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Postactivation depression of the Hoffmann reflex is reduced in Parkinson's disease (PD), but how the recovery is influenced by the state of the muscle is unknown. The present pilot study examined postactivation depression in PD at rest and during a voluntary contraction while patients were off treatment and while receiving medications and/or deep brain stimulation.The authors recruited nine patients with PD treated with implanted deep brain stimulation and examined postactivation depression under four treatment conditions. Paired pulses were delivered 25 to 300 ms apart, and soleus Hoffmann reflex recovery was tested at rest and during voluntary plantar flexion. Trials were matched for background muscle activity and compared with 10 age-matched controls.Patients with Parkinson disease who were OFF medications (OFF meds) and OFF stimulation (OFF stim) at rest showed less postactivation depression at the 300 ms interpulse interval (86.1% ± 21.0%) relative to control subjects (36.4% ± 6.1%; P0.05). Postactivation depression was restored when dopaminergic medication and/or deep brain stimulation was applied. Comparisons between resting and active motor states revealed that the recovery curves were similar OFF meds/OFF stim owing to faster recovery in PD seen at rest. In contrast, the effect of the motor state was different ON meds/OFF stim and ON meds/ON stim (both P0.05), with a nonsignificant trend OFF meds/ON stim ( P0.08). During a contraction, recovery curves were similar between all treatment conditions in PD and control.Disrupted Hoffmann reflex recovery is restored to control levels in PD patients at rest when receiving medications and/or deep brain stimulation or when engaged in voluntary contraction.

Background Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) and globus pallidus interna (GPi) is an effective treatment for cardinal motor symptoms and motor complications in Parkinson’s Disease (PD). However, malpositioned DBS electrodes can result in suboptimal therapeutic response. Objective We explored whether recovery of the H-reflex—an easily measured electrophysiological analogue of the stretch reflex, known to be altered in PD—could serve as an adjunct biomarker of suboptimal versus optimal electrode position during STN- or GPi-DBS implantation. Methods Changes in soleus H-reflex recovery were investigated intraoperatively throughout awake DBS target refinement across 26 nuclei (14 STN). H-reflex recovery was evaluated during microelectrode recording (MER) and macrostimulation at multiple locations within and outside target nuclei, at varying stimulus intensities. Results Following MER, H-reflex recovery normalized (i.e., became less Parkinsonian) in 21/26 nuclei, and correlated with on-table motor improvement consistent with an insertional effect. During macrostimulation, H-reflex recovery was maximally normalized in 23/26 nuclei when current was applied at the location within the nucleus producing optimal motor benefit. At these optimal sites, H-reflex normalization was greatest at stimulation intensities generating maximum motor benefit free of stimulation-induced side effects, with subthreshold or suprathreshold intensities generating less dramatic normalization. Conclusion H-reflex recovery is modulated by stimulation of the STN or GPi in patients with PD and varies depending on the location and intensity of stimulation within the target nucleus. H-reflex recovery shows potential as an easily-measured, objective, patient-specific, adjunct biomarker of suboptimal versus optimal electrode position during DBS surgery for PD.

Background: Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI. Methods: We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a > 50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques. Results: Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity. Limitations: Normalization by intracranial volume nullified some between-group differences in volumetric measures. Conclusion: There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.

ObjectiveAfter deep brain stimulation (DBS) for Parkinson disease (PD), patients often do not report the level of satisfaction anticipated. This misalignment can relate to patients' expectations for an invasive treatment and insufficient knowledge of DBS's effectiveness in relieving motor and nonmotor symptoms (NMS). Patient satisfaction depends on expectations and goals for treatment. We hypothesized that improving patient education with a patient-centered shared decision-making tool emphasizing autonomy would improve patient satisfaction and clinical outcome.MethodsWe developed a computer application (DBS-Edmonton app), allowing patients with PD to input their symptoms and to learn how effective DBS addresses their prioritized symptoms. Sixty-two volunteers referred for DBS used the DBS-Edmonton app. DBS-related knowledge and patient perceptions of the DBS-Edmonton app were assessed with pre- and post-use questionnaires. Fourteen of 24 patients who proceeded to DBS achieved optimization at 6 months. Perceived functional improvement was assessed and compared with 12 control patients with DBS who did not use the DBS-Edmonton app.ResultsAll 62 volunteers considered the DBS-Edmonton app helpful and would recommend it to others. There was improved knowledge about how NMS and axial symptoms respond to DBS. Postoperatively, there was no significant difference in symptoms improvement assessed by standard scales between the groups. Volunteers who used the DBS-Edmonton app had greater satisfaction (p = 0.014).ConclusionThis interventional study showed that the DBS-Edmonton app improved DBS-related knowledge and patient satisfaction, independent of the objective motor outcome. It may assist patients in deciding to proceed to DBS and can be easily incorporated into practice to improve patient satisfaction post-DBS.

ObjectiveRefractory psychiatric disease is a major cause of morbidity and mortality worldwide, and there is a great need for new treatments. In the last decade, investigators piloted novel deep brain stimulation (DBS)-based therapies for depression and obsessive–compulsive disorder (OCD). Results from recent pivotal trials of these therapies, however, did not demonstrate the degree of efficacy expected from previous smaller trials. To discuss next steps, neurosurgeons, neurologists, psychiatrists and representatives from industry convened a workshop sponsored by the American Society for Stereotactic and Functional Neurosurgery in Chicago, Illinois, in June of 2016.DesignHere we summarise the proceedings of the workshop. Participants discussed a number of issues of importance to the community. First, we discussed how to interpret results from the recent pivotal trials of DBS for OCD and depression. We then reviewed what can be learnt from lesions and closed-loop neurostimulation. Subsequently, representatives from the National Institutes of Health, the Food and Drug Administration and industry discussed their views on neuromodulation for psychiatric disorders. In particular, these third parties discussed their criteria for moving forward with new trials. Finally, we discussed the best way of confirming safety and efficacy of these therapies, including registries and clinical trial design. We close by discussing next steps in the journey to new neuromodulatory therapies for these devastating illnesses.ConclusionInterest and motivation remain strong for deep brain stimulation for psychiatric disease. Progress will require coordinated efforts by all stakeholders.

OBJECTIVEThe aim of this study was to evaluate the safety of 3-T MRI in patients with implanted deep brain stimulation (DBS) systems.METHODSThis study was performed in 2 phases. In an initial phantom study, a Lucite phantom filled with tissue-mimicking gel was assembled. The system was equipped with a single DBS electrode connected to an internal pulse generator. The tip of the electrode was coupled to a fiber optic thermometer with a temperature resolution of 0.1°C. Both anatomical (T1- and T2-weighted) and functional MRI sequences were tested. A temperature change within 2°C from baseline was considered safe. After findings from the phantom study suggested safety, 10 patients with implanted DBS systems targeting various brain areas provided informed consent and underwent 3-T MRI using the same imaging sequences. Detailed neurological evaluations and internal pulse generator interrogations were performed before and after imaging.RESULTSDuring phantom testing, the maximum temperature increase was registered using the T2-weighted sequence. The maximal temperature changes at the tip of the DBS electrode were < 1°C for all sequences tested. In all patients, adequate images were obtained with structural imaging, although a significant artifact from lead connectors interfered with functional imaging quality. No heating, warmth, or adverse neurological effects were observed.CONCLUSIONSTo the authors' knowledge, this was the first study to assess the clinical safety of 3-T MRI in patients with a fully implanted DBS system (electrodes, extensions, and pulse generator). It provided preliminary data that will allow further examination and assessment of the safety of 3-T imaging studies in patients with implanted DBS systems. The authors cannot advocate widespread use of this type of imaging in patients with DBS implants until more safety data are obtained.

During the “DBS Canada Day” symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to discuss three main questions on target selection for deep brain stimulation (DBS) of patients with Parkinson’s disease (PD). First, is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) the ideal target? In summary, both targets are equally effective in improving the motor symptoms of PD. STN allows a greater medications reduction, while GPi exerts a direct antidyskinetic effect. Second, are there further potential targets? Ventral intermediate nucleus DBS has significant long-term benefit for tremor control but insufficiently addresses other motor features of PD. DBS in the posterior subthalamic area also reduces tremor. The pedunculopontine nucleus remains an investigational target. Third, should DBS for PD be performed unilaterally, bilaterally or staged? Unilateral STN DBS can be proposed to asymmetric patients. There is no evidence that a staged bilateral approach reduces the incidence of DBS-related adverse events.

Background Chronic high-frequency electrical deep brain stimulation (DBS) of the subcallosal cingulate region is currently being investigated clinically as a therapy for treatment of refractory depression. Experimental DBS of the homologous region, the ventromedial prefrontal cortex (VMPFC), in rodent models has previously demonstrated anti-depressant-like effects. Our goal was to determine if structural remodeling accompanies the alterations of brain function previously observed as a result of chronic DBS. Methods Here we applied 6 h of high-frequency bilateral VMPFC DBS daily to 8 9-week old C57Bl/6 mice for 5 days. We investigated the “micro-lesion” effect by using a sham stimulation group (8 mice) and a control group (8 mice with a hole drilled into the skull only). Whole brain anatomy was investigated post-mortem using high-resolution magnetic resonance imaging and areas demonstrating volumetric expansion were further investigated using histology and immunohistochemistry. Results The DBS group demonstrated bilateral increases in whole hippocampus and the left thalamus volume compared to both sham and control groups. Local hippocampal and thalamic volume increases were also observed at the voxel-level; however these increases were observed in both DBS and sham groups. Follow-up immunohistochemistry in the hippocampus revealed DBS increased blood vessel size and synaptic density relative to the control group whereas the sham group demonstrated increased astrocyte size. Conclusions Our work demonstrates that DBS not only works by altering function with neural circuits, but also by structurally altering circuits at the cellular level. Neuroplastic alterations may play a role in mediating the clinical efficacy of DBS therapy.

Background Deep Brain Stimulation (DBS) is thought to improve the symptoms of selected neurological disorders by modulating activity within dysfunctional brain circuits. To date, there is no evidence that DBS counteracts progressive neurodegeneration in any particular disorder. Objective/Hypothesis We hypothesized that DBS applied to the fornix in patients with Alzheimer's Disease (AD) could have an effect on brain structure. Methods In six AD patients receiving fornix DBS, we used structural MRI to assess one-year change in hippocampal, fornix, and mammillary body volume. We also used deformation-based morphometry to identify whole-brain structural changes. We correlated volumetric changes to hippocampal glucose metabolism. We also compared volumetric changes to those in an age-, sex-, and severity-matched group of AD patients ( n = 25) not receiving DBS. Results We observed bilateral hippocampal volume increases in the two patients with the best clinical response to fornix DBS. In one patient, hippocampal volume was preserved three years after diagnosis. Overall, mean hippocampal atrophy was significantly slower in the DBS group compared to the matched AD group, and no matched AD patients demonstrated bilateral hippocampal enlargement. Across DBS patients, hippocampal volume change correlated strongly with hippocampal metabolism and with volume change in the fornix and mammillary bodies, suggesting a circuit-wide effect of stimulation. Deformation-based morphometry in DBS patients revealed local volume expansions in several regions typically atrophied in AD. Conclusion We present the first in-human evidence that, in addition to modulating neural circuit activity, DBS may influence the natural course of brain atrophy in a neurodegenerative disease.

Ventromedial prefrontal cortex (vmPFC) forms a core region of larger brain circuits that assign value to sensory inputs and interfaces motivational and cognitive dominated brain processes. This network function of the vmPFC could be realized by synchronizing local activity at time scales that are shared by connected brain areas, but it is unknown whether vmPFC circuitry engages in functionally specific synchronization. Here, we recorded in human subcallosal vmPFC while subjects engaged in an emotion tracking task that required the assignment of positive or negative affective value to ambiguous (happy-sad) facial expressions. We found that vmPFC engages in low beta-band (15-20 Hz) coherent activation just before subjects subjectively judged ambiguous facial expressions as conveying negative valence ('sad') information, but not before positive valence ('happy') judgments. The predictive beta coherence emerged particularly for conflicting rather than pure emotional facial cues and dissipated slowly after the choice was made. These results suggest that 15-20 Hz coherent activity within vmPFC marks a functional signature of a valuation process that informs categorical affective choices. We hypothesize that coherent beta band activation signifies functional interactions to anatomical vmPFC projection targets, raising the possibility that dysfunctional biases in affective valuation and an enhanced decision conflict in clinical depression could be indexed by alterations of beta coherent network activation.

Deep brain stimulation (DBS) is now widely used in the treatment of Parkinson's disease, tremor, and dystonia. This review examines recent developments in the application of DBS to the management of movement disorders.In Parkinson's disease, recent work has demonstrated that early DBS may have a significant benefit on quality of life and motor symptoms while permitting a decrease in levodopa equivalent dosage. Thalamic DBS continues to be a well established target for the treatment of tremor, although recent work suggests that alternative targets such as the posterior subthalamic area may be similarly efficacious. The treatment of primary dystonia with DBS has been established in multiple recent trials, demonstrating prolonged symptomatic benefit.DBS is now an established symptomatic treatment modality for Parkinson's disease and other movement disorders. Future work will undoubtedly involve establishing new indications and targets in the treatment of movement disorders with further refinements to existing technology. Ultimately, these methods combined with biologically based therapies may catalyze a shift from symptomatic treatment to actually modifying the natural history of neurodegenerative diseases such as Parkinson's disease.

UNLABELLED Deep brain stimulation (DBS) for psychiatric disorders needs to be investigated in proper research trials. However, there are rare circumstances in which DBS could be offered to psychiatric patients as a form of surgical innovation, therefore potentially blurring the lines between these research trials and health care. In this article, we discuss the conditions under which surgical innovation may be accepted as a practice falling at the frontiers of standard clinical care and research per se. However, recognizing this distinction does not settle all ethical issues. Our article offers ethical guideposts to allow clinicians, surgical teams, institutions, and institutional review boards to deliberate about some of the fundamental issues that should be considered before surgical innovation with psychiatric DBS is undertaken. We provide key guiding questions to sustain this deliberation. Then we review the normative and empirical literature that exists to guide reflection about the ethics of surgical innovation and psychiatric DBS with respect to general ethical questions pertinent to psychiatric DBS, multidisciplinary team perspectives in psychiatric DBS, mechanisms for oversight in psychiatric DBS, and capacity and consent in psychiatric DBS. The considerations presented here are to recognize the very specific nature of surgical innovation and to ensure that surgical innovation in the context of psychiatric DBS remains a limited, special category of activity that does not replace appropriate surgical research or become the standard of care based on limited evidence. ABBREVIATIONS DBS, deep brain stimulationIRB, institutional review boardOCD, obsessive-compulsive disorder.

Functional surgery is the branch of neurosurgery concerned with surgically altering the nervous system and modulating activity in neural circuits to treat neurological illness. Safe and effective functional surgery depends on accurate brain mapping and selecting appropriate brain targets in various disease states. We briefly review the history of functional surgery, from early lesioning procedures to the development of stereotaxis. We then review the principles and applications of deep brain stimulation, a key technique at the functional neurosurgeon's disposal. We conclude by highlighting emerging technologies that have the potential to increase the scope and efficacy of functional surgery.

The next several decades will see an exponential rise in the number of patients with disorders of memory and cognition, and of Alzheimer’s disease in particular. Impending demographic shifts, an absence of effective treatments, and the significant burden these conditions place on patients, caregivers, and society, mean there is an urgent need to develop novel therapies. Deep brain stimulation (DBS) is a neurosurgical procedure that is a standard-of-care for many patients with treatment-refractory Parkinson’s disease, dystonia, and essential tremor. DBS has proven to be an effective means of modulating activity in disrupted motor circuitry, and has shown promise as a modulator of other dysfunctional circuits, including for mood and anxiety disorders. The deficits in Alzheimer’s disease and other disorders of memory and cognition are also beginning to be thought of as arising from dysfunction in neural circuits. Such dysfunction may be amenable to modulation using focal brain stimulation. A global experience is now emerging for the use of DBS for these conditions, targeting key nodes in the memory circuit, including the fornix and nucleus basalis of Meynert. Such work holds promise as a novel therapeutic approach for one of medicine’s most urgent priorities.

Major depressive disorder is among the most prevalent psychiatric disorders and is a leading cause of morbidity and lost productivity.[1][1] The 1-year prevalence of major depressive disorder in the Canadian population is 3.2%–4.6%.[2][2] A large, multisite prospective trial showed that only 28%

Summary Background Essential tremor is the most common movement disorder and is often refractory to medical treatment. Surgical therapies, using lesioning and deep brain stimulation in the thalamus, have been used to treat essential tremor that is disabling and resistant to medication. Although often effective, these treatments have risks associated with an open neurosurgical procedure. MR-guided focused ultrasound has been developed as a non-invasive means of generating precisely placed focal lesions. We examined its application to the management of essential tremor. Methods Our study was done in Toronto, Canada, between May, 2012, and January, 2013. Four patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus. Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery. Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events. Findings Patients showed immediate and sustained improvements in tremor in the dominant hand. Mean reduction in tremor score of the treated hand was 89·4% at 1 month and 81·3% at 3 months. This reduction was accompanied by functional benefits and improvements in writing and motor tasks. One patient had postoperative paraesthesias which persisted at 3 months. Another patient developed a deep vein thrombosis, potentially related to the length of the procedure. Interpretation MR-guided focused ultrasound might be a safe and effective approach to generation of focal intracranial lesions for the management of disabling, medication-resistant essential tremor. If larger trials validate the safety and ascertain the efficacy and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated. Funding Focused Ultrasound Foundation.

The field of functional neurosurgery has developed a number of recent innovative neuromodulatory approaches to treat disease that remains resistant to the best medical therapy. These include novel surgical techniques to intervene in motor and cognitive sequelae of refractory epilepsy, neurodegenerative disease, and certain psychiatric conditions. To a large extent, much of the innovation in our field continues to be driven by a systems-level understanding of the impact of disease on the brain. For example, several groups have exploited findings from neuroimaging work to identify a number of new potential neuromodulatory targets for the treatment of refractory depression. Ongoing discoveries at the cellular and molecular level promise targeted gene or drug delivery aimed at curing disease. Neurosurgeons will certainly remain at the forefront of translating these strategies into practical clinical applications. Several randomized trials are now underway to assess the safety and efficacy of a number of new approaches, and we will continue to acquire better knowledge of optimal patient selection, identification of the most effective neuromodulatory targets, and recognition of adverse effects as these studies progress.

Many patients treated chronically with l-dopa for Parkinson disease (PD) become functionally disabled by l-dopa-induced dyskinesias (LID). Evolved from early empirical procedures, modern stereotactic surgical lesioning techniques and deep brain stimulation (DBS) can effectively treat LID while simultaneously improving the cardinal motor symptoms of PD. Here we review the common surgical targets used to treat LID, and compare their relative efficacy. We explain the anti-dyskinetic action of surgery at each of these targets based on evolving models of basal ganglia function. Finally, we discuss the appropriate selection of patients with LID for surgery and address relevant technical and management issues in these patients.

There are a number of emerging surgical indications for deep brain stimulation. We have shown that modulation of activity within motor, mood, and cognitive circuits has beneficial effects in patients with Parkinson's disease, treatment-resistant depression, and perhaps Alzheimer's type dementia. We review the rationale, safety, and efficacy for each of these indications, focusing on disease mechanisms and relevant data that are necessary to document therapeutic value in each case. The review closes with some thoughts on possible future directions for deep brain stimulation. It is likely that applications for deep brain stimulation will continue to expand as accumulating data establish its safety and efficacy profile in these and other conditions.

There are a number of emerging surgical indications for deep brain stimulation. We have shown that modulation of activity within motor, mood, and cognitive circuits has beneficial effects in patients with Parkinson's disease, treatment-resistant depression, and perhaps Alzheimer's type dementia. We review the rationale, safety, and efficacy for each of these indications, focusing on disease mechanisms and relevant data that are necessary to document therapeutic value in each case. The review closes with some thoughts on possible future directions for deep brain stimulation. It is likely that applications for deep brain stimulation will continue to expand as accumulating data establish its safety and efficacy profile in these and other conditions.

Determining the incidence of intracerebral hemorrhagic complications caused by functional neurosurgical procedures—and what should be done to avoid them—has proven to be a controversial issue since the early days of stereotaxy. Most surgeons performing modern functional neurosurgery would probably agree, thankfully, that hemorrhages are rare events. Nevertheless, the real potential for these uncommon occurrences to produce devastating neurological morbidity or death in patients with degenerative but otherwise nonlethal conditions, rightly continues to be a source of concern. In their study, “Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review,” Zrinzo et al.1 bring their considerable institutional experience to bear on the issue. The study consists of 2 parts. In the first, the authors report on the incidence of hemorrhagic complications in their own consecutive series of 214 patients they have treated with “image-guided ” implantation of deep brain stimulation (DBS) systems since 2002. Secondly, they perform a “systematic review” of series published over the past decade—including both DBS and lesioning procedures—to compute a literature-wide incidence of hemorrhage in modern functional neurosurgery and to address the relative contribution to hemorrhagic risk of several clinical and surgical factors. Ultimately, they find that the incidence of hemorrhage following functional neurosurgical interventions is about 5%, with symptomatic or permanently disabling hemorrhages being even less likely (2.1% and 1.1%, respectively). Hypertension and increasing age appear to be the most significant patient-related risk factors. The authors also conclude that using microelectrode recording (MER) or transgressing either sulci or the ventricles during surgery may increase the risk of hemorrhage and can be avoided by adopting an “image-guided” technique such as theirs. Zrinzo et al.1 are to be congratulated for the record of safety they have achieved over the past decade at their institution during surgery for DBS. As they point out, their hemorrhage rate of 0.9% per patient is among the lowest reported to date. They should also be commended for attempting to sort through the substantial literature related to hemorrhage risk in functional neurosurgery, which consists almost entirely of retrospective series of variable size and quality. Tabulating these individual series in a single paper provides a useful resource for functional neurosurgeons. Furthermore, their division of risk factors for hemorrhage into patient-related and surgical categories is a logical approach that authors of future studies would be wise to adopt. As they point out, their study does have a number of important limitations. Among others, publication bias, noncontemporaneous series, varying levels of expertise of the treating center, the learning curve across centers, differences in patient selection, and the omission of data on long-term efficacy and nonhemorrhagic side effects limit the conclusions that can be drawn from this kind of analysis. Perhaps the most salient is that in a retrospective review of the literature all kinds of observations can be made but their significance can be sometimes rather dubious. Specific findings can be associative rather than causal. As a famous example, 99% of patients with cancer have eaten pickles, but not too many would go as far as to say that this is the cause of their cancer. Similarly, the observation that there are more reports of patients with some intrinsic or extrinsic attribute (for example, pickle eaters) who have had a particular negative outcome such as hemorrhage does not prove causation. No doubt the meticulous use of MR imaging–based planning as Zrinzo et al.1 advocate has the potential to reduce the number of passes made into the brain by surgical instruments, theoretically providing less occasion to induce hemorrhage. But this theoretical advantage may be offset by the need to reposition suboptimally placed electrodes or by diminished therapeutic efficacy, which is why physiological targeting using MER remains so widespread even in this era of rapid improvements in imaging quality. Functional neurosurgery is still waiting for an unbiased, methodologically sound study that establishes the superiority of one approach over the other. Unfortunately, it is unlikely that a randomized controlled trial designed to ascertain the true hemorrhage risk conferred by various clinical and surgical factors will ever be undertaken; any such trial is doomed to be underpowered because hemorrhage is such a rare outcome and open to criticism because surgical methods are far from standardized across functional neurosurgery centers. As a result, all we can really say is that Zrinzo and colleagues have made a good attempt to address this issue, that their particular brand of “image-guided” approach to DBS surgery works well for them, and that the debate goes on.

The success of deep brain stimulation (DBS) surgery in treating medically refractory symptoms of some movement disorders has inspired further investigation into a wide variety of other treatment-resistant conditions. These range from disorders of gait, mood, and memory to problems as diverse as obesity, consciousness, and addiction. We review the emerging indications, rationale, and outcomes for some of the most promising new applications of DBS in the treatment of postural instability associated with Parkinson's disease, depression, obsessive-compulsive disorder, obesity, substance abuse, epilepsy, Alzheimer's-type dementia, and traumatic brain injury. These studies reveal some of the excitement in a field at the edge of a rapidly expanding frontier. Much work still remains to be done on basic mechanism of DBS, optimal target and patient selection, and long-term durability of this technology in treating new indications.