Differential responses to breath-holding, voluntary deep breathing and hypercapnia in left and right dorsal anterior cingulate.

NEW FINDINGS: What is the central question of this study? What is the role of dorsal anterior cingulate cortex (ACC) in respiration control in humans? What is the main finding and its importance? Direct evidence is provided for a role of the ACC in respiratory control in humans. The neurophysiological responses in dorsal ACC to different breathing tasks varied and were different between left and right ACC. ABSTRACT: The role of subcortical structures and cerebral cortex in the maintenance of respiratory homeostasis in humans remains poorly understood. Emerging evidence suggests an important role of the anterior cingulate cortex (ACC) in respiratory control. In this study, local field potentials (LFPs) from dorsal ACC were recorded in humans through implanted deep brain electrodes during several breathing activities, including voluntary activities of breath-holding and deep breathing, and involuntary activities of inspiration of varying concentrations of carbon dioxide (1%, 3%, 5% and 7%). We found that the breath-holding task induced significant unilateral left-sided ACC changes in LFP power, including an increased activity in lower frequency bands (3-5 Hz) and decreased activity in higher frequency bands (12-26 Hz). The respiratory task involving reflex increase in ventilation due to hypercapnia (raised inspired CO2 ) was associated with bilateral changes in activity of the ACC (again with increased activity in lower frequency bands and reduced activity in higher frequency bands). The voluntary breathing task with associated hypocapnia (deep breathing) induced bilateral changes in activity within low frequency bands. Furthermore, probabilistic diffusion tractography analysis showed left-sided connection of the ACC with the insula and frontal operculum, and bilateral connections within subsections of the cingulate gyrus and the thalamus. This electrophysiological analysis provides direct evidence for a role of the ACC in respiratory control in humans.

Dorsal Anterior Cingulate Cortices Differentially Lateralize Prediction Errors and Outcome Valence in a Decision-Making Task.

The dorsal anterior cingulate cortex (dACC) is proposed to facilitate learning by signaling mismatches between the expected outcome of decisions and the actual outcomes in the form of prediction errors. The dACC is also proposed to discriminate outcome valence-whether a result has positive (either expected or desirable) or negative (either unexpected or undesirable) value. However, direct electrophysiological recordings from human dACC to validate these separate, but integrated, dimensions have not been previously performed. We hypothesized that local field potentials (LFPs) would reveal changes in the dACC related to prediction error and valence and used the unique opportunity offered by deep brain stimulation (DBS) surgery in the dACC of three human subjects to test this hypothesis. We used a cognitive task that involved the presentation of object pairs, a motor response, and audiovisual feedback to guide future object selection choices. The dACC displayed distinctly lateralized theta frequency (3-8 Hz) event-related potential responses-the left hemisphere dACC signaled outcome valence and prediction errors while the right hemisphere dACC was involved in prediction formation. Multivariate analyses provided evidence that the human dACC response to decision outcomes reflects two spatiotemporally distinct early and late systems that are consistent with both our lateralized electrophysiological results and the involvement of the theta frequency oscillatory activity in dACC cognitive processing. Further findings suggested that dACC does not respond to other phases of action-outcome-feedback tasks such as the motor response which supports the notion that dACC primarily signals information that is crucial for behavioral monitoring and not for motor control.

Unexpected Complications of Novel Deep Brain Stimulation Treatments: Ethical Issues and Clinical Recommendations.

BACKGROUND: Innovative neurosurgical treatments present a number of known risks, the natures and probabilities of which can be adequately communicated to patients via the standard procedures governing obtaining informed consent. However, due to their novelty, these treatments also come with unknown risks, which require an augmented approach to obtaining informed consent. OBJECTIVE: This paper aims to discuss and provide concrete procedural guidance on the ethical issues raised by serious unexpected complications of novel deep brain stimulation treatments. APPROACH: We illustrate our analysis using a case study of the unexpected development of recurrent stereotyped events in patients following the use of deep brain stimulation (DBS) to treat severe chronic pain. Examining these unexpected complications in light of medical ethical principles, we argue that serious complications of novel DBS treatments do not necessarily make it unethical to offer the intervention to eligible patients. However, the difficulty the clinician faces in determining whether the intervention is in the patient's best interests generates reasons to take extra steps to promote the autonomous decision making of these patients. CONCLUSION AND RECOMMENDATIONS: We conclude with clinical recommendations, including details of an augmented consent process for novel DBS treatment.

Long-Term Results of Deep Brain Stimulation of the Anterior Cingulate Cortex for Neuropathic Pain.

BACKGROUND: Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a recent technique that has shown some promising short-term results in patients with chronic refractory neuropathic pain. Three years after the first case series, we assessed its efficacy on a larger cohort, with longer follow-up. METHODS: Twenty-four patients (19 males; average age, 49.1 years) with neuropathic pain underwent bilateral ACC DBS. Patient-reported outcome measures were collected before and after surgery, using the Numerical Rating Scale (NRS), Short-Form 36 quality of life (SF-36), McGill Pain Questionnaire (MPQ), and EuroQol 5-domain quality of life (EQ-5D) questionnaire. RESULTS: Twenty-two patients after a trial week were fully internalized and 12 had a mean follow-up of 38.9 months. Six months after surgery the mean NRS score decreased from 8.0 to 4.27 (P = 0.004). There was a significant improvement in the MPQ (mean, -36%; P = 0.021) and EQ-5D score significantly decreased (mean, -21%; P = 0.036). The physical functioning domain of SF-36 was significantly improved (mean, +54.2%; P = 0.01). Furthermore, in 83% of these patients, at 6 months, NRS score was improved by 60% (P < 0.001) and MPQ decreased by 47% (P < 0.01). After 1 year, NRS score decreased by 43% (P < 0.01), EQ-5D was significantly reduced (mean, -30.8; P = 0.05) and significant improvements were also observed for different domains of the SF-36. At longer follow-ups, efficacy was sustained up to 42 months in some patients, with an NRS score as low as 3. CONCLUSIONS: Follow-up results confirm that ACC DBS alleviates chronic neuropathic pain refractory to pharmacotherapy and improves quality of life in many patients.

Post-Traumatic Tremor and Thalamic Deep Brain Stimulation: Evidence for Use of Diffusion Tensor Imaging.

BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment to reduce tremor, notably in Parkinson disease. DBS may also be effective in post-traumatic tremor, one of the most common movement disorders caused by head injury. However, the cohorts of patients often have multiple lesions that may impact the outcome depending on which fiber tracts are affected. CASE DESCRIPTION: A 20-year-old man presented after road traffic accident with severe closed head injury and polytrauma. Computed tomography scan showed left frontal and basal ganglia hemorrhagic contusions and intraventricular hemorrhage. A disabling tremor evolved in step with motor recovery. Despite high-intensity signals in the intended thalamic target, a visual analysis of the preoperative diffusion tensor imaging revealed preservation of connectivity of the intended target, ventralis oralis posterior thalamic nucleus (VOP). This was confirmed by the postoperative tractography study presented here. DBS of the VOP/zona incerta was performed. Six months postimplant, marked improvement of action (postural, kinetic, and intention) tremor was achieved. CONCLUSIONS: We demonstrated a strong connectivity between the VOP and the superior frontal gyrus containing the premotor cortex and other central brain areas responsible for movement control. In spite of an existing lesion in the target, the preservation of these tracts may be relevant to the improvement of the patient's symptoms by DBS.

Brainjacking: Implant Security Issues in Invasive Neuromodulation.

The security of medical devices is critical to good patient care, especially when the devices are implanted. In light of recent developments in information security, there is reason to be concerned that medical implants are vulnerable to attack. The ability of attackers to exert malicious control over brain implants ("brainjacking") has unique challenges that we address in this review, with particular focus on deep brain stimulation implants. To illustrate the potential severity of this risk, we identify several mechanisms through which attackers could manipulate patients if unauthorized access to an implant can be achieved. These include blind attacks in which the attacker requires no patient-specific knowledge and targeted attacks that require patient-specific information. Blind attacks include cessation of stimulation, draining implant batteries, inducing tissue damage, and information theft. Targeted attacks include impairment of motor function, alteration of impulse control, modification of emotions or affect, induction of pain, and modulation of the reward system. We also discuss the limitations inherent in designing implants and the trade-offs that must be made to balance device security with battery life and practicality. We conclude that researchers, clinicians, manufacturers, and regulatory bodies should cooperate to minimize the risk posed by brainjacking.

Tractography Study of Deep Brain Stimulation of the Anterior Cingulate Cortex in Chronic Pain: Key to Improve the Targeting.

BACKGROUND: Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a new treatment for alleviating intractable neuropathic pain. However, it fails to help some patients. The large size of the ACC and the intersubject variability make it difficult to determine the optimal site to position DBS electrodes. The aim of this work was therefore to compare the ACC connectivity of patients with successful versus unsuccessful DBS outcomes to help guide future electrode placement. METHODS: Diffusion magnetic resonance imaging (dMRI) and probabilistic tractography were performed preoperatively in 8 chronic pain patients (age 53.4 ± 6.1 years, 2 females) with ACC DBS, of whom 6 had successful (SO) and 2 unsuccessful outcomes (UOs) during a period of trialing. RESULTS: The number of patients was too small to demonstrate any statistically significant differences. Nevertheless, we observed differences between patients with successful and unsuccessful outcomes in the fiber tract projections emanating from the volume of activated tissue around the electrodes. A strong connectivity to the precuneus area seems to predict unsuccessful outcomes in our patients (UO: 160n/SO: 27n), with (n), the number of streamlines per nonzero voxel. On the other hand, connectivity to the thalamus and brainstem through the medial forebrain bundle (MFB) was only observed in SO patients. CONCLUSIONS: These findings could help improve presurgical planning by optimizing electrode placement, to selectively target the tracts that help to relieve patients' pain and to avoid those leading to unwanted effects.

In vivo siRNA distribution and pharmacokinetics assessed by nuclear imaging are modulated according to radiolabelling site.

INTRODUCTION: RNA interference is efficient in in vitro studies, and appears as a therapeutic tool of major clinical interest. Nevertheless, the clinical utilisation of siRNAs is restrained by the poor availability of biodistribution data on this new class of pharmaceutics. This study aimed at defining the biodistribution and pharmacokinetics properties of an siRNA directed to the Casein Kinase-2 beta (CK2ß) subunit, a potential target in cancer therapy. METHODS: Four CK2ß siRNAs were chemically modified on each extremity of sense or anti-sense strand and radioiodinated. The biodistribution of each entity was analysed in glioblastoma-bearing mice using nuclear imaging and compared to a control GFP siRNA. RESULTS: The labelling process was associated with preservation of interference activity, except when applied to the 5' antisense terminus. Radioactivity was predominantly observed in organs of the excretory system after intravenous administration: liver, kidneys and bladder. Tumor/Contralateral muscle ratio showed significant differences depending on the labelling site. Activity associated with CK2ß5's was quite constant over 2 hours, while CK2ß3'as activity decreased by 40% in tumor. Finally, synchrotron X-ray analysis showed that CK2ß3's is more abundant in tumor than in liver, brain or muscle, and uniformly distributed between intra- and extracellular compartments. CONCLUSIONS: In this study, we highlighted the large influence of siRNAs radiolabelling position on their biodistribution and pharmacokinetic profiles, and proposed a systematic approach for the imaging of all siRNAs of clinical interest.

Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study.

Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition.

Deep brain stimulation for chronic pain.

Deep brain stimulation (DBS) is a neurosurgical intervention popularised in movement disorders such as Parkinson's disease, and also reported to improve symptoms of epilepsy, Tourette's syndrome, obsessive compulsive disorders and cluster headache. Since the 1950s, DBS has been used as a treatment to relieve intractable pain of several aetiologies including post stroke pain, phantom limb pain, facial pain and brachial plexus avulsion. Several patient series have shown benefits in stimulating various brain areas, including the sensory thalamus (ventral posterior lateral and medial), the periaqueductal and periventricular grey, or, more recently, the anterior cingulate cortex. However, this technique remains "off label" in the USA as it does not have Federal Drug Administration approval. Consequently, only a small number of surgeons report DBS for pain using current technology and techniques and few regions approve it. Randomised, blinded and controlled clinical trials that may use novel trial methodologies are desirable to evaluate the efficacy of DBS in patients who are refractory to other therapies. New imaging techniques, including tractography, may help optimise electrode placement and clinical outcome.

Targeting the affective component of chronic pain: a case series of deep brain stimulation of the anterior cingulate cortex.

BACKGROUND: Deep brain stimulation (DBS) has shown considerable promise for relieving nociceptive and neuropathic symptoms of refractory chronic pain. Nevertheless, for some patients, standard DBS for pain remains poorly efficacious. Pain is a multidimensional experience with an affective component: the unpleasantness. The anterior cingulate cortex (ACC) is a structure involved in this affective component, and targeting it may relieve patients' pain. OBJECTIVE: To describe the first case series of ACC DBS to relieve the affective component of chronic neuropathic pain. METHODS: Sixteen patients (13 male and 3 female patients) with neuropathic pain underwent bilateral ACC DBS. The mean age at surgery was 48.7 years (range, 33-63 years). Patient-reported outcome measures were collected before and after surgery using a Visual Analog Scale, SF-36 quality of life survey, McGill Pain Questionnaire, and EQ-5D (EQ-5D and EQ-5D Health State) questionnaires. RESULTS: Fifteen patients (93.3%) transitioned from externalized to fully internalized systems. Eleven patients had data to be analyzed with a mean follow-up of 13.2 months. Post-surgery, the Visual Analog Scale score dropped below 4 for 5 of the patients, with 1 patient free of pain. Highly significant improvement on the EQ-5D was observed (mean, +20.3%; range, +0%-+83%; P = .008). Moreover, statistically significant improvements were observed for the physical functioning and bodily pain domains of the SF-36 quality-of-life survey: mean, +64.7% (range, -8.9%-+276%; P = .015) and mean +39.0% (range, -33.8%-+159%; P = .050), respectively. CONCLUSION: Affective ACC DBS can relieve chronic neuropathic pain refractory to pharmacotherapy and restore quality of life.

Deep brain stimulation of the anterior cingulate cortex: targeting the affective component of chronic pain.

Deep brain stimulation (DBS) has shown promise for relieving nociceptive and neuropathic symptoms of refractory chronic pain. We assessed the efficacy of a new target for the affective component of pain, the anterior cingulate cortex (ACC). A 49-year-old man with neuropathic pain underwent bilateral ACC DBS. Patient-reported outcome measures were collected before and 2 years after surgery using a Visual Analogue Scale, Short-Form 36 quality of life survey, McGill pain questionnaire, EuroQol-5D questionnaires (EQ-5D; Health State) and neuropsychological assessments. The patient improved with DBS. Two years after surgery, the Visual Analogue Scale decreased from 6.7 to 3.0, McGill pain questionnaire improved by 42% and EQ-5D Health State increased by 150%. Stimulating the ACC at 130 Hz, 330 µs and 3 V facilitated neuropathic pain relief. The DBS remained efficacious during the 2-year follow-up period. Affective ACC DBS can relieve chronic neuropathic pain refractory to pharmacotherapy and restore quality of life.

Evidence for post-translational processing of vascular endothelial (VE)-cadherin in brain tumors: towards a candidate biomarker.

Vessel abnormalities are among the most important features in malignant glioma. Vascular endothelial (VE)-cadherin is of major importance for vascular integrity. Upon cytokine challenge, VE-cadherin structural modifications have been described including tyrosine phosphorylation and cleavage. The goal of this study was to examine whether these events occurred in human glioma vessels. We demonstrated that VE-cadherin is highly expressed in human glioma tissue and tyrosine phosphorylated at site Y(685), a site previously found phosphorylated upon VEGF challenge, via Src activation. In vitro experiments showed that VEGF-induced VE-cadherin phosphorylation, preceded the cleavage of its extracellular adhesive domain (sVE, 90 kDa). Interestingly, metalloproteases (MMPs) secreted by glioma cell lines were responsible for sVE release. Because VEGF and MMPs are important components of tumor microenvironment, we hypothesized that VE-cadherin proteolysis might occur in human brain tumors. Analysis of glioma patient sera prior treatment confirmed the presence of sVE in bloodstream. Furthermore, sVE levels studied in a cohort of 53 glioma patients were significantly predictive of the overall survival at three years (HR 0.13 [0.04; 0.40] p ≤ 0.001), irrespective to histopathological grade of tumors. Altogether, these results suggest that VE-cadherin structural modifications should be examined as candidate biomarkers of tumor vessel abnormalities, with promising applications in oncology.

Thalamic deep brain stimulation for neuropathic pain after amputation or brachial plexus avulsion.

OBJECT: Fifteen hundred patients have received deep brain stimulation (DBS) to treat neuropathic pain refractory to pharmacotherapy over the last half-century, but few during the last decade. Deep brain stimulation for neuropathic pain has shown variable outcomes and gained consensus approval in Europe but not the US. This study prospectively evaluated the efficacy at 1 year of DBS for phantom limb pain after amputation, and deafferentation pain after brachial plexus avulsion (BPA), in a single-center case series. METHODS: Patient-reported outcome measures were collated before and after surgery, using a visual analog scale (VAS) score, 36-Item Short-Form Health Survey (SF-36), Brief Pain Inventory (BPI), and University of Washington Neuropathic Pain Score (UWNPS). RESULTS: Twelve patients were treated over 29 months, receiving contralateral, ventroposterolateral sensory thalamic DBS. Five patients were amputees and 7 had BPAs, all from traumas. A postoperative trial of externalized DBS failed in 1 patient with BPA. Eleven patients proceeded to implantation and gained improvement in pain scores at 12 months. No surgical complications or stimulation side effects were noted. In the amputation group, after 12 months the mean VAS score improved by 90.0% ± 10.0% (p = 0.001), SF-36 by 57.5% ± 97.9% (p = 0.127), UWNPS by 80.4% ± 12.7% (p < 0.001), and BPI by 79.9% ± 14.7% (p < 0.001). In the BPA group, after 12 months the mean VAS score improved by 52.7% ± 30.2% (p < 0.001), SF-36 by 15.6% ± 30.5% (p = 1.000), UWNPS by 26.2% ± 40.8% (p = 0.399), and BPI by 38.4% ± 41.7% (p = 0.018). Mean DBS parameters were 2.5 V, 213 microseconds, and 25 Hz. CONCLUSIONS: Deep brain stimulation demonstrated efficacy at 1 year for chronic neuropathic pain after traumatic amputation and BPA. Clinical trials that retain patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.

Long-term outcomes of deep brain stimulation for neuropathic pain.

BACKGROUND: Deep brain stimulation (DBS) to treat neuropathic pain refractory to pharmacotherapy has reported variable outcomes and has gained United Kingdom but not USA regulatory approval. OBJECTIVE: To prospectively assess long-term efficacy of DBS for chronic neuropathic pain in a single-center case series. METHODS: Patient reported outcome measures were collated before and after surgery, using a visual analog score, short-form 36-question quality-of-life survey, McGill pain questionnaire, and EuroQol-5D questionnaires (EQ-5D and health state). RESULTS: One hundred ninety-seven patients were referred over 12 years, of whom 85 received DBS for various etiologies: 9 amputees, 7 brachial plexus injuries, 31 after stroke, 13 with spinal pathology, 15 with head and face pain, and 10 miscellaneous. Mean age at surgery was 52 years, and mean follow-up was 19.6 months. Contralateral DBS targeted the periventricular gray area (n = 33), the ventral posterior nuclei of the thalamus (n = 15), or both targets (n = 37). Almost 70% (69.4%) of patients retained implants 6 months after surgery. Thirty-nine of 59 (66%) of those implanted gained benefit and efficacy varied by etiology, improving outcomes in 89% after amputation and 70% after stroke. In this cohort, >30% improvements sustained in visual analog score, McGill pain questionnaire, short-form 36-question quality-of-life survey, and EuroQol-5D questionnaire were observed in 15 patients with >42 months of follow-up, with several outcome measures improving from those assessed at 1 year. CONCLUSION: DBS for pain has long-term efficacy for select etiologies. Clinical trials retaining patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.