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A number of mitochondrial diseases arise from single- nucleotide variant (SNV) accumulation in multiple mitochondria. Here, we present a method for identification of variants present at the single-mitochondrion level in individual mouse and human neuronal cells, allowing for extremely high-resolution study of mitochondrial mutation dynamics. We identified extensive heteroplasmy between individual mitochondrion, along with three high-confidence variants in mouse and one in human that were present in multiple mitochondria across cells. The pattern of variation revealed by single-mitochondrion data shows surprisingly pervasive levels of heteroplasmy in inbred mice. Distribution of SNV loci suggests inheritance of variants across generations, resulting in Poisson jackpot lines with large SNV load. Comparison of human and mouse variants suggests that the two species might employ distinct modes of somatic segregation. Single-mitochondrion resolution revealed mitochondria mutational dynamics that we hypothesize to affect risk probabilities for mutations reaching disease thresholds. [ABSTRACT FROM AUTHOR]

Summary Investigation of human CNS disease and drug effects has been hampered by the lack of a system that enables single-cell analysis of live adult patient brain cells. We developed a culturing system, based on a papain-aided procedure, for resected adult human brain tissue removed during neurosurgery. We performed single-cell transcriptomics on over 300 cells, permitting identification of oligodendrocytes, microglia, neurons, endothelial cells, and astrocytes after 3 weeks in culture. Using deep sequencing, we detected over 12,000 expressed genes, including hundreds of cell-type-enriched mRNAs, lncRNAs and pri-miRNAs. We describe cell-type- and patient-specific transcriptional hierarchies. Single-cell transcriptomics on cultured live adult patient derived cells is a prime example of the promise of personalized precision medicine. Because these cells derive from subjects ranging in age into their sixties, this system permits human aging studies previously possible only in rodent systems. [ABSTRACT FROM AUTHOR]

Abstract: Deep brain stimulation (DBS) is an efficacious surgical treatment for many conditions, including obsessive-compulsive disorder and treatment-resistant depression. DBS provides a unique opportunity to not only ameliorate disease but also to study mood, cognition, and behavioral effects in the brain. However, there are many ethical questions that must be fully addressed in designing clinical research trials. It is crucial to maintain sound ethical boundaries in this new era so as to permit the proper testing of the potential therapeutic role DBS may play in ameliorating these devastating and frequently treatment-refractory psychiatric disorders. In this review, we focus on the selection of patients for study, informed consent, clinical trial design, DBS in the pediatric population, concerns about intentionally or inadvertently altering an individual’s personal identity, potential use of DBS for brain enhancement, direct modification of behavior through neuromodulation, and resource allocation. [Copyright &y& Elsevier]

Summary: Many patients with epilepsy suffer from persistent seizures despite maximal anti-epileptic drug therapy. Chronic, intermittent vagus nerve stimulation has been proven to be an effective option for many patients suffering from refractory seizures who are not candidates for surgical resection. Although only a small minority of patients will be entirely seizure-free, vagus nerve stimulation, as an adjunct to medical therapy, may result in significant improvements in quality of life. Vagus nerve stimulation is generally well-tolerated, as device implantation is associated with a low rate of perioperative complications, and the majority of side effects are stimulation-dependent and thus reversible. [Copyright &y& Elsevier]

Summary: Many patients with epilepsy suffer from persistent seizures despite maximal antiepileptic drug (AED) therapy. Chronic, intermittent vagus nerve stimulation (VNS) has proven to be a safe, effective option for patients suffering from refractory seizures who are not candidates for surgical resection. Although only a small minority of patients will be entirely seizure-free, VNS as an adjunct to medical therapy does appear to provide a significant amount of improvement in quality of life. Reports of antidepressant effects independent of seizure control, along with the use of multiple AEDs in the treatment of depression, has led to the investigation of VNS as a potential adjunctive treatment for major depressive disorder. Both the number of severely depressed patients refractory to available pharmacologic options and the need for repeated treatments and significant side effects associated with electroconvulsive therapy have heightened the interest in VNS for this patient population. Pilot studies of VNS for depression have shown impressive response rates; however, the effect appears to be gradual in onset, as demonstrated by the lack of a favorable response in a short-term, randomized controlled study. Investigation is thus needed to establish the potential role of VNS as an adjunctive treatment for severe depression. [Copyright &y& Elsevier]

Summary: Many patients who suffer from medically refractory epilepsy are not candidates for resective brain surgery. Success of deep brain stimulation (DBS) in relieving a significant number of symptoms of various movement disorders paved the way for investigations into this modality for epilepsy. Open-label and small blinded trials have provided promising evidence for the use of DBS in refractory seizures, and the first randomized control trial of DBS of the anterior thalamic nucleus is currently underway. There are multiple potential targets, because many neural regions have been implicated in seizure propagation. Thus, it is difficult as yet to make any definitive judgments about the efficacy of DBS for seizure control. Future study is necessary to identify a patient population for whom this technique would be indicated, the most efficacious target, and optimal stimulation parameters. [Copyright &y& Elsevier]

Abstract: We aimed to determine whether our targeting method for the subthalamic nucleus (STN) in Parkinson’s disease informs the initial programming sequence. We evaluated 100 STN-lead pairs from 50 patients who underwent bilateral STN-deep brain stimulation operations. All patients had at least one year of follow-up. In each patient, we measured coordinates of the STN borders and determined the center from special T2-weighted MRI. We then measured the postoperative location of the lead tip by MRI registered to preoperative images. Finally, we determined the mode and active contact(s). Programming was monopolar 71% of the time. A total of 52% of left and 72% of right STN active contacts were located posterolateral to the STN center. In z, only 14% of the active contact(s) were >1mm below the STN center. Contacts 1 or 2 were active 90% of the time. The consistent location of active contacts suggests that initial programming began with contact 1 or 2. [Copyright &y& Elsevier]

Background: Prevention of surgical site infections is critical in deep brain stimulation (DBS). In the present study, we tested the ability of a self-administered preoperative alcohol-based (70% ethyl alcohol) preparation to reduce the rate of postoperative infection after DBS surgery. Methods: This Institutional Review Board–approved retrospective review was conducted at our institution between January 2005 and October 2007 (mean follow-up, 23 months). The participants comprised a consecutive sample of 172 patients with movement disorders who underwent DBS surgery at our institution. Starting in January 2007, all patients were required to use the alcohol-based preparation. These patients (n = 48) were instructed to self-administer the wash on the night before surgery and the morning of surgery. Before this time, no self-administered wash was used (n = 122). Results: There was no difference in preoperative skin cleansing between the 2 groups, and all patients received intravenous antibiotics immediately before and after surgery for 24 hours. We compared the rate of postoperative infection in the 2 groups and reviewed other possible factors underlying infection. We found 11 cases of infection (6.47%), all in the group without the preoperative antiseptic wash. The infection rate was 9.02% in the group without the preoperative wash and 0 in the group with the preoperative wash (P < .029). There was no difference between the 2 groups in terms of mean age, duration of operative procedure, or number of microelectrode tracts attempted. Conclusions: Our results support the incorporation of this self-administered antiseptic wash into our standard antiseptic protocol for patients undergoing DBS surgery. [ABSTRACT FROM AUTHOR]

In deep brain stimulation (DBS) for essential tremor, the primary target ventrointermedius (VIM) nucleus cannot be clearly visualized with structural imaging. As such, there has been much interest in the dentatorubrothalamic tract (DRTT) for target localization, but evidence for the DRTT as a putative stimulation target in tremor suppression is lacking. We evaluated proximity of the DRTT in relation to DBS stimulation parameters. This is a retrospective analysis of 26 consecutive patients who underwent DBS with microelectrode recordings (46 leads). Fiber tracking was performed with a published deterministic technique. Clinically optimized stimulation parameters were obtained in all patients at the time of most recent follow-up (6.2 months). Volume of tissue activated (VTA) around contacts was calculated from a published model. Tremor severity was reduced in all treated hemispheres, with 70% improvement in the treated hand score of the Clinical Rating Scale for Tremor. At the level of the active contact (2.9 ± 2.0 mm superior to the commissural plane), the center of the DRTT was lateral to the contacts (5.1 ± 2.1 mm). The nearest fibers of the DRTT were 2.4 ± 1.7 mm from the contacts, whereas the radius of the VTA was 2.9 ± 0.7 mm. The VTA overlapped with the DRTT in 77% of active contacts. The distance from active contact to the DRTT was positively correlated with stimulation voltage requirements (Kendall τ = 0.33, P = 0.006), whereas distance to the atlas-based VIM coordinates was not. Active contacts in proximity to the DRTT had lower voltage requirements. Data from a large cohort provide support for the DRTT as an effective stimulation target for tremor control. [ABSTRACT FROM AUTHOR]

Gene therapy has been employed in the human brain for a number of disorders in clinical trials and may serve as an avenue for the treatment of Parkinson's disease (PD). Several gene therapy treatment strategies have been developed and evaluated in patients with PD. Three main strategies have been used-enhancement of dopamine synthesis, expression of trophic factors, and neuromodulation. Typically, genes are delivered via viral vectors and expressed within neurons in PD-relevant areas of the brain such as the striatum. These methods of gene delivery have the potential for long-term expression and may only need to be delivered once. Notably, current gene therapy strategies do not address the non-motor symptoms of PD and do not curtail α-synuclein aggregation/spread. Furthermore, many of the completed trials were open-label trials and are subject to placebo effects and bias. Clinical trials have, however, demonstrated safety and studies are ongoing. Here, we review the current landscape of the development of gene therapy for PD and discuss the future of this novel treatment strategy. [ABSTRACT FROM AUTHOR]

Background Multiple open-label trials of deep brain stimulation (DBS) for treatment-resistant depression (TRD), including those targeting the ventral capsule/ventral striatum target, have shown encouraging response rates. However, no randomized controlled trials of DBS for TRD have been published. Methods Thirty patients with TRD participated in a sham-controlled trial of DBS at the ventral capsule/ventral striatum target for TRD. Patients were randomized to active versus sham DBS treatment in a blinded fashion for 16 weeks, followed by an open-label continuation phase. The primary outcome measure was response, defined as a 50% or greater improvement on the Montgomery–Åsberg Depression Rating Scale from baseline. Results There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery–Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively. Conclusion The results of this first randomized controlled study of DBS for the treatment of TRD did not demonstrate a significant difference in response rates between the active and control groups at the end of the 16-week controlled phase. However, a range of 20% to 26.7% of patients did achieve response at any time during the open-label continuation phase. Future studies, perhaps utilizing alternative study designs and stimulation parameters, are needed. [ABSTRACT FROM AUTHOR]

Objective We sought to characterize the effects of eye closure on EEG power using electrocorticography (ECoG). Specifically, we sought to elucidate the anatomical areas demonstrating an eye closure effect, and at which frequencies this effect occurs. Methods ECoG was recorded from 32 patients undergoing invasive monitoring for seizure focus localization. Patients were instructed to close and open their eyes repeatedly. ECoG power was compared in the epochs following eye closure and opening, for various frequency bands and brain regions. Results We found that at low frequencies, eye closure causes widespread power increases involving all lobes of the brain. This effect was significant not only in the α (8–12 Hz) band but in the δ (2–4 Hz), θ (4–8 Hz), and β (15–30 Hz) bands as well. At high frequencies, eye closure causes comparatively focal power decreases over occipital cortex and frontal Brodmann areas 8 and 9. Conclusions Eye closure (1) affects a broad range of frequencies outside the α band and (2) involves a distributed network of neural activity in anatomical areas outside visual cortex. Significance This study constitutes the first large-scale, systematic application of ECoG to study eye closure, which is shown to influence a broad range of frequencies and brain regions. [ABSTRACT FROM AUTHOR]

Summary: Background: The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson''s disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. Methods: This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18–80 years, had Parkinson''s disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients'' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. Findings: Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87–4·16]; p=0·003). Unified Parkinson''s disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. Interpretation: Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation. Funding: St Jude Medical Neuromodulation Division. [Copyright &y& Elsevier]

Abstract: We report a patient with advanced Parkinson''s disease (PD) who developed a recurrence of major depression with psychotic features after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. Electroconvulsive therapy (ECT) dramatically improved the depression without shifting electrode position or damaging the DBS hardware. This case suggests that ECT can be a safe and effective option for severe depression in PD patients treated with STN DBS. [Copyright &y& Elsevier]

Background: The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus.Methods: This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18-80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474.Findings: Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87-4·16]; p=0·003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups.Interpretation: Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation.Funding: St Jude Medical Neuromodulation Division. [ABSTRACT FROM AUTHOR]