evoked potentials generated by deep brain stimulation for Parkinson's disease

Background and objectivesThe goal of this review is to describe the general features, mechanisms, technical recording factors, and clinical applications of brain evoked potentials (EPs) generated by deep brain stimulation (DBS) for Parkinson's disease (PD).ResultsEvoked potentials in response to DBS pulses occur on the timescale of milliseconds and are found both locally at the site of stimulation and remotely in the cortex. DBS evoked potentials arise from a complex integration of antidromic and orthodromic conduction pathway responses, and provide information valuable for understanding the mechanisms and circuits involved in symptom treatment. Furthermore, these signals may provide biomarkers for improving DBS outcomes and function. For example, evoked potentials may have utility as control signals for DBS programming or adaptive DBS. Despite their promise there are still critical gaps in our understanding of the mechanisms by which evoked potentials arise and how these signals may be measured and applied in the clinical setting. Technical challenges of recording a highly transient signal at sufficient resolution without the interference of stimulation artifact present a barrier to understanding better DBS-induced EPs.ConclusionsWe describe the current scientific landscape of evoked potentials to facilitate and stimulate further investigation.     

Structural and functional correlates of subthalamic deep brain stimulation-induced apathy in Parkinson’s disease

BackgroundNotwithstanding the large improvement in motor function in Parkinson’s disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase. Postoperative apathy cannot always be related to a dose reduction of dopaminergic medication and stimulation itself may play a role.ObjectiveWe studied whether apathy in DBS-treated PD patients could be a stimulation effect.MethodsIn 26 PD patients we acquired apathy scores before and >6 months after DBS of the subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation) were performed ≥6 months after DBS placement. Change in apathy severity was correlated with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii) stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in functional connectivity of brain regions that have an alleged role in apathy.ResultsAverage apathy severity significantly increased after DBS (p < 0.001) and the number of patients considered apathetic increased from two to nine. Change in apathy severity did not correlate with improvement in motor function or dose reduction of dopaminergic medication. For the left hemisphere, increase in apathy was associated with a more dorsolateral stimulation location (p = 0.010). The increase in apathy severity correlated with a decrease in alpha1 functional connectivity of the dorsolateral prefrontal cortex (p = 0.006), but not with changes of the medial orbitofrontal or the anterior cingulate cortex.ConclusionsThe present observations suggest that apathy after STN-DBS is not necessarily related to dose reductions of dopaminergic medication, but may be an effect of the stimulation itself. This highlights the importance of determining optimal DBS settings based on both motor and non-motor symptoms.     

Effect of Deep Brain Stimulation of the ventromedial prefrontal cortex on the noradrenergic system in rats

Background

Deep Brain Stimulation (DBS) of the subgenual cingulate cortex (SCC) is a promising therapeutic alternative to treat resistant major depressive disorder. In preclinical studies, DBS of the ventromedial prefrontal cortex (vmPFC, the rodent SCC correlate) provokes an antidepressant-like effect, along with changes in noradrenaline levels at the site of stimulation. Hence, DBS appears to activate the noradrenergic-locus coeruleus (LC) system.

Biomarkers for Deep Brain Stimulation in Animal Models of Depression

ObjectivesDespite recent advances in depression treatment, many patients still do not respond to serial conventional therapies and are considered “treatment resistant.” Deep brain stimulation (DBS) has therapeutic potential in this context. This comprehensive review of recent studies of DBS for depression in animal models identifies potential biomarkers for improving therapeutic efficacy and predictability of conventional DBS to aid future development of closed-loop control of DBS systems.Materials and MethodsA systematic search was performed in Pubmed, EMBASE, and Cochrane Review using relevant keywords. Overall, 56 animal studies satisfied the inclusion criteria.ResultsOutcomes were divided into biochemical/physiological, electrophysiological, and behavioral categories. Promising biomarkers include biochemical assays (in particular, microdialysis and electrochemical measurements), which provide real-time results in awake animals. Electrophysiological tests, showing changes at both the target site and downstream structures, also revealed characteristic changes at several anatomic targets (such as the medial prefrontal cortex and locus coeruleus). However, the substantial range of models and DBS targets limits the ability to draw generalizable conclusions in animal behavioral models.ConclusionsOverall, DBS is a promising therapeutic modality for treatment-resistant depression. Different outcomes have been used to assess its efficacy in animal studies. From the review, electrophysiological and biochemical markers appear to offer the greatest potential as biomarkers for depression. However, to develop closed-loop DBS for depression, additional preclinical and clinical studies with a focus on identifying reliable, safe, and effective biomarkers are warranted.     

Tractography-Activation Models Applied to Subcallosal Cingulate Deep Brain Stimulation

Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCWM) is an experimental therapy for major depressive disorder (MDD). The specific axonal pathways that mediate the anti-depressant effects of DBS remain unknown. Patient-specific tractography-activation models (TAMs) are a new tool to help identify pathways modulated by DBS. TAMs consist of four basic components: 1) anatomical and diffusion-weighted imaging data acquired on the patient; 2) probabilistic tractography from the brain region surrounding the implanted DBS electrode; 3) finite element models of the electric field generated by the patient-specific DBS parameter settings; and 4) application of the DBS electric field to multi-compartment cable models of axons, with trajectories defined by the tractography, to predict action potential generation in specific pathways. This study presents TAM predictions from DBS of the SCCWM in one MDD patient. Our findings suggest that small differences in electrode location can generate substantial differences in the directly activated pathways.     

Anterior Cingulate Cortex in Addiction: New Insights for Neuromodulation

ObjectivesSubstance use disorder (SUD) is characterized by compulsive use of addictive substances with considerable impact on both the medical system and society as a whole. The craving of substances leads to relapse in the majority of patients within one year of traditional treatments. In recent decades, neuromodulation approaches have emerged as potential novel treatments of SUD, but the ideal neural target remains contentious.Materials and MethodsIn this review, we discuss new insights on the anterior cingulate cortex (ACC) as a neuromodulation target for SUD.Results and ConclusionFirst, we illustrate that the ACC serves as a central “hub” in addiction-related neural networks of cognitive functions, including, but not limited to, decision-making, cognitive inhibition, emotion, and motivation. Then, we summarize the literature targeting the ACC to treat SUDs via available neuromodulation approaches. Finally, we propose potential directions to improve the effect of stimulating the ACC in SUD treatment. We emphasize that the ACC can be divided into at least four sub-regions, which have distinctive functions and connections. Studies focusing on these sub-regions may help to develop more precise and effective ACC stimulation according to patients’ symptom profiles and cognitive deficits.     

Anatomical and fMRI-network comparison of multiple DLPFC targeting strategies for repetitive transcranial magnetic stimulation treatment of depression

BackgroundThe efficacy of repetitive transcranial magnetic stimulation (rTMS) for depression may vary depending on the subregion stimulated within the dorsolateral prefrontal cortex (DLPFC). Clinical TMS typically uses scalp-based landmarks for DLPFC targeting, rather than individualized MRI guidance.ObjectiveIn rTMS patients, determine the brain systems targeted by multiple DLPFC stimulation rules by computing several surrogate measures: underlying brain targets labeled with connectivity-based atlases, subgenual cingulate anticorrelation strength, and functionally connected networks.MethodsForty-nine patients in a randomized controlled trial of rTMS therapy for treatment resistant major depression underwent structural and functional MRI. DLPFC rules were applied virtually using MR-image guidance. Underlying cortical regions were labeled, and connectivity with the subgenual cingulate and whole-brain computed.ResultsScalp-targeting rules applied post hoc to these MRIs that adjusted for head size, including Beam F3, were comparably precise, successful in directly targeting classical DLPFC and frontal networks, and anticorrelated with the subgenual cingulate. In contrast, all rules involving fixed distances introduced variability in regions and networks targeted. The 5 cm rule targeted a transitional DLPFC region with a different connectivity profile from the adjusted rules. Seed-based connectivity analyses identified multiple regions, such as posterior cingulate and inferior parietal lobe, that warrant further study in order to understand their potential contribution to clinical response.ConclusionEEG-based rules consistently targeted DLPFC brain regions with resting-state fMRI features known to be associated with depression response. These results provide a bridge from lab to clinic by enabling clinicians to relate scalp-targeting rules to functionally connected brain systems.     

Stimulation therapeutic approaches to better understand Obsessive Compulsive Disorder: The issue of ‘where’ to treat

The use of invasive and non-invasive brain stimulation and neuromodulation technologies combined with neuroimaging approaches can help refine with causal evidence our physiopathological understanding of the Obsessive-Compulsive Disorder (OCD). Two key structures, the Orbitofrontal Cortex (OFC) and the Anterior Cingulate Cortex (ACC) have been found dysfunctional in OCD compared to healthy volunteers and on such basis have been tested as therapeutic targets for invasive and non-invasive neuromodulation therapy. Hereinafter, evidence addressing the cognitive processes subtended by to those two brain regions and their role in wider associated cortico-subcortical networks is reviewed. Very specifically, their relevance for OCD clinical features is discussed in extenso and its modulation with invasive and non-invasive focal brain stimulation such as deep brain stimulation (DBS) or transcranial magnetic Stimulation (TMS). Most importantly, this article brings new insights bridging causal evidence on the structural and functional neuroanatomy subtending OCD and novel therapeutic perspectives based on focal brain stimulation.     

Clinical trials for deep brain stimulation: Current state of affairs

BackgroundDeep brain stimulation (DBS) is a surgical neuromodulation procedure with a historically wide range of possible therapeutic indications, including movement disorders, neuropsychiatric conditions, and cognitive disorders. Ongoing research in this field is critical to gain further insights into the mechanisms of DBS, to discover novel brain targets for new and existing indications, and to refine targeting and post-operative programming techniques for the optimization of therapeutic outcomes.ObjectiveTo update on the state of DBS-related clinical human research by cataloging and summarizing clinical trials that have been completed or are currently ongoing in this field worldwide.MethodsA search was conducted for clinical trials pertaining to DBS, currently listed on the ClinicalTrials.gov database. Trials were analyzed to generate a detailed overview of ongoing DBS-related research. Specifically, trials were categorized by trial start date, study completion status, clinical phase, projected subject enrollment, disorder, brain target, country of origin, device manufacturer, funding source, and study topic.ResultsIn total, 384 relevant clinical trials were identified. The trials spanned 28 different disorders across 26 distinct brain targets, with almost 40% of trials being for conditions other than movement disorders. The majority of DBS trials have been US-based (41.9% of studies) but many countries are becoming increasingly active. The ratio of investigator-sponsored to industry-sponsored trials was 3:1. Emphasizing the need to better understand the mechanism of action of DBS, one-third of the studies predominantly focus on imaging or electrophysiological changes associated with DBS.ConclusionsThis overview of current DBS-related clinical trials provides insight into the status of DBS research and what we can anticipate in the future concerning new brain targets, indications, techniques, and developing a better understanding of the mechanisms of action of DBS.     

Consistent linear and non-linear responses to invasive electrical brain stimulation across individuals and primate species with implanted electrodes

BackgroundElectrical neuromodulation via implanted electrodes is used in treating numerous neurological disorders, yet our knowledge of how different brain regions respond to varying stimulation parameters is sparse.Objective/HypothesisWe hypothesized that the neural response to electrical stimulation is both region-specific and non-linearly related to amplitude and frequency.MethodsWe examined evoked neural responses following 400 ms trains of 10–400 Hz electrical stimulation ranging from 0.1 to 10 mA. We stimulated electrodes implanted in cingulate cortex (dorsal anterior cingulate and rostral anterior cingulate) and subcortical regions (nucleus accumbens, amygdala) of non-human primates (NHP, N = 4) and patients with intractable epilepsy (N = 15) being monitored via intracranial electrodes. Recordings were performed in prefrontal, subcortical, and temporal lobe locations.ResultsIn subcortical regions as well as dorsal and rostral anterior cingulate cortex, response waveforms depended non-linearly on frequency (Pearson's linear correlation r < 0.39), but linearly on current (r > 0.58). These relationships between location, and input-output characteristics were similar in homologous brain regions with average Pearson's linear correlation values r > 0.75 between species and linear correlation values between participants r > 0.75 across frequency and current values per brain region. Evoked waveforms could be described by three main principal components (PCs) which allowed us to successfully predict response waveforms across individuals and across frequencies using PC strengths as functions of current and frequency using brain region specific regression models.ConclusionsThese results provide a framework for creation of an atlas of input-output relationships which could be used in the principled selection of stimulation parameters per brain region.