Neuromodulation Approaches in Parkinson's Disease Using Deep Brain Stimulation and Transcranial Magnetic Stimulation.

Parkinson's Disease (PD) is the second most common neurodegenerative disease, characterized by progressive motor (such as resting tremor, hypokinesia, postural instability) and non-motor symptoms (such as neuropsychiatric decline and autonomic dysfunction). Since its introduction in the late 1980s, deep brain stimulation (DBS) has revolutionized the treatment of PD. Initially used in patients' with advanced PD with either medically refractory motor symptoms or medication intolerance, DBS typically provides excellent improvement in motor symptoms. Indications for DBS have continued to expand, with demonstrated efficacy in early PD and essential tremor, and promising preliminary results in the treatment of epilepsy, psychiatric disease, and depression. Advancements in DBS hardware, programming, neuroimaging, and surgical techniques have led to progressive improvement in efficacy and safety profiles. Thanks to ongoing research into remote programming, adaptive DBS, new targets, and alternative interventions, such as transcranial magnetic stimulation, the opportunities for further improvements in DBS and neuromodulation are bright.

Diffusion tensor imaging findings and neuropsychological performance in adults with TBI across the spectrum of severity in the chronic-phase.

PRIMARY OBJECTIVE: To examine associations between neuroimaging indicators of cerebral tract integrity and neurocognitive functioning in traumatic brain injury (TBI). RESEARCH DESIGN: Between-Groups design with two TBI groups and controls. METHOD AND PROCEDURES: Forty-four participants with TBI and 27 matched controls completed diffusion tensor imaging and neuropsychological measures of processing speed, attention, memory, and executive function. Multivariate analyses were conducted to examine group differences in white matter integrity (fractional anisotropy) for 11 regions of interest and cognitive performance among adult males with chronic phase, mild, moderate, or severe TBI. Correlational analyses investigated associations between white matter integrity, brain injury severity, and cognitive status. MAIN OUTCOMES AND RESULTS: Participants with moderate or severe TBI exhibited reduced white matter integrity in 8 of 11 ROIs and worse performance on most cognitive measures, relative to control participants. Persons with mild TBI did not differ from controls on white matter integrity values and differed on one measure of processing speed. Significant correlations were found between injury severity ratings and 10 ROIs, most notably between ROIs and measures of processing speed or memory. CONCLUSIONS: These findings provide nuanced information regarding white matter connectivity as it relates to neurocognitive abilities across the TBI severity spectrum.

Impact of psychiatric symptomatology on neuropsychological assessment performance in persons with TBI: A comparison of OEF/OIF veteran and civilian samples.

OBJECTIVE: To assess whether increased incidence of post-traumatic stress disorder and depressive symptomatology in veterans with combat-related traumatic brain injury might help account for neurocognitive impairment relative to civilians with traumatic brain injury. PARTICIPANTS: Neuropsychological assessment data of 53 Operation Enduring Freedom/Operation Iraqi Freedom veterans and 48 civilians with positive history of traumatic brain injury were analyzed to assess differences with respect to cognitive performance. DESIGN: Retrospective analysis of data including neurocognitive test performance and self-reported symptoms of post-traumatic stress disorder and depression. RESULTS: Results showed worse neurocognitive performance (i.e. RBANS Total Index score) in the veteran sample relative to the civilian sample [F(1,99) = 3.92, p = .05, ƞ2 = .04], particularly on tasks measuring attentional capabilities [F(1,99) = 9.18, p = .003, ƞ2 = .09]. Additional analyses found that after controlling for post-traumatic stress disorder symptomatology, differences were no longer significant. Broad correlations between measures also showcased attenuated relationships after controlling for both post-traumatic stress disorder and depressive symptomatology using partial correlations Conclusion: Findings suggest that the presence of post-traumatic stress disorder and depressive symptomatology negatively impacts cognitive performance across neuropsychological assessment above and beyond deficits related to traumatic brain injury.

Best of the Radiosurgery Society® Scientific Meeting 2014: stereotactic radiosurgery/stereotactic body radiotherapy treatment of extracranial and intracranial lesions.

The SRS/SBRT Scientific Meeting 2014, Minneapolis, MN, USA, 7-10 May 2014. The Radiosurgery Society(®), a professional medical society dedicated to advancing the field of stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT), held the international Radiosurgery Society Scientific Meeting, from 7-10 May 2014 in Minneapolis (MN, USA). This year's conference attracted over 400 attendants from around the world and featured over 100 presentations (46 oral) describing the role of SRS/SBRT for the treatment of intracranial and extracranial malignant and nonmalignant lesions. This article summarizes the meeting highlights for SRS/SBRT treatments, both intracranial and extracranial, in a concise review.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. METHODS: The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. RESULTS: Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. CONCLUSIONS: The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. TRIAL REGISTRATION: NCT04539964; August 31, 2020.

A Technique of Deep Brain Stimulation of the Globus Pallidus Interna for Dystonia Under General Anesthesia With Sevoflurane.

Background Globus pallidus interna (GPi) deep brain stimulation (DBS) is an established surgical procedure that confers a benefit in medication refractory dystonia. Patients with generalized dystonia require general anesthesia (GA) for the surgery as their movements may hinder the surgical procedure. General anesthetics tend to dampen the microelectrode recordings (MERs) from the GPi. Methods We describe our experience with a series of consecutive patients with dystonia who underwent bilateral GPi DBS using standard DBS and MER under GA using sevoflurane as the maintenance general anesthetic drug. All patients had Medtronic 3,387 leads implanted and connected to an RC battery. Patients underwent sequential programming of the DBS after the surgery. Results The mean age of the 13 patients who underwent DBS of the GPi for dystonia was 46.5 years with a range from 29 to 71 years. Every patient in our case series received various doses of (1.37% to 2.11%) inhaled sevoflurane for anesthesia maintenance. Sevoflurane provided adequate anesthesia and allowed accurate MERs from the GPi. No adverse effects were encountered. On follow-up and sequential DBS programming, patients had significant improvements in dystonia attesting to the accuracy of the electrode placements. Conclusions We report our experience using sevoflurane for maintenance of GA for bilateral GPi DBS for dystonia. The main benefits identified have been adequate anesthesia and reduction of dystonia-related movements to allow the performance of the DBS surgery. The MER signals from the GPi were not suppressed by sevoflurane. This allowed accurate mapping and placement of the DBS implants in the GPi.

Endoscope-Assisted Evacuation of Acute-on-Chronic Subdural Hematomas: A Single-Center Series.

PURPOSE: Acute subdural hematomas are frequent, highly morbid, and affect all age groups. The most common mechanism of injury is a low-velocity fall, and the incidence of the disease is growing due to increasingly aggressive antithrombotic and anticoagulant therapies. In this study, we aimed to share our experience with the endoscopic-assisted evacuation of acute subdural hematoma, a less invasive procedure compared to standard craniotomy. METHODS: We retrospectively reviewed data of all consecutive patients aged 18 years and older who underwent endoscopic-assisted evacuation of acute-on-chronic subdural hematoma at our institution from 2015 to 2019. Preoperative, intraoperative, postoperative, and follow-up data were collected and reported. Statistical tests were done using Python statistical packages. RESULTS: Of the 35 patients that underwent this procedure, 32 were 18 years and older. The median age was 69.5 years and 37.5% were female. Twenty patients (62.5%) were on antiplatelet therapy, and six patients (18.75%) were on anticoagulants upon presentation. A fall was the most common cause of trauma (71.88%). The median operative time was 107 minutes. The median length of stay in days and Glasgow Coma Scale (GCS) at discharge were 8.5 and 15, respectively. There were no surgical site infections or in-hospital mortality in this series. At the latest follow-up, the median GCS and modified Rankin Scale were 15 and 1, respectively. CONCLUSION: Evacuation of acute-on-chronic subdural hematomas can be performed safely and efficiently via a smaller craniotomy and with the assistance of an endoscope. This may represent a less invasive alternative than standard craniotomy/craniectomy in selected patients.

Marked Response to VNS in a Post-Cingulotomy Patient: Implications for the Mechanism of Action of VNS in TRD.

Treatment-resistant major depression (TRMD, major depressive disorder that fails to respond to numerous therapies) is a relatively common and clinically challenging disorder. In many cases, the most severely affected TRMD patients have received surgical intervention (subcaudate tractotomy, limbic leucotomy, anterior capsulotomy, and anterior cingulotomy). New treatments, including vagus nerve stimulation (VNS) and deep brain stimulation, have emerged to treat individuals with TRMD. We describe the case of a woman, 53 years of age, with a long and sustained history of TRMD (33 years), which was unresponsive to numerous treatments (multiple pharmacotherapies, psychotherapy, electroconvulsive therapy [ECT]). Additionally, her TRMD failed to respond to a bilateral anterior cingulotomy. She underwent placement of a cervical vagus nerve stimulator and a brief course of ECT (3 unilateral treatments). Her depression improved markedly, and it has remained in sustained remission for 3.5 years. This case suggests a potential synergistic effect of VNS and ECT, as well as provides possible clues to the neural circuitry of VNS in TRMD.

Operating room integration and telehealth.

The increasing use of advanced automated and computer-controlled systems and devices in surgical procedures has resulted in problems arising from the crowding of the operating room with equipment and the incompatible control and communication standards associated with each system. This lack of compatibility between systems and centralized control means that the surgeon is frequently required to interact with multiple computer interfaces in order to obtain updates and exert control over the various devices at his disposal. To reduce this complexity and provide the surgeon with more complete and precise control of the operating room systems, a unified interface and communication network has been developed. In addition to improving efficiency, this network also allows the surgeon to grant remote access to consultants and observers at other institutions, enabling experts to participate in the procedure without having to travel to the site.

An integrated surgical communication network--SurgON.

An integrated communication network, SurgON, has been developed to enable a surgeon to control multiple operating room systems and devices and monitor data streams from diverse sources via a single console. The system also enables the surgeon to grant access and control to remote observers and participants. A test configuration has been evaluated.

Physiology of Cultured Human Microglia Maintained in a Defined Culture Medium.

Microglia are the primary immune cell of the CNS, comprising 5-20% of the ∼60 billion neuroglia in the human brain. In the developing and adult CNS, they preferentially target active neurons to guide synapse maturation and remodeling. At the same time, they are the first line of defense against bacterial, fungal, and viral CNS infections. Although an extensive literature details their roles in rodents, less is known about how they function in humans because of the difficulty in obtaining tissue samples and the understandable inability to extensively study human microglia in situ. In this study, we use recent advances in the study of brain microenvironments to establish cultures of primary human microglia in a serum-free medium. Postsurgical samples of human brain were enzymatically and mechanically dissociated into single cells, and microglia were isolated at high purity by positive selection using CD11b Ab-coated microbeads. The CD11b+ cells were plated on poly-l-lysine-coated surfaces and bathed in serum-free DMEM/F12 supplemented with three essential components (TGF-ß, IL-34, and cholesterol). Under these conditions, microglia assumed a ramified morphology, showed limited proliferation, actively surveyed their surroundings, and phagocytosed bacterial microparticles. In the presence of LPS, they assumed a more compact shape and began production of proinflammatory cytokines and reactive oxygen species. LPS on its own triggered release of TNF-α, whereas release of IL-1ß required costimulation by ATP. Thus, human microglia maintained in a defined medium replicate many of the characteristics expected of native cells in the brain and provide an accessible preparation for investigations of human microglial physiology, pharmacology, and pathophysiology.

Ballistic lobar trajectory outcomes in civilian firearm penetrating brain injury.

OBJECTIVE: Penetrating brain injury (PBI) is the most lethal of all firearm injuries, with reported survival rates of less than 20%. The projectile trajectory (PT) has been shown to impact mortality, but the significant lobar tracks have not been defined. The aim of this retrospective case-control study was to test for associations between distinct ballistic trajectories, missile types, and patient outcomes. METHODS: A total of 243 patients who presented with a PBI to the Saint Louis University emergency department from 2008 through 2019 were identified from the hospital registry. Conventional CT scans combined with 3D CT reconstructions and medical records were reviewed for each patient to identify distinct PTs. RESULTS: A total of 65 ballistic lobar trajectories were identified. Multivariable regression models were used, and the results were compared with those in the literature. Penetrating and perforating types of PBI associated with bitemporal (t-statistic = -2.283, p = 0.023) or frontal-to-contralateral parietal (t-statistic = -2.311, p = 0.025) projectile paths were universally found to be fatal. In the group in which the Glasgow Coma Scale (GCS) score at presentation was lower than 8, a favorable penetrating missile trajectory was one that involved a single frontal lobe (adjusted OR 0.02 [95% CI 0.00-0.38], p = 0.022) or parietal lobe (adjusted OR 0.15 [95% CI 0.02-0.97], p = 0.048). Expanding or fragmenting types of projectiles carry higher mortality rates (OR 2.53 [95% CI 1.32-4.83], p < 0.001) than do nondeformable missiles. Patient age was not associated with worse outcomes when controlled by other significant predictive factors. CONCLUSIONS: Patients with penetrating or perforating types of PBI associated with bitemporal or frontal-to-contralateral parietal PTs should be considered as potential donor candidates. Trauma patients with penetrating missile trajectories involving a single frontal or parietal lobe should be considered for early neurosurgical intervention, especially in the circumstances of a low GCS score (< 8). Surgeons should not base their decision-making solely on advanced patient age to defer further treatment. Patients with PBIs caused by nondeformable types of projectiles can survive multiple simultaneous intracranial missile trajectories.

The Value of White Matter Tractography by Diffusion Tensor Imaging in Altering a Neurosurgeon's Operative Plan.

OBJECTIVE: To investigate if the implementation of white matter (WM) fiber tractography by diffusion tensor imaging in presurgical planning for supratentorial tumors proximal to eloquent WM tracts can alter a neurosurgeon's operative strategy. METHODS: A retrospective review was conducted of patients with supratentorial brain tumors within eloquent WM tracts who underwent diffusion tensor imaging (DTI) tractography as part of their preoperative assessment. These patients were classified into 3 different DTI groups per the radiology reports: group 1, intact WM tracts; group 2, deviated and/or displaced WM bundles; and group 3, patients with an established WM injury (interrupted and/or destroyed tracts). A blinded prospective behavioral study followed, in which 4 neurosurgeons reviewed the preoperative images at 2 different times (magnetic resonance imaging without DTI, followed by a review of the DTI). They provided estimations about the DTI group of each individual eloquent WM category in every patient, and their planned surgical approach. RESULTS: Fifteen patients (mean age, 58.3 years) were included in the study. The neurosurgeons provided a correct DTI group estimation in 53%, 60%, and 57% of the cases that involved motor/sensory pathway tracts, optic tracts, and language tracts, respectively. The neurosurgeons underestimated DTI group 3 in the motor category and in the optic category 75% of the time. DTI did not alter the planned surgical approach. CONCLUSIONS: DTI WM tractography helped neurosurgeons to correctly identify patients with interrupted motor and optic pathway tracts so they could be more aggressive with the extent of tumor resection, despite its inability to alter the operative approach.

The Clinical Utility of the Conners' Continuous Performance Test-II in Traumatic Brain Injury.

OBJECTIVE: The Conners' Continuous Performance Test Second Edition (CPT-II) is a measure commonly used in persons with suspected attentional deficits. Our study examined the utility of the CPT-II as a measure of attention in adults with traumatic brain injury (TBI) of varying severity. METHOD: As part of a larger investigation, several measures of cognitive functioning, including the CPT-II, were administered to 30 healthy control participants (HCP), 30 mild TBI participants (M-TBI), and 30 moderate to severe TBI participants (MS-TBI). Multivariate and correlational analyses compared group performances and examined convergent and divergent relationships between the CPT-II and various measures, including other tests of attention and neuropsychological function. RESULTS: Group differences were found for four of six CPT-II variables, with the MS-TBI group exhibiting greater impairment, relative to M-TBI and HCP. In addition, the CPT-II commission and detectability variables were found to correlate significantly with TBI severity. The CPT-II variables also demonstrated correlations of varying magnitude between commonly used neuropsychological measures. CONCLUSIONS: These findings support the utility of the CPT-II for assessing attentional abilities in persons with TBI of varying severity, particularly those with moderate to severe status. Moreover, the current study also demonstrates relationships that are consistent with convergent validity but inconsistent findings with regard to divergent validity. As a result, the CPT-II measures components of attention that is unique to other commonly used neuropsychological measures of attentive functioning. Further research examining CPT-II performance in TBI populations is recommended.

MRI-based high-dimensional hippocampal mapping in mesial temporal lobe epilepsy.

MRI-based evaluation of the hippocampus is important in the assessment and treatment of patients with mesial temporal lobe epilepsy (MTLE). Using MRI-based large-deformation high-dimensional mapping (HDM-LD), which allows structural evaluation of regions of the hippocampus, we document the HDM-LD-defined pattern of hippocampal deformation in MTLE patients compared with matched controls. In 30 subjects with MTLE and confirmed medial temporal lobe sclerosis (MTS), we performed measurements of intracranial area, brain parenchymal volume and deformation-based hippocampal segmentations, and then grouped patients into right and left MTS groups (resulting in 15 subjects in each group). Using HDM-LD techniques, we compared the right and left MTS groups with a group of 15 matched controls. Analysis included both the MTS and contralateral hippocampi, and covariance for changes in brain parenchymal volume. Final results were interpreted using a segmentation showing normal hippocampal surface subfield anatomy. Comparing the MTS groups with controls, after covarying with brain parenchymal volume, the MTS hippocampi showed significant volume loss (P < 0.0001), contralateral hippocampi showed no significant volume loss. HDM-LD techniques showed significant shape changes, with marked inward deviation in the Sommer sector of the MTS hippocampi. In the contralateral hippocampi, the inferior surface of the hippocampal body showed inward deformation in the medial aspect of the subiculum, with minimal involvement of the Sommer sector. HDM-LD shows involvement of subregions of the hippocampus which are consistent with MTS histopathology. Contralateral hippocampi show different HDM-LD changes, suggesting that the underlying disease process in the contralateral hippocampi is different from MTS.

The next generation of navigational technology.

Registration for image guidance has become significantly simplified and will continue to improve in accuracy. Unparalleled visualization of target tissues has been made possible through advances in imaging technologies,some of which have been modified to be employed directly in the operating room. With the advent of functional imaging techniques, the promise of functional rather than structural imaging suggests potentially fascinating interventions based on functional disturbances in tissue. Given the aggressive nature of the technology industry, some of the issues in surgical navigation discussed in this article have probably already been resolved and may be on their way to market. Undoubtedly, other points will also soon be addressed in novel and imaginative ways. As a result, the authors hope, the practice of rhinology will continue to evolve to improve the standard of care for patients. The future of many therapeutic interventions seems to be tied to the information infrastructure provided by information-guided therapy. Only through the innovative use of information-guided technology will further minimization of risks and maximization of benefit be achieved.

Cognitive and self-reported psychological outcomes of blast-induced mild traumatic brain injury in veterans: a preliminary study.

The increased use of explosives in combat has resulted in a large number of returning veterans suffering from blast-related mild traumatic brain injury (mTBI) and self-reported complications. It remains unclear whether this increase in self-reported difficulties is unique to the blast mechanism or stressful preinjury environment and whether cognitive-functioning deficits correspond with these difficulties in the postacute phase. This study examined the relationship between cognitive performance and self-reported psychological and somatic symptoms of blast-related mTBI compared with civilian mTBI, independent of comorbid posttraumatic stress disorder (PTSD) symptoms. Twelve veterans with blast-related mTBI were compared to 18 individuals with civilian mTBI on cognitive tests and self-report questionnaires. Univariate analyses failed to reveal differences on any individual cognitive test. Further, veterans reported more psychological and somatic complaints. These self-reported difficulties were not significantly correlated with neuropsychological performance. Overall, preliminary results suggest that in the postacute phase, subjective complaints related to blast-related mTBI do not covary with objective cognitive performance. Additionally, cognitive outcomes from blast-related mTBI were similar to those of civilian forms of mTBI. Future studies should identify the cognitive and self-reported sequelae of blast-related mTBI independent of comorbid PTSD in a larger sample of veterans.

Evaluation of Cortical Thickness after Traumatic Brain Injury in Military Veterans.

Military service members frequently sustain traumatic brain injuries (TBI) while on active duty, a majority of which are related to explosive blasts and are mild in severity. Studies evaluating the cortical gray matter in persons with injuries of this nature remain scarce. The purpose of this study was to assess cortical thickness in a sample of military veterans with chronic blast-related TBI. Thirty-eight veterans with mild TBI and 17 veterans with moderate TBI were compared with 58 demographically matched healthy civilians. All veterans with TBI sustained injuries related to a blast and were between 5 and 120 months post-injury (M = 62.08). Measures of post-traumatic stress disorder (PTSD) and depression were administered, along with a battery of neuropsychological tests to assess cognition. The Freesurfer software package was used to calculate cortical thickness of the participants. Results demonstrated significant clusters of cortical thinning in the right hemispheric insula and inferior portions of the temporal and frontal lobe in both mild and moderate TBI participants. The TBI sample from this study demonstrated a high incidence of comorbid PTSD and depression symptoms, which is consistent with the previous literature. Cortical thickness values correlated with measures of PTSD, depression, and post-concussive symptoms. This study provides evidence of cortical thinning in the context of chronic blast-related mild and moderate TBI in military veterans who have comorbid psychiatric symptoms. Our findings provide important insight into the natural progression of long-term cortical change in this population and may have implications for future clinical evaluation and treatment.

Complexity analysis of resting state magnetoencephalography activity in traumatic brain injury patients.

Diagnosis of mild traumatic brain injuries (TBIs) has been difficult because of the absence of obvious focal brain lesions, using conventional computed tomography (CT) or magnetic resonance imaging (MRI) scans, in a large percentage of TBIs. One useful measure that can characterize potential tissue and neural network damage objectively is Lempel-Ziv complexity (LZC) applied to magnetoencephalography (MEG) signals. LZC is a model-independent estimator of system complexity that estimates the number of different patterns in a sequence. We hypothesized that because of the potential network damage, TBIs would show a reduced level of complexity in regions that are impaired. We included 18 healthy controls and 18 military veterans with TBI in the study. Resting state MEG data were acquired, and the LZCs were analyzed across the whole brain. Our results indicated reduced complexity in multiple brain areas in TBI patients relative to the healthy controls. In addition, we detected several neuropsychological measures associated with motor responses, visual perception, and memory, correlated with LZC, which likely explains some of the cognitive deficits in TBI patients.

Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression.

BACKGROUND: Vagus nerve stimulation (VNS) has antidepressant effects in treatment resistant major depression (TRMD); these effects are poorly understood. This trial examines associations of subacute (3 months) and chronic (12 months) VNS with cerebral metabolism in TRMD. OBJECTIVE: (17)Fluorodeoxyglucose positron emission tomography was used to examine associations between 12-month antidepressant VNS response and cerebral metabolic rate for glucose (CMRGlu) changes at 3 and 12 months. METHODS: Thirteen TRMD patients received 12 months of VNS. Depression assessments (Hamilton Depression Rating Scale [HDRS]) and PET scans were obtained at baseline (pre-VNS) and 3/12 months. CMRGlu was assessed in eight a priori selected brain regions (bilateral anterior insular [AIC], orbitofrontal [OFC], dorsolateral prefrontal [DLPFC], and anterior cingulate cortices [ACC]). Regional CMRGlu changes over time were studied in VNS responders (decreased 12 month HDRS by ≥50%) and nonresponders. RESULTS: A significant trend (decreased 3 month CMRGlu) in the right DLPFC was observed over time in VNS responders (n = 9; P = 0.006). An exploratory whole brain analysis (P(uncorrected) = 0.005) demonstrated decreased 3 month right rostral cingulate and DLPFC CMRGlu, and increased 12 month left ventral tegmental CMRGlu in responders. CONCLUSIONS/LIMITATIONS: VNS response may involve gradual (months in duration) brain adaptations. Early on, this process may involve decreased right-sided DLPFC/cingulate cortical activity; longer term effects (12 months) may lead to brainstem dopaminergic activation. Study limitations included: a) a small VNS nonresponders sample (N = 4), which limited conclusions about nonresponder CMRGlu changes; b) no control group; and, c) patients maintained their psychotropic medications.