Deep Brain Stimulation (DBS) in Treatment-Resistant Depression (TRD): Hope and Concern.

In this chapter, we explore the historical evolution, current applications, and future directions of Deep Brain Stimulation (DBS) for Treatment-Resistant Depression (TRD). We begin by highlighting the early efforts of neurologists and neurosurgeons who laid the foundations for today's DBS techniques, moving from controversial lobotomies to the precision of stereotactic surgery. We focus on the advent of DBS, emphasizing its emergence as a significant breakthrough for movement disorders and its extension to psychiatric conditions, including TRD. We provide an overview of the neural networks implicated in depression, detailing the rationale for the choice of common DBS targets. We also cover the technical aspects of DBS, from electrode placement to programming and parameter selection. We then critically review the evidence from clinical trials and open-label studies, acknowledging the mixed outcomes and the challenges posed by placebo effects and trial design. Safety and ethical considerations are also discussed. Finally, we explore innovative directions for DBS research, including the potential of closed-loop systems, dual stimulation strategies, and noninvasive alternatives like ultrasound neuromodulation. In the last section, we outline recommendations for future DBS studies, including the use of alternative designs for placebo control, the collection of neural and behavioral recordings, and the application of machine-learning approaches.

Deep brain stimulation of the "medial forebrain bundle": a strategy to modulate the reward system and manage treatment-resistant depression.

The medial forebrain bundle-a white matter pathway projecting from the ventral tegmental area-is a structure that has been under a lot of scrutinies recently due to its implications in the modulation of certain affective disorders such as major depression. In the following, we will discuss major depression in the context of being a disorder dependent on multiple relevant networks, the pathological performance of which is responsible for the manifestation of various symptoms of the disease which extend into emotional, motivational, physiological, and also cognitive domains of daily living. We will focus on the reward system, an evolutionarily conserved pathway whose underperformance leads to anhedonia and lack of motivation, which are key traits in depression. In the field of deep brain stimulation (DBS), different "hypothesis-driven" targets have been chosen as the subject of clinical trials on efficacy in the treatment-resistant depressed patient. The "medial forebrain bundle" is one such target for DBS, and has had remarkably rapid success in alleviating depressive symptoms, improving anhedonia and motivation. We will review what we have learned from pre-clinical animal studies on defining this white matter tract, its connectivity, and the complex molecular (i.e., neurotransmitter) mechanisms by which its modulation exerts its effects. Imaging studies in the form of tractographic depictions have elucidated its presence in the human brain. Such has led to ongoing clinical trials of DBS targeting this pathway to assess efficacy, which is promising yet still lack in sufficient numbers. Ultimately, one must confirm the mechanism of action and validate proof of antidepressant effect in order to have such treatment become mainstream, to promote widespread improvement in the quality of life of suffering patients.

Brain metabolic changes and clinical response to superolateral medial forebrain bundle deep brain stimulation for treatment-resistant depression.

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle is an efficacious therapy for treatment-resistant depression, providing rapid antidepressant effects. In this study, we use 18F-fluorodeoxyglucose-positron emission tomography (PET) to identify brain metabolic changes over 12 months post-DBS implantation in ten of our patients, compared to baseline. The primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score, which was interpreted as a response. Deterministic fiber tracking was used to individually map the target area; probabilistic tractography was used to identify modulated fiber tracts modeled using the cathodal contacts. Eight of the ten patients included in this study were responders. PET imaging revealed significant decreases in bilateral caudate, mediodorsal thalamus, and dorsal anterior cingulate cortex metabolism that was evident at 6 months and continued to 12 months post surgery. At 12 months post-surgery, significant left ventral prefrontal cortical metabolic decreases were also observed. Right caudate metabolic decrease at 12 months was significantly correlated with mean MADRS reduction. Probabilistic tractography modeling revealed that such metabolic changes lay along cortico-limbic nodes structurally connected to the DBS target site. Such observed metabolic changes following DBS correlated with clinical response provide insights into how future studies can elaborate such data to create biomarkers to predict response, the development of which likely will require multimodal imaging analysis.

Deep brain stimulation of the "medial forebrain bundle": sustained efficacy of antidepressant effect over years.

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has emerged as a quite efficacious therapy for treatment resistant depression (TRD), leading to rapid antidepressant effects. In this study, we complete our assessment of our first 10 enrolled patients throughout one year post-implantation, showing sustained antidepressant effect up to 5 years. The primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score, which was interpreted as a response. Deterministic fiber tracking was used to individually map the target area. An insertional effect was seen during the 4-week sham stimulation phase (29% mean MADRS reduction, p = 0.02). However, after 2 weeks of initiating stimulation, five patients met response criteria (47% mean MADRS reduction, p < 0.001). One patient withdrew from study participation at 6 weeks. Twelve weeks after initiating stimulation, six of nine remaining patients had a >50% decrease in MADRS scores relative to baseline (52% mean MADRS reduction, p = 0.001); these same six patients continued to meet response criteria at 52 weeks (63% overall mean MADRS reduction, p < 0.001). Four of five patients who achieved the 5-year time point analysis continued to be responders (81% mean MADRS reduction, p < 0.001). Evaluation of modulated fiber tracts reveals significant common prefrontal/orbitofrontal connectivity to the target region in all responders. Key points learned from this study that we can incorporate in future protocols to better elucidate the effect of this therapy are a longer blinded sham stimulation phase and use of scheduled discontinuation concomitant with functional imaging.

Comparison of tractography-assisted to atlas-based targeting for deep brain stimulation in essential tremor.

BACKGROUND: Direct targeting of the dentato-rubro-thalamic tract is efficacious in DBS for tremor suppression. OBJECTIVES: We sought to compare outcomes and optimal stimulation parameters for tremor control using the technique of directly targeting the dentato-rubro-thalamic tract to those who underwent indirect targeting of the ventral intermediate nucleus thalamus. METHODS: Twenty consecutive essential tremor patients obtained preoperative diffusion MRIs, where the dentato-rubro-thalamic tract was individually drawn and used to directly target the ventral intermediate nucleus of the thalamus during surgery. These patients were compared to an earlier cohort of 20 consecutive patients who underwent surgery using atlas-based coordinates. Baseline and 1-year postsurgery tremor amplitude using The Essential Tremor Rating Assessment Scale was recorded, as were the parameters needed for successful tremor control. RESULTS: The indirectly targeted group had greater baseline and postop tremor severity relative to those directly targeted (baseline, 2.9 vs. 2.6; P = 0.02; postop, 1.1 vs. 0.8; P = 0.03). Mean voltage, pulse width, and frequency for optimal tremor control in the directly targeted group (38 electrodes) = 2.8 V, 80 µs, 153 Hz; the parameters for the indirectly targeted group (38 electrodes) = 2.9 V, 86 µs, 179 Hz (significantly greater, P < 0.001). Both groups had significant improvement in arm tremor amplitude from baseline (P < 0.001) without sustained side effects. CONCLUSION: Direct targeting of the dentato-rubro-thalamic tract provides excellent tremor control, comparable to indirectly targeting the ventral intermediate nucleus of the thalamus. Use of lower stimulation parameters, especially frequency, to control tremor in the directly targeted group suggests that it is a more efficient targeting methodology, which may minimize battery depletion. © 2018 International Parkinson and Movement Disorder Society.

Acute and Subacute Presentations of Cerebral Edema following Deep Brain Stimulation Lead Implantation.

BACKGROUND/AIMS: Postoperative cerebral edema around a deep brain stimulation (DBS) electrode is an uncommon reported complication. The goal of this study was to identify instances of postoperative edema based on clinical presentation, and to remark on their management. METHODS: A retrospective chart review was performed on all patients who underwent DBS electrode implantation over a 3-year period. Routine CT imaging on postoperative day (POD) 1 was negative. Patients were identified based on clinical neurological changes, leading to imaging and subsequent diagnosis. RESULTS: Five of 145 patients (3.4%) presented with new neurological symptoms from POD 1 to 14, which were confirmed by CT imaging to show perilead and/or subcortical edema around 6 of 281 electrodes (2.1%). Four of 5 patients had unilateral edema despite bilateral implantation. Clinical presentations varied widely. Two patients presenting on POD 1 with deteriorating conditions required longer inpatient stays with supportive measures than those presenting later (p = 0.0002). All patients were treated with corticosteroids and returned to baseline by 3 months after surgery. CONCLUSIONS: Acute instances of DBS lead edema may occur as early as POD 1 and can rapidly progress into profound deficits. Treatment with supportive care and corticosteroids is otherwise identical to those cases presenting later.

Deep Brain Stimulation of the Dentato-Rubro-Thalamic Tract: Outcomes of Direct Targeting for Tremor.

OBJECTIVES: Targeting the dentato-rubro-thalamic tract (DRTt) has been suggested to be efficacious in deep brain stimulation (DBS) for tremor suppression, both in case reports and post-hoc analyses. This prospective observational study sought to analyze outcomes after directly targeting the DRTt in tremor patients. METHODS: 20 consecutively enrolled intention tremor patients obtained pre-operative MRI with diffusion tensor (dTi) sequences. Mean baseline tremor amplitude based on The Essential Tremor Rating Assessment Scale was recorded. The DRTt was drawn for each individual on StealthViz software (Medtronic) using the dentate nucleus as the seed region and the ipsilateral pre-central gyrus as the end region and then directly targeted during surgery. Intraoperative testing confirmed successful tremor control. Post-operative analysis of electrode position relative to the DRTt was performed, as was post-operative assessment of tremor improvement. RESULTS: The mean age of patients was 66.8 years; mean duration of tremor was 16 years. Mean voltage for the L electrode = 3.4 V; R = 2.6 V. Mean distance from the center of the active electrode contact to the DRTt was 0.9 mm on the L, and 0.8 mm on the R. Improvement in arm tremor amplitude from baseline after DBS was significant (P < 0.001). CONCLUSION: Direct targeting of the DRTt in DBS is an effective strategy for tremor suppression. Accounting for hardware, software, and model limitations, depiction of the DRTt allows for placement of electrode contacts directly within the fiber tract for modulation despite any anatomical variation, which reproducibly resulted in good tremor control.

Evaluating functional connectivity differences between DBS ON/OFF states in essential tremor.

Deep brain stimulation (DBS) targeting the ventral intermediate (Vim) nucleus of the thalamus is an effective treatment for essential tremor (ET). We studied 15 â€‹ET patients undergoing DBS to a major input/output tract of the Vim, the dentato-rubro-thalamic tract (DRTt), using resting state functional MRI (rsfMRI) to evaluate connectivity differences between DBS ON and OFF and elucidate significant regions most influential in impacting tremor control and/or concomitant gait ataxia. Anatomical/functional 1.5T MRIs were acquired and replicated for each DBS state. Tremor severity and gait ataxia severity were scored with DBS ON at optimal stimulation parameters and immediately upon DBS OFF. Whole brain analysis was performed using dual regression analysis followed by randomized permutation testing for multiple correction comparison. Regions of interest (ROI) analysis was also performed. All 15 patients had tremor improvement between DBS ON/OFF (p â€‹< â€‹0.001). Whole brain analysis revealed significant connectivity changes between states in the left pre-central gyrus and left supplemental motor area. Group analysis of ROIs revealed that, with threshold p â€‹< â€‹0.05, in DBS ON vs. OFF both tremor duration and tremor improvement were significantly correlated to changes in connectivity. A sub-group analysis of patients with greater ataxia had significantly decreased functional connectivity between multiple ROIs in the cortex and cerebellum when DBS was ON compared to OFF. Stimulation of the DRTt and concordant improvement of tremor resulted in connectivity changes seen in multiple regions outside the motor network; when combined with both structural and electrophysiologic connectivity, this may help to serve as a biomarker to improve DBS targeting and possibly predict outcome.

Thalamo-cortical evoked potentials during stimulation of the dentato-rubro-thalamic tract demonstrate synaptic filtering.

Essential tremor DBS targeting the ventral intermediate nucleus (Vim) of the thalamus and its input, the dentato-rubro-thalamic tract (DRTt), has proven to be an effective treatment strategy. We examined thalamo-cortical evoked potentials (TCEPs) and cortical dynamics during stimulation of the DRTt. We recorded TCEPs in primary motor cortex during clinical and supra-clinical stimulation of the DRTt in ten essential tremor patients. Stimulation was varied over pulse amplitude (2-10 â€‹mA) and pulse width (30-250 â€‹µs) to allow for strength-duration testing. Testing at clinical levels (3 â€‹mA, 60 â€‹µs) for stimulation frequencies of 1-160 â€‹Hz was performed and phase amplitude coupling (PAC) of beta phase and gamma power was calculated. Primary motor cortex TCEPs displayed two responses: early and all-or-none (<20 â€‹ms) or delayed and charge-dependent (>50 â€‹ms). Strength-duration curve approximation indicates that the chronaxie of the neural elements related to the TCEPs is <200 â€‹µs. At the range of clinical stimulation (amplitude 2-5 â€‹mA, pulse width 30-60 â€‹µs), TCEPs were not noted over primary motor cortex. Decreased pathophysiological phase-amplitude coupling was seen above 70 â€‹Hz stimulation without changes in power spectra and below the threshold of TCEPs. Our findings demonstrate that DRTt stimulation within normal clinical bounds does not excite fibers directly connected with primary motor cortex but that supra-clinical stimulation can excite a direct axonal tract. Both clinical efficacy and phase-amplitude coupling were frequency-dependent, favoring a synaptic filtering model as a possible mechanism of action.

Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov.

Background: Although deep brain stimulation (DBS) has established uses for patients with movement disorders and epilepsy, it is under consideration for a wide range of neurologic and neuropsychiatric conditions. Objective: To review successful and unsuccessful DBS clinical trials and identify factors associated with early trial termination. Methods: The ClinicalTrials.gov database was screened for all studies related to DBS. Information regarding condition of interest, study aim, trial design, trial success, and, if applicable, reason for failure was collected. Trials were compared and logistic regression was utilized to identify independent factors associated with trial termination. Results: Of 325 identified trials, 79.7% were successful and 20.3% unsuccessful. Patient recruitment, sponsor decision, and device issues were the most cited reasons for termination. 242 trials (74.5%) were interventional with 78.1% successful. There was a statistically significant difference between successful and unsuccessful trials in number of funding sources (p = 0.0375). NIH funding was associated with successful trials while utilization of other funding sources (academic institutions and community organizations) was associated with unsuccessful trials. 83 trials (25.5%) were observational with 84.0% successful; there were no statistically significant differences between successful and unsuccessful observational trials. Conclusion: One in five clinical trials for DBS were found to be unsuccessful, most commonly due to patient recruitment difficulties. The source of funding was the only factor associated with trial success. As DBS research continues to grow, understanding the current state of clinical trials will help design successful future studies, thereby minimizing futile expenditures of time, cost, and patient engagement.

Frameless Robot-Assisted vs Frame-Based Awake Deep Brain Stimulation Surgery: An Evaluation of Technique and New Challenges.

BACKGROUND: Methodological approaches to deep brain stimulation (DBS) continue to evolve from awake frame-based to asleep frameless procedures with robotic assistance, primarily directed to optimize operative efficiency, lead accuracy, and patient comfort. Comparison between the 2 is scarce. OBJECTIVE: To analyze the impacts of methodological differences on operative efficiency and stereotactic accuracy using a frame compared with a frameless robotic platform while maintaining the awake state and use of multiple microelectrode recording (MER) trajectories. METHODS: Thirty-four consecutive patients who underwent bilateral awake frameless robot-assisted DBS were compared with a previous cohort of 30 patients who underwent frame-based surgery. Patient demographics, operative times, and MER data were collected for both cohorts. Two-dimensional radial errors of lead placements were calculated. RESULTS: Preoperative setup, surgical, and total operating room times were all significantly greater for the robot-assisted cohort (P < .001). The need for computed tomography imaging when referencing the robotic fiducials led to increased setup duration because of patient transport, unnecessary for the frame-based cohort. Multiple simultaneous MER trajectories increased surgical time (mean 26 min) for the robot-assisted cohort only. The mean radial errors in the robot-assisted and frame cohorts were 0.98 ± 0.66 and 0.74 ± 0.49 mm (P = .03), respectively. CONCLUSION: The use of a truly frameless robotic platform such as the Mazor Renaissance (Mazor Robotics Ltd) presented challenges when implementing techniques used during awake frame-based surgery. Maintaining good accuracy, intraoperative reference imaging, and limited MER trajectories will help integrate frameless robot assistance into the awake DBS surgical workflow.

A narrative review on invasive brain stimulation for treatment-resistant depression.

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Surgical Management for Dystonia: Efficacy of Deep Brain Stimulation in the Long Term.

INTRODUCTION: Dystonia is a movement disorder substantially affecting the quality of life. Botulinum Neurotoxin (BoNT) is used intramuscularly as a treatment for dystonia; however, not all dystonia patients respond to this treatment. Deep brain stimulation (DBS) is an established treatment for Parkinson's disease (PD) and essential tremor, but it can help in dystonia as well. OBJECTIVES: We studied a total of 67 dystonia patients who were treated with DBS over a period of 7 years to find out the long-term efficacy of DBS in those patients. First, we calculated patient improvement in post-surgery follow-up programs using the Global Dystonia Severity scale (GDS) and Burke-Fahn-Marsden dystonia rating scale (BFMDRS). Secondly, we analyzed the scales scores to see if there was any statistical significance. METHODS: In our study we analyzed patients with ages from 38 to 78 years with dystonia who underwent DBS surgery between January 2014 and December 2020 in four different centers (India, Kuwait, Egypt, and Turkey). The motor response to DBS surgery was retrospectively measured for each patient during every follow-up visit using the GDS and the BFMDRS scales. RESULTS: Five to 7 years post-DBS, the mean reduction in the GDS score was 30 ± 1.0 and for the BFMDRS score 26 ± 1.0. The longitudinal change in scores at 12 and 24 months post-op was also significant with mean reductions in GDS and BFMDRS scores of 68 ± 1.0 and 56 ± 1.0, respectively. The p-values were <0.05 for our post-DBS dystonia patients. CONCLUSIONS: This study illustrates DBS is an established, effective treatment option for patients with different dystonias, such as generalized, cervical, and various brain pathology-induced dystonias. Although symptoms are not completely eliminated, continuous improvements are noticed throughout the post-stimulation time frame.

Influence of Intraoperative Microelectrode Recording in Deep Brain Stimulation.

BACKGROUND: There is considerable debate regarding the use of intraoperative microelectrode recording (MER) in deep brain stimulation (DBS). OBJECTIVE: To determine if the use of intraoperative MER impacts the final position of the lead implant in DBS of the subthalamic nucleus (STN) and globus pallidus (GPi) and to evaluate the incidence of complications. METHODS: The authors conducted a retrospective chart review of all patients who underwent STN and GPi DBS with MER, at the University of Texas Health Science Center in Houston from June 1, 2009 to October 1, 2013 to compare initial and final coordinates. Hemorrhagic and infectious complications were reviewed. RESULTS: A total of 90 lead implants on 46 patients implanted at the center during this time period were reviewed and included in the study. A statistically significant difference between the initial and final coordinates was observed in the superior-inferior direction with a mean difference of 0.40 mm inferiorly (±0.96 mm, P<0.05) and 0.96 mm inferiorly (±1.32 mm, P<0.05) in the STN and GPi locations, respectively. A nonstatistically significant difference was also observed in the anterior-posterior direction in both locations. There were no intraparenchymal hemorrhages on postoperative computed tomography. Two patients developed postoperative seizures (7.4%). One STN electrode (1.1%) required revision because of a suboptimal response. CONCLUSIONS: Intraoperative MER in STN and GPi DBS implant does not seem to have a higher rate of surgical complications compared with historical series not using MER and might also be useful in determining the final lead location.

Case report of hyperacute edema and cavitation following deep brain stimulation lead implantation.

BACKGROUND: Postoperative cerebral edema around a deep brain stimulation (DBS) electrode is an uncommonly reported complication of DBS surgery. The etiology of this remains unknown, and the presentation is highly variable; however, the patients generally report a good outcome. CASE DESCRIPTION: Here, we report an unusual presentation of postoperative edema in a 66-year-old female who has bilateral dentatorubrothalamic tract (specifically, the ventral intermediate nucleus) DBS for a mixed type tremor disorder. Initial postoperative computed tomography (CT) was unremarkable and the patient was admitted for observation. She declined later on postoperative day (POD) 1 and became lethargic. Stat head CT scan performed revealed marked left-sided peri-lead edema extending into the centrum semiovale with cystic cavitation, and trace right-sided edema. On POD 2, the patient was alert, but with global aphasia, right-sided neglect, and a plegic right upper extremity. Corticosteroids were started and a complete infectious workup was unremarkable. She was intubated and ultimately required a tracheostomy and percutaneous gastrostomy tube. She returned to the clinic 3 months postoperatively completely recovered and ready for battery implantation. CONCLUSION: While this is an unusual presentation of cerebral edema following DBS placement, ultimately, the outcome was good similar to other reported cases. Supportive care and corticosteroids remain the treatment of choice for this phenomenon.

Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines.

Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) displays a promising antidepressant effects in patients with treatment-refractory depression; however, a clear consensus on underlying mechanisms is still enigmatic. Herein, we investigated the effects of MFB-DBS on anhedonic-like behavior using the Froot Loops® consumption in a chronic unpredictable mild stress (CUS) model of depression, biochemical estimation of peripheral and central inflammatory cytokines, stress hormone, and brain-derived neurotrophic factor (BDNF). Seven days of MFB-DBS significantly reversed the 42-day CUS-generated anhedonic-like phenotype (p < 0.02) indicated by an increase in Froot Loops® consumption. Gross locomotor activity and body weight remained unaffected across the different groups. A dramatic augmentation of adrenocorticotropic hormone levels was seen in the plasma and cerebrospinal fluid (CSF) samples of CUS rats, which significantly reduced following MFB-DBS treatment. However, C-reactive protein levels were found to be unaffected. Interestingly, decreased levels of BDNF in the CUS animals were augmented in the plasma, CSF, and hippocampus following MFB-DBS, but remained unaltered in the nucleus accumbens (NAc). While multiplex assay revealed no change in the neuronal levels of inflammatory cytokines including IL-1α, IL-4, IL-10, IL-12, IL-13, and IL-17 in the neuroanatomical framework of the hippocampus and NAc, increased levels of IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-18, TNF-α, and INF-γ were seen in these brain structures after CUS and were differentially modulated in the presence of MFB stimulation. Here, we show that there is dysregulation of BDNF and neuroimmune mediators in a stress-driven chronic depression model, and that chronic MFB-DBS has the potential to undo these aberrations.

Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: MRI-Based Anatomoclinical Correlations and Optimal Target.

BACKGROUND: Experimental studies led to testing of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) as a new therapy to treat freezing of gait (FOG) in Parkinson disease (PD). Despite promising initial results fueling a growing interest toward that approach, several clinical studies reported heterogeneity in patient responses. Variation in the position of electrode contacts within the rostral brainstem likely contributes to such heterogeneity. OBJECTIVE: To provide anatomoclinical correlations of the effect of DBS of the caudal mesencephalic reticular formation (cMRF) including the PPN to treat FOG by comparing the normalized positions of the active contacts among a series of 11 patients at 1- and 2-yr follow-up and to provide an optimal target through an open-label study. METHODS: We defined a brainstem normalized coordinate system in relation to the pontomesencephalic junction. Clinical evaluations were based on a composite score using objective motor measurements and questionnaires allowing classification of patients as "bad responders" (2 patients), "mild responders" (1 patient) and "good responders" (6 patients). Two patients, whose long-term evaluation could not be completed, were excluded from the analysis. RESULTS: Most effective DBS electrode contacts to treat FOG in PD patients were located in the posterior part of the cMRF (encompassing the posterior PPN and cuneiform nucleus) at the level of the pontomesencephalic junction. CONCLUSION: In the present exploratory study, we performed an anatomoclinical analysis using a new coordinate system adapted to the brainstem in 9 patients who underwent PPN area DBS. We propose an optimal DBS target that allows a safe and efficient electrode implantation in the cMRF.

Craniocervical junction fusions in patients with hindbrain herniation and syringohydromyelia.

OBJECT: Patients with hindbrain herniation or the so-called Chiari malformation Type I (CM-I) and/or syringohydromyelia are treated with dorsal decompression alone; however, a small percentage of patients with other associated abnormalities require concomitant dorsal craniocervical junction (CCJ) fusion. The authors surveyed the indications for CCJ fusions in this population. METHODS: A retrospective review of University of Iowa medical records and radiographs obtained between 1996 and 2005 was performed. Inclusion criteria encompassed patients with diagnoses of CM-I and/or syringohydromyelia requiring dorsal CCJ fusions, and others with CCJ abnormalities who had CM-I and/or syringohydromyelia. RESULTS: Two hundred thirty-four patients were identified, all of whom were symptomatic at presentation. Their ages ranged from 2.5 to 86 years; 33% of the patients were < 16 years of age. Patients were categorized as follows, with some being assigned to > 1 category: Group I, congenital or acquired CCJ abnormalities with reducible bone compression (25% of patients); Group II, previous anterior CCJ/upper brainstem decompression (44%); Group III, occipitocervical complex instability with CM-I and/or syringohydromyelia but without CCJ bone abnormalities requiring adjunctive posterior fossa decompression (26%); and Group IV, musculoligamentous instability, either from pathological states or from muscle dehiscence from repeated posterior fossa procedures (14%). Instrumentation was used in 96% of patients, with all 96% receiving semirigid fixation with titanium loop and sublaminar cables; all fusion constructs incorporated autologous bone. At last follow-up evaluation, fusion was radiographically complete in 97%, and symptom improvement was seen in 92%. CONCLUSIONS: Dorsal CCJ fusions are required in patients with CM-I and/or syringohydromyelia who have concomitant CCJ abnormalities (Groups I and II). A definite group (CM-I and/or syringohydromyelia) without bone abnormality exists (Groups III and IV). This may be due to muscle weakness secondary to a high syrinx.

Calcium pyrophosphate dihydrate crystal deposition in the craniovertebral junction.

OBJECT: Calcium pyrophosphate dihydrate (CPPD) deposition is a rare cause of retroodontoid mass lesions in elderly individuals. However, this condition may be severely underdiagnosed if sufficient attention is not paid to imaging characteristics and clinical presentation. The authors sought to evaluate the decision-making process in both the diagnosis and surgical treatment of CPPD. METHODS: A retrospective review of University of Iowa medical records and radiographs accumulated between 1977 and 2006 was performed. The inclusion criterion was histopathological findings consistent with pseudogout at the craniovertebral junction (CVJ). Twenty-one patients with a mean age of 70.3 years and a mean symptom duration prior to presentation of 17.5 months were identified and included in this study. RESULTS: The patients presented most frequently with occipital and neck pain (85%) and numbness or paresthesias (61%). Lower cranial nerve deficits were seen in 29%. Calcification of the mass or transverse ligament was seen on computed tomography in all included patients. Gross-total resection was achieved in all patients: 19 of 21 patients underwent transoral-transpalatopharyngeal resection, with only 16 requiring concomitant dorsal occipital-cervical fusion. The mean follow-up duration was 15 months. Eighteen patients (86%) had improvement or resolution of symptoms after treatment, and 3 were lost to follow-up. CONCLUSIONS: Although rare, CPPD deposition at the CVJ should be suspected on finding calcification of and around the transverse ligament on neuroimaging. Transoral-transpalatopharyngeal resection is preferred to halt the progression of neurological deterioration; dorsal fusion is not always mandatory as concomitant ligamentous calcification and atlantoaxial joint ankylosis may provide added stability.