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OBJECTIVE To obtain individual clinical and neuroimaging data of patients undergoing Deep Brain Stimulation for essential tremor from five different European centers to identify predictors of outcome and to identify an optimal stimulation site. METHODS We analysed retrospectively baseline covariates, pre- and postoperative clinical tremor scores (12-month) as well as individual imaging data from 119 patients to obtain individual electrode positions and stimulation volumes. Individual imaging and clinical data was used to calculate a probabilistic stimulation map in normalized space using voxel-wise statistical analysis. Finally, we used this map to train a classifier to predict tremor improvement. RESULTS Probabilistic mapping of stimulation effects yielded a statistically significant cluster that was associated with a tremor improvement greater than 50%. This cluster of optimal stimulation extended from the posterior subthalamic area to the ventralis intermedius nucleus and coincided with a normative structural-connectivity-based cerebello-thalamic tract (CTT). The combined features "distance between the stimulation volume and the significant cluster" and "CTT activation" were used as a predictor of tremor improvement. This correctly classified a greater than 50% tremor improvement with a sensitivity of 89% and a specificity of 57%. INTERPRETATION Our multicentre ET probabilistic stimulation map identified an area of optimal stimulation along the course of the CTT. The results of this study are mainly descriptive until confirmed in independent datasets, ideally through prospective testing. This target will be made openly available and may be used to guide surgical planning and for computer-assisted programming of deep brain stimulation in the future. This article is protected by copyright. All rights reserved.

The field of neurostimulation for the treatment of chronic pain is a rapidly developing area of medicine. Although neurostimulation therapies have advanced significantly as a result of technologic improvements, surgical planning, device placement, and postoperative care are of equal importance to optimize outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for these often-overlooked areas of neurostimulation practice.Authors were chosen based on their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from the last NACC publication in 2017 to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on evidence strength and consensus when evidence was scant.This NACC project provides guidance on preoperative assessment, intraoperative techniques, and postoperative management in the form of consensus points with supportive evidence. These results are based on grade of evidence, strength of consensus, and expert opinion.The NACC has given guidance for a surgical plan that encompasses the patient journey from the planning stage through the surgical experience and postoperative care. The overall recommendations are designed to improve efficacy and the safety of patients undergoing these neuromodulation procedures and are intended to apply throughout the international community.

Background Dorsal root ganglion (DRG) stimulation, an invasive method of neuromodulation, and transcranial direct current stimulation (tDCS), a non-invasive method of altering cortical excitability, have both proven effective in relieving chronic pain. Objective We employed a randomized, sham-controlled crossover study design to investigate whether single-session tDCS would have an additive therapeutic effect alongside DRG stimulation (DRGS) in the treatment of chronic pain. Methods Sixteen neuropathic pain patients who were previously implanted with DRG stimulators were recruited. Baseline pain scores were established with DRGS-OFF. Pain scores were then recorded with DRGS-ON, after paired sham tDCS stimulation, and after paired active anodal tDCS (a-tDCS) stimulation. For active tDCS, patients were randomized to ‘MEG (magnetoencephalography) localized’ tDCS or contralateral motor cortex (M1) tDCS for 30 min. EEG recordings and evaluations of tDCS adverse effects were also collected. Results All participants reported the interventions to be tolerable with no significant adverse effects during the session. Paired DRGS/active tDCS resulted in a significant reduction in pain scores compared to paired DRGS-ON/sham tDCS or DRGS alone. There was no difference in the additive effect of M1 vs. MEG-localized tDCS. Significant augmentation of beta activity was observed between DRGS-OFF and DRGS-ON conditions, as well as between paired DRGS-ON/sham tDCS and paired DRGS-ON/active tDCS. Conclusion Our results indicate that a single session of tDCS alongside DRGS is safe and can significantly reduce pain acutely in neuropathic pain patients. Paired invasive/non-invasive neuromodulation is a promising new treatment strategy for pain management and should be evaluated further to assess long-term benefits.

Cancer pain is common and challenging to manage - it is estimated that approximately 30% of cancer patients have pain that is not adequately controlled by analgesia. This paper discusses safe and effective neuroablative treatment options for refractory cancer pain. Current management of cancer pain predominantly focuses on the use of medications, resulting in a relative loss of knowledge of these surgical techniques and the erosion of the skills required to perform them. Here, we review surgical methods of modulating various points of the neural axis with the aim to expand the knowledge base of those managing cancer pain. Integration of neuroablative approaches may lead to higher rates of pain relief, and the opportunity to dose reduce analgesic agents with potential deleterious side effects. With an ever-increasing population of cancer patients, it is essential that neurosurgeons maintain or train in these techniques in tandem with the oncological multi-disciplinary team.

BackgroundIn Essential tremor (ET), involuntary shaking of the upper limbs during isometric muscle contraction closely reflects the patterns of neural activity measured in the thalamus - a key element of the tremorgenic circuit. Phase-specific deep brain stimulation (DBS) builds upon this observation while using accelerometery of the trembling limb to trigger repetitive electrical perturbations to the thalamus and surrounding areas at a specific time within the tremor cycle. This closed-loop strategy has been shown to induce clinically significant postural tremor relief while delivering less than half the energy of conventional DBS.ObjectiveThe main aim of the study was to evaluate treatment efficacy across different contexts and movement states.MethodsWe used accelerometery and a digitizing tablet to record the peripheral tremor dynamics of 4 DBS implanted ET patients while alternating stimulation strategies (no stimulation, continuous open-loop and phase-specific) and movement states (intermittent posture holding and spiral drawing).ResultsIn addition to observing a suppressive effect of phase-specific DBS on both postural and kinetic tremor, our results reinforce the key role of phase-specificity to achieve tremor control in postural motor states and highlight the difficulty of quantifying phase-dependent effects during continuous movement. Moreover, this study supports the hypothesis that ET patients with more stable tremor characteristics benefit the most from phase-specific DBS.ConclusionsBy creating a better understanding of the dynamic relationship between central and peripheral tremor activity, this study provides important insights for the development of effective patient and context-specific therapeutic approaches for ET.

Visual Abstract, Highlights • DRGS at upper lumbar levels significantly reduces sympathetic nerve firing • Reduction in sympathetic activity appears to be independent to pain relief • DRGS significantly reduced BP at 6 months and 2 years • BP reduction was lateralized to DRGS on the left side • Three refractory hypertensives became normotensive after chronic stimulation., Summary This study hypothesized that dorsal root ganglion (DRG) stimulation would reduce sympathetic nerve activity and would alter hemodynamic variables. This study directly recorded muscle sympathetic nerve activity during ON and OFF stimulation of the DRG while measuring hemodynamic parameters. DRG stimulation significantly reduced the firing frequency of sympathetic nerves, as well as significantly reducing blood pressure, with greater reductions evident when stimulation was left-sided. Left-sided DRG stimulation lowers sympathetic nerve activity, leading to long-term phenotypic changes. This raises the potential of DRG stimulation being used to treat de novo autonomic disorders such as hypertension or heart failure.

Objective Deep brain stimulation (DBS) is a treatment option for refractory chronic cluster headache (CCH). Despite several recent prospective case series reporting a good outcome, the effectiveness and the optimal stimulation target of DBS for CCH remain unclear. We aimed to obtain precise estimates and predictors of long-term pain relief in an individual patient data meta-analysis. Furthermore, we aimed to construct a probabilistic stimulation map of effective DBS. Methods We invited investigators of published cohorts of patients undergoing DBS for CCH, identified by a systematic review of MEDLINE from inception to Febuary 15, 2019, to provide individual patient data on baseline covariates, pre- and postoperative headache scores at median (12-month) and long-term follow-up, in addition to individual imaging data to obtain individual electrode positions. We calculated a stimulation map using voxel-wise statistical analysis. We used multiple regression analysis to estimate predictors of pain relief. Results Among 40 patients from four different cohorts representing ~50% of all previously published cases, we found a significant 77% mean reduction in headache attack frequency over a mean follow-up of 44 months, with an overall response rate of 75%. Positive outcome was not associated with baseline covariates. We identified 2 hotspots of stimulation covering the midbrain ventral and retrorubral tegmentum. Interpretation This study supports the hypothesis that DBS provides long-term pain relief for the majority of CCH patients. Our stimulation map of the region of influence of therapeutic DBS identified an optimal anatomical target site that can help surgeons to guide their surgical planning in the future. ANN NEUROL 2020;88:956-969.

The practice of surgical intervention for the treatment of psychiatric disorders has a rich and fascinating history. Arguably dating back to more than 7 millennia ago, neurosurgery for psychiatric disease is shrouded in stigma, being widely portrayed in the media (almost invariably negatively). The first such procedure to be performed in modern history was conducted by the Swiss psychiatrist Gottlieb Burckhardt in 1882. The landscape of neurosurgery for psychiatric conditions has shifted constantly since, guided by new developments in neuroscience and surgical technology. In this article, we outline the salient events in the story of this field.

Neural oscillatory activities in basal ganglia have prominent roles in cognitive processes on local and global scales. However, the characteristics of high frequency oscillatory activities during cognitive tasks have not been extensively explored in human Globus Pallidus internus (GPi). This study aimed to investigate amplitude and interhemispheric coupling of bilateral GPi high gamma bursts in dystonia and Parkinson’s Disease (PD) patients, in on and off medication states, after feedback during the Intra-Extra-Dimension shift (IED) task. Bilateral GPi Local Field Potentials (LFP) activity was recorded via externalized DBS electrodes during the IED task. Inter hemisphere phase synchrony was assessed using Inter-Site Phase Clustering (ISPC). Transient high gamma activity (∼100-150Hz) was observed immediately after feedback in the dystonia patient. Moreover, these bursts were phase synchronous between left and right GPis with an antiphase clustering of phase differences. In contrast, no synchronous high gamma activity was detected in the PD patient with or without dopamine administration. The off-med PD patient displayed enhanced low frequency clusters ameliorated by medication in the on-med state. Furthermore, an increased low frequency activity was observed after feedback of incorrect trials in both disease states. The current study provides a rare report of antiphase homotopic synchrony in human GPi, potentially related to incorporating and processing feedback information. The absence of these activities in off and on-med PD indicates the potential presence of impaired medication independent circuits related to feedback processing. Together, these findings are helpful in pointing to the potential role of GPi’s synchronized high frequency activity in cognitive tasks and feedback information processing.

Graphical abstract, Highlights • The PAG/PVG carries out its biology function by oscillatory network. • Three distinct local networks of oscillations involved in pain perception, sensory and affective. • The delta oscillation is a key hub for coding pain perception. • The high-gamma oscillation is a key hub for coding sensory pain., The periventricular/periaqueductal gray (PAG/PVG) is critical for pain perception and is associated with the emotional feelings caused by pain. However, the electrophysiological characteristics of the PAG/PVG have been little investigated in humans with chronic pain. The present study analyzed the oscillatory characteristics of local field potentials (LFPs) in the PAG/PVG of eighteen neuropathic pain patients. Power spectrum analysis and neural state analysis were applied to the PAG/PVG LFPs. Neural state analysis is based on a dynamic neural state identification approach and discriminates the LFPs into different neural states, including a single neural state based on one oscillation and a combinational neural state based on two paired oscillations. The durations and occurrence rates were used to quantify the dynamic features of the neural state. The results show that the combined neural state forms three local networks based on neural oscillations that are responsible for the perceptive, sensory, and affective components of pain. The first network is formed by the interaction of the delta oscillation with other oscillations and is responsible for the coding of pain perception. The second network is responsible for the coding of sensory pain information, uses high gamma as the main node, and is widely connected with other neural oscillations. The third network is responsible for the coding of affective pain information, and beta oscillations play an important role in it. This study suggested that the combination of two neural oscillations in the PAG/PVG is essential for encoding perceptive, sensory, and affective measures of pain.

Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson’s disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = −0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.

Objectives: Dorsal root ganglion stimulation (DRGS) has become a popular neuromodulatory treatment for neuropathic pain. We used magnetoencephalography (MEG) to investigate potential biomarkers of pain and pain relief, based on the differences in power spectral density (PSD) during varying degrees of pain and how these oscillations change during DRGS-mediated pain relief. Materials and Methods: Thirteen chronic pain patients with implanted dorsal root ganglion stimulators were included in the MEG analysis. MEG Recordings were performed at rest while the stimulator was turned ON or OFF. Numerical rating scale (NRS) scores were also recorded before and after DRGS was turned OFF and ON. Power spectral and source localization analyses were then performed on preprocessed MEG recordings. Results: With DRGS-OFF, patients in severe pain had significantly increased cortical theta (4–7 Hz) power and decreased cortical alpha (7–13 Hz) power compared to patients reporting less pain. This shift in power toward lower frequencies was contrasted by a shift toward the higher frequency power spectrum (low beta 13–20 Hz activity) during DRGS-mediated pain relief. A significant correlation was found between the increase in low beta activity and the degree of reported pain relief. Conclusion: Our results demonstrate increased low-frequency power spectral activity in chronic pain patients in the absence of stimulation which shifts toward higher frequency power spectrum activity in response to therapeutic DRGS. These cortical changes in response to DRGS provide support for the use of neuroimaging in the search for potential biomarkers of pain.

Background: The subthalamic nucleus (STN) is a common target for deep brain stimulation (DBS) in Parkinson’s disease (PD) and is believed to serve a role in sensorimotor integration. In addition to therapeutic neuromodulation, DBS facilitates the recording of local-field potentials (LFPs) in order to further understand the neurophysiological basis of disease. The capacity to wirelessly transmit these signals in real time has overcome the obstacle of externalization of electrodes during LFP recordings. Objective: Using the G102RS device (PINS Medical, China), we investigated the LFP changes in response to mechanical pain stimulation to further elucidate the representation of pain sensation in the basal ganglia. Methods: LFPs from 2 patients who had undergone bilateral STN-DBS were wirelessly recorded during no stimulation, low-frequency stimulation (60 and 90 Hz), and high-frequency stimulation (130 and 150 Hz) while introducing painful and nonpainful stimuli. Power spectral analysis was conducted to compare the changes in β frequency (13–30 Hz) during each stimulus. Results: During painful stimuli, STN power spectra (n = 4) revealed a significant increase in β activity compared to non-painful and no-stimulus epochs. Both low- and high-frequency stimulation produced a significant decrease in pain-related β activity. Conclusion: These 2 cases have demonstrated the potential for acute noxious stimuli to exacerbate pathologic β oscillatory activity in the STN. Our findings represent novel evidence of the neurophysiologic representation of pain in the STN of PD patients.

Deep brain stimulation (DBS) of single-target nuclei has produced remarkable functional outcomes in a number of movement disorders such as Parkinson’s disease, essential tremor, and dystonia. While these benefits are well established, DBS efficacy and strategy for unusual, unclassified movement disorder syndromes is less clear. A strategy of dual pallidal and thalamic electrode placement is a rational approach in such cases where there is profound, medically refractory functional impairment. The authors report a series of such cases: midbrain cavernoma hemorrhage with olivary hypertrophy, spinocerebellar ataxia-like disorder of probable genetic origin, Holmes tremor secondary to brainstem stroke, and hemiballismus due to traumatic thalamic hemorrhage, all treated by dual pallidal and thalamic DBS. All patients demonstrated robust benefit from DBS, maintained in long-term follow-up. This series demonstrates the flexibility and efficacy, but also the limitations, of dual thalamo-pallidal stimulation for managing axial and limb symptoms of tremors, dystonia, chorea, and hemiballismus in patients with complex movement disorders.

Indirect targeting of the Ventralis Intermedius Nucleus (Vim) is widely used for functional neurosurgical procedures to treat essential tremor (ET). Here, we review if the laterality of the Vim depends on the diameter of the third ventricle and if a targeting approach that incorporates this correlation can facilitate targeting and yields accurate lead placement. We analyzed 15 consecutive ET patients. Vim targeting was adapted according to the width of the third ventricle and the lateral distance to the internal capsule (IC). Postoperative outcome was assessed 12 months post-OP based on the Bain-Findley score. Application of this targeting approach resulted in mean target coordinates of LAT 12.8 ± 1.5; AP −3.6 ± 1.0 and VERT 0 ± 0 mm and which projected onto the Vim. The laterality of IC and Vim are correlated to the width of the third ventricle. The mean postoperative tremor reduction was 63.0%. In summary, adjusting the lateral coordinate according to the width of the third ventricle leads to accurate targeting and effective tremor reduction.

Understanding the functional dynamics of neural oscillations in the sensory thalamus is essential for elucidating the perception and modulation of neuropathic pain. Local field potentials were recorded from the sensory thalamus of twelve neuropathic pain patients. Single and combinational neural states were defined by the activity state of a single or paired oscillations. Relationships between the duration or occurrence rate of neural state and pre-operative pain level or pain relief induced by deep brain stimulation were evaluated. Results showed that the occurrence rate of the single neural state of low-beta oscillation was significantly correlated with pain relief. The duration and occurrence rate of combinational neural states of the paired low-beta with delta, theta, alpha, high-beta or low-gamma oscillations were more significantly correlated with pain relief than the single neural states. Moreover, these significant combinational neural states formed a local oscillatory network with low-beta oscillation as a key node. The results also showed correlations between measures of combinational neural states and subjective pain level as well. The duration of combinational neural states of paired alpha with delta or theta oscillations and the occurrence rate of neural states of the paired delta with low-beta or low-gamma oscillations were significantly correlated with pre-operative pain level. In conclusion, this study revealed that the integration of oscillations and the functional dynamics of neural states were differentially involved in modulation and perception of neuropathic pain. The functional dynamics could be biomarkers for developing neural state-dependent deep brain stimulation for neuropathic pain.

Purpose Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result in changes in autonomic performance. Methods To determine whether pedunculopontine nucleus stimulation improves cardiovascular responses to autonomic challenges of postural tilt and Valsalva manoeuver, eight patients with pedunculopontine nucleus deep brain stimulation were recruited to the study; two were excluded for technical reasons during testing. Participants underwent head up tilt and Valsalva manoeuver with stimulation turned ON and OFF. Continuous blood pressure and ECG waveforms were recorded during these tests. In a single patient, local field potential activity was recorded from the implanted electrode during tilt. Results The fall in systolic blood pressure after tilt was significantly smaller with stimulation ON (mean − 8.3% versus − 17.2%, p = 0.044). Valsalva ratio increased with stimulation from median 1.15 OFF to 1.20 ON (p = 0.028). Baroreflex sensitivity increased during Valsalva compared to rest with stimulation ON versus OFF (p = 0.028). The increase in baroreflex sensitivity correlated significantly with the mean depth of PPN stimulating electrode contacts. This accounted for 89% of its variance (r = 0.943, p = 0.005). Conclusion PPN stimulation can modulate the cardiovascular system in patients with PD. In this study, it reduced the postural fall in systolic blood pressure during head-up tilt and improved the cardiovascular response during Valsalva, presumably by altering the neural control of baroreflex activation.

Beta power suppression in the basal ganglia is stronger during movements that require high force levels and high movement effort but it has been difficult to dissociate the two. We recorded scalp EEG and basal ganglia local field potentials in Parkinson's disease patients (11 STN, 7 GPi) ON and OFF dopaminergic medication while they performed a visually-guided force matching task using a pen on a force-sensitive graphics tablet. Force adjustments were accompanied by beta power suppression irrespective of whether the force was increased or reduced. Before the adjustment was completed, beta activity returned. High beta power was specifically associated with slowing of the force adjustment. ON medication, the peak force rate was faster and cortico-basal ganglia beta phase coupling was more readily modulated. In particular, phase decoupling was stronger during faster adjustments. The results suggest that beta power in the basal ganglia does not covary with force per se, but rather with a related factor, the absolute force rate, or a more general concept of movement effort. The results also highlight that beta activity reappears during stabilization of isometric contractions, and that dopamine-related suppression of cortico-basal ganglia beta coupling is linked to faster force adjustments.

OBJECTIVES: Minimally conscious state (MCS) is a disorder of consciousness in which minimal but definite behavioral evidence of self-awareness or environmental awareness is demonstrated. Deep brain stimulation (DBS) of various targets has been used to promote recovery in patients with disorders of consciousness with varying results. The aim of this systematic review was to assess the effects of DBS in MCS following traumatic brain injury (TBI). MATERIALS AND METHODS: A systematic literature review was carried out using a number of electronic bibliographic data bases to identify relevant studies. We included all studies describing applications of DBS on patients in MCS following TBI. RESULTS: Eight studies were identified, including a total of ten patients, aged 15-58 years. The time from injury to stimulation ranged from 3 to 252 months, with the duration of follow-up post-DBS ranging from 10 to 120 months. Seven patients improved their postsurgical outcome score measures (three patients with the coma recovery scale, one with the near coma scale, and three with the Glasgow outcome score). A descriptive favorable outcome was reported in one patient. Two patients were reported not to have shown any improvements following the intervention. CONCLUSIONS: Current evidence is based on a small population of heterogeneous patients. The time from injury to stimulation was significantly variable and problematic, as spontaneous recovery can occur within the first year of injury. Although seven patients showed promising results in validated outcome measures, evidence supporting the use of DBS in MCS patients following TBI is lacking. There is need for controlled and randomized studies.

Objective Respiratory abnormalities such as upper airway obstruction are common in Parkinson's disease (PD) and are an important cause of mortality and morbidity. We tested the effect of pedunculopontine region (PPNr) stimulation on respiratory maneuvers in human participants with PD, and separately recorded PPNr neural activity reflected in the local field potential (LFP) during these maneuvers. Methods Nine patients with deep brain stimulation electrodes in PPNr, and seven in globus pallidus interna (GPi) were studied during trials of maximal inspiration followed by forced expiration with stimulation OFF and ON. Local field potentials (LFPs) were recorded in the unstimulated condition. Results PEFR increased from 6.41 ± 0.63 L/sec in the OFF stimulation state to 7.5 L ± 0.65 L/sec in the ON stimulation state (z = −2.666, df = 8, P = 0.024). Percentage improvement in PEFR was strongly correlated with proximity of the stimulated electrode contact to the mesencephalic locomotor region in the rostral PPN (r = 0.814, n = 9, P = 0.008). Mean PPNr LFP power increased within the alpha band (7–11 Hz) during forced respiratory maneuvers (1.63 ± 0.16 μV2/Hz) compared to resting breathing (0.77 ± 0.16 μV2/Hz; z = −2.197, df = 6, P = 0.028). No changes in alpha activity or spirometric indices were seen with GPi recording or stimulation. Percentage improvement in PEFR was strongly positively correlated with increase in alpha power (r = 0.653, n = 14 (7 PPNr patients recorded bilaterally), P = 0.0096). Interpretation PPNr stimulation in PD improves indices of upper airway function. Increased alpha‐band activity is seen within the PPNr during forced respiratory maneuvers. Our findings suggest a link between the PPNr and respiratory performance in PD.

Objective We present long-term follow-up results and analysis of stimulation sites of a prospective cohort study of six patients with chronic cluster headaches undergoing deep brain stimulation of the ipsilateral posterior hypothalamic region. Methods The primary endpoint was the postoperative change in the composite headache severity score “headache load” after 12 months of chronic stimulation. Secondary endpoints were the changes in headache attack frequency, headache attack duration and headache intensity, quality of life measures at 12, 24, and 48 months following surgery. Stimulating contact positions were analysed and projected onto the steroetactic atlas of Schaltenbrand and Wahren. Results There was a significant reduction of headache load of over 93% on average at 12 months postoperatively that persisted over the follow-up period of 48 months ( p = 0.0041) and that was accompanied by a significant increase of reported quality of life measures ( p = 0.03). Anatomical analysis revealed that individual stimulating electrodes were located in the red nucleus, posterior hypothalamic region, mesencephalic pretectal area and centromedian nucleus of the thalamus. Conclusions Our findings confirming long-term effectiveness of deep brain stimulation for chronic cluster headaches suggest that the neuroanatomical substrate of deep brain stimulation-induced headache relief is probably not restricted to the posterior hypothalamic area but encompasses a more widespread area.