Embedded Human Closed-Loop Deep Brain Stimulation for Tourette Syndrome: A Nonrandomized Controlled Trial.

Importance: Because Tourette syndrome (TS) is a paroxysmal disorder, symptomatic relief in individuals with TS may be possible through the application of stimulation only during the manifestation of human tic neural signatures. This technique could be capable of suppressing both motor and vocal tics and would have similar effectiveness to conventional continuous deep brain stimulation (DBS). Objective: To evaluate the feasibility, safety, and clinical effectiveness of bilateral centromedian-parafascicular complex thalamic closed-loop DBS as a treatment for medication-refractory TS. Design, Setting, and Participants: This single-center double-blinded safety and feasibility trial was conducted between February 2014 and June 2020. Six individuals with TS were screened and recruited from the Norman Fixel Institute at the University of Florida. The primary outcome was measured at 6 months, and participants were followed up for the duration of the neurostimulator battery life. Independent ratings that compared closed-loop and conventional DBS were videotaped. The first 2 of 6 individuals with TS were excluded from the study because the technology for embedded closed-loop capability was not yet available. The date of analysis was August 2020. Interventions: DBS therapy controlled by an embedded closed-loop stimulation system. Main Outcomes and Measures: The primary clinical outcome measure was a minimum of a 40% reduction in the YGTSS score at 6 months following DBS. There was also a comparison of conventional DBS with closed-loop DBS using the Modified Rush Videotape Rating Scale for Tic. Results: The mean (SD) age at TS diagnosis for the cohort was 8.5 (2.9), and the mean (SD) disease duration was 23.7 (5.8) years. Four individuals with TS were analyzed (2 male, 2 female; mean [SD] age, 23.7 [5.8] years). The study showed the closed-loop approach was both feasible and safe. One of the novelties of this study was that a patient-specific closed-loop paradigm was created for each participant. The features and stimulation transition speed were customized based on the signal quality and the tolerance to adverse reactions. The mean (SD) therapeutic outcome with conventional DBS was 33.3% (35.7%) improvement on the YGTSS and 52.8% (21.9%) improvement on the Modified Rush Videotape Rating Scale. Two of 4 participants had a primary outcome variable improvement of 40% meeting the primary efficacy target. When comparing closed-loop DBS with conventional DBS using a Wilcoxon sign-rank test, there was no statistical difference between tic severity score and both approaches revealed a lower tic severity score compared with baseline. The study was feasible in all 4 participants, and there were 25 total reported adverse events with 3 study-related events (12%). The most common adverse events were headache and anxiety. Conclusions and Relevance: Embedded closed-loop deep DBS was feasible, safe, and had a comparable outcome to conventional TS DBS for the treatment of tics. Trial Registration: ClinicalTrials.gov Identifier: NCT02056873.

Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial.

(Appeared originally in American Journal of Psychiatry 2019; 176:931-938) Reprinted with permission from American Psychiatric Association Publishing.

Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults.

Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD. METHODS: Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers. RESULTS: Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024). CONCLUSIONS: Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.

Double blind randomized controlled trial of deep brain stimulation for obsessive-compulsive disorder: Clinical trial design.

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.

The Decline of Deep Brain Stimulation for Obsessive-Compulsive Disorder Following FDA Humanitarian Device Exemption Approval.

Background: In February 2009, the US Food and Drug Administration (FDA) granted Humanitarian Device Exemption (HDE) for deep brain stimulation (DBS) in the anterior limb of the internal capsule (ALIC) for the treatment of severely debilitating, treatment refractory obsessive-compulsive disorder (OCD). Despite its promise as a life altering treatment for patients with otherwise refractory, severely debilitating OCD, the use of DBS for the treatment of OCD has diminished since the FDA HDE endorsement and is now rarely performed even at busy referral centers. We sought to identify factors hindering OCD patients from receiving DBS therapy. Materials and Methods: University of Florida (UF) clinical research databases were queried to identify patients evaluated as potential candidates for OCD DBS from January 1, 2002 to July 30, 2020. A retrospective review of these patients' medical records was performed to obtain demographic information, data related to their OCD, and details relevant to payment such as third-party payer, study participation, evaluation prior to or after HDE approval, and any stated factors prohibiting surgical intervention. Results: Out of 25 patients with severe OCD identified as candidates for DBS surgery during the past 18 years, 15 underwent surgery. Prior to FDA HDE approval, 6 out of 7 identified candidates were treated. After the HDE, only 9 out of 18 identified candidates were treated. Seven of the 9 were funded by Medicare, 1 paid out of pocket, and 1 had "pre-authorization" from her private insurer who ultimately refused to pay after the procedure. Among the 10 identified OCD DBS candidates who were ultimately not treated, 7 patients-all with private health insurance-were approved for surgery by the interdisciplinary team but were unable to proceed with surgery due to lack of insurance coverage, 1 decided against surgical intervention, 1 was excluded due to medical comorbidities and excessive perceived surgical risk, and no clear reason was identified for 1 patient evaluated in 2004 during our initial NIH OCD DBS trial. Conclusion: Based on compelling evidence that DBS provides substantial improvement of OCD symptoms and markedly improved functional capacity in 2 out of 3 patients with severely debilitating, treatment refractory OCD, the FDA approved this procedure under a Humanitarian Device Exemption in 2009, offering new hope to this unfortunate patient population. A careful review of our experience with OCD DBS at the University of Florida shows that since the HDE approval, only 50% of the severe OCD patients (9 of 18) identified as candidates for this potentially life altering treatment have been able to access the therapy. We found the most common limiting factor to be failure of private insurance policies to cover DBS for OCD, despite readily covering DBS for Parkinson's disease, essential tremor, and even dystonia-another HDE approved indication for DBS. We have identified an inherent discrimination in the US healthcare system against patients with medication-refractory OCD who are economically challenged and do not qualify for Medicare. We urge policy makers, insurance companies, and hospital administrations to recognize this health care disparity and seek to rectify it.

Utility of nuclear stress imaging in predicting long-term outcomes one-year post CABG Surgery.

BACKGROUND: Early MPI after CABG is currently considered rarely appropriate in asymptomatic patients. This study aimed to identify prognostic value of nuclear stress-imaging post-CABG. METHODS: This was a single center prospective study looking at long-term outcomes post-CABG. Per protocol participants underwent SPECT-MPI stress testing and coronary angiogram on the same day, 1-year following CABG. Defect size was semi-quantified. The primary outcomes were the composite of death and congestive heart failure. RESULTS: Eighty-four participants underwent nuclear stress-imaging and angiography, with a median follow-up of 11.1 years. Three separate stress findings predicted the primary outcome: inability to reach stage 3 of a Bruce protocol (OR 7.3, CI 2.4-22.1, P < 0.001), LVEF < 45% (OR 4.0, CI 1.1-15.3, P = 0.041) and a moderate-large stress defect size (HR 2.31, CI 1.1-1.5, P = 0.04). These findings appear to be additive and strongest among patients who underwent exercise stress testing (HR 10.6, CI 3.6-30.6, P < 0.001). Graft disease was identified in 39 (46%) patients and compared to those individuals with no graft disease, did not predict long-term adverse outcomes (P = 0.29). CONCLUSION: In clinically stable patients early after revascularization with CABG, SPECT-MPI can identify patients at higher risk of heart failure and death.

Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic and disabling condition that often responds unsatisfactorily to pharmacological and psychological treatments. Converging evidence suggests a dysfunction of the cortical-striatal-thalamic-cortical circuit in OCD, and a previous feasibility study indicated beneficial effects of deep transcranial magnetic stimulation (dTMS) targeting the medial prefrontal cortex and the anterior cingulate cortex. The authors examined the therapeutic effect of dTMS in a multicenter double-blind sham-controlled study. METHODS: At 11 centers, 99 OCD patients were randomly allocated to treatment with either high-frequency (20 Hz) or sham dTMS and received daily treatments following individualized symptom provocation, for 6 weeks. Clinical response to treatment was determined using the Yale-Brown Obsessive Compulsive Scale (YBOCS), and the primary efficacy endpoint was the change in score from baseline to posttreatment assessment. Additional measures were response rates (defined as a reduction of ≥30% in YBOCS score) at the posttreatment assessment and after another month of follow-up. RESULTS: Eighty-nine percent of the active treatment group and 96% of the sham treatment group completed the study. The reduction in YBOCS score among patients who received active dTMS treatment was significantly greater than among patients who received sham treatment (reductions of 6.0 points and 3.3 points, respectively), with response rates of 38.1% and 11.1%, respectively. At the 1-month follow-up, the response rates were 45.2% in the active treatment group and 17.8% in the sham treatment group. Significant differences between the groups were maintained at follow-up. CONCLUSIONS: High-frequency dTMS over the medial prefrontal cortex and anterior cingulate cortex significantly improved OCD symptoms and may be considered as a potential intervention for patients who do not respond adequately to pharmacological and psychological interventions.

Surgical Swine Model of Chronic Cardiac Ischemia Treated by Off-Pump Coronary Artery Bypass Graft Surgery.

Chronic cardiac ischemia that impairs cardiac function, but does not result in infarct, is termed hibernating myocardium (HM). A large clinical subset of coronary artery disease (CAD) patients have HM, which in addition to causing impaired function, puts them at higher risk for arrhythmia and future cardiac events. The standard treatment for this condition is revascularization, but this has been shown to be an imperfect therapy. The majority of pre-clinical cardiac research focuses on infarct models of cardiac ischemia, leaving this subset of chronic ischemia patients largely underserved. To address this gap in research, we have developed a well-characterized and highly reproducible model of hibernating myocardium in swine, as swine are ideal translational models for human heart disease. In addition to creating this unique disease model, we have optimized a clinically relevant treatment model of coronary artery bypass surgery in swine. This allows us to accurately study the effects of bypass surgery on heart disease, as well as investigate additional or alternate therapies. This model surgically induces single vessel stenosis by implanting a constrictor on the left anterior descending (LAD) artery in a young pig. As the pig grows, the constrictor creates a gradual stenosis, resulting in chronic ischemia with impaired regional function, but preserving tissue viability. Following the establishment of the hibernating myocardium phenotype, we perform off-pump coronary artery bypass graft surgery to revascularize the ischemic region, mimicking the gold-standard treatment for patients in the clinic.

Depressive Symptoms are Frequent in Atypical Parkinsonian Disorders.

OBJECTIVE: To compare the incidence and prevalence of depressive symptoms in atypical parkinsonian (APD) syndromes versus Parkinson disease (PD). METHODS: In a large retrospective patient cohort we analyzed the incidence and prevalence of depressive symptoms using the Beck Depression Inventory (BDI) and evaluated subjects longitudinally on subsequent visits. For individuals who followed in subsequent visits we calculated incidence rates in person-years as a measure of incidence. RESULTS: We identified 361 patients with APD including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB), and 2352 PD controls. The mean BDI values were significantly higher in APD (F=14.19, p < 0.001). A significantly higher proportion of APD subjects screened positive for depressive symptoms both at initial and subsequent patient visits (p < 0.001), which appeared to be more severe in the APD subgroups. UPDRS part III and disease duration weakly correlated with depressive symptoms. CONCLUSIONS: Our results suggest that the incidence and prevalence of depressive symptoms are higher in APD and appear also to be more severe than in PD. Depressive symptoms in APD are common and affect patients regardless of disease duration or motor severity.

Magnetic resonance imaging assessment of cardiac function in a swine model of hibernating myocardium 3 months following bypass surgery.

OBJECTIVE: Clinical studies demonstrate delayed recovery of hibernating myocardium (HM) following coronary artery bypass graft (CABG) surgery. Cardiac magnetic resonance (CMR) imaging is effective in identifying HM in clinical settings. Our animal model of HM shows partial but incomplete functional recovery 1 month following CABG using echocardiography. This study uses CMR imaging to determine completeness of recovery 3 months post-CABG. METHODS: Swine (N = 12) underwent left anterior descending artery (LAD) 1.5-cm constrictor placement creating a territory of HM over 12 weeks. CMR at 12 weeks confirmed hibernation without infarction (N = 12). Off-pump left internal thoracic artery (LITA) to the LAD was performed in 9 animals. Three animals were killed as HM controls. CMR imaging was repeated in revascularized animals before death at 1 (n = 4) or 3 months (n = 5). CMR imaging was performed at baseline and with dobutamine infusion (5 µg/kg/min). RESULTS: Twelve weeks after constrictor placement, CMR imaging confirmed viability in LAD region and LAD stenosis in all animals. In HM, wall thickening is reduced at baseline but with contractile reserve present during dobutamine infusion. Following revascularization, CMR imaging confirmed patent LITA graft (n = 9). Analysis of baseline regional function shows incomplete recovery of HM following CABG, with reduced contractile reserve at both 1 and 3 months post-CABG. CONCLUSIONS: CMR imaging provides accurate spatial resolution of regional contractile function and confirms the presence of HM at 12 weeks following instrumentation of the LAD. Three months following CABG, partial recovery of HM with contractile reserve is present in the single LAD territory.

Six-Nine Year Follow-Up of Deep Brain Stimulation for Obsessive-Compulsive Disorder.

OBJECTIVE: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) region has shown promise as a neurosurgical intervention for adults with severe treatment-refractory obsessive-compulsive disorder (OCD). Pilot studies have revealed improvement in obsessive-compulsive symptoms and secondary outcomes following DBS. We sought to establish the long-term safety and effectiveness of DBS of the VC/VS for adults with OCD. MATERIALS AND METHODS: A long term follow-up study (73-112 months) was conducted on the six patients who were enrolled in the original National Institute of Mental Health pilot study of DBS for OCD. Qualitative and quantitative data were collected. RESULTS: Reduction in OCD symptoms mirrored the one-year follow-up data. The same four participants who were treatment responders after one year of treatment showed a consistent OCD response (greater than 35% reduction in Yale Brown Obsessive Compulsive Scale (YBOCS)). Another subject, classified as a non-responder, achieved a 26% reduction in YBOCS score at long term follow-up. The only patient who did not achieve a 25% or greater reduction in YBOCS was no longer receiving active DBS treatment. Secondary outcomes generally matched the one-year follow-up with the exception of depressive symptoms, which significantly increased over the follow-up period. Qualitative feedback indicated that DBS was well tolerated by the subjects. DISCUSSION: These data indicate that DBS was safe and conferred a long-term benefit in reduction of obsessive-compulsive symptoms. DBS of the VC/VS region did not reveal a sustained response for comorbid depressive symptoms in patients with a primary diagnosis of OCD.

Scheduled, intermittent stimulation of the thalamus reduces tics in Tourette syndrome.

INTRODUCTION: Personalized, scheduled deep brain stimulation in Tourette syndrome (TS) may permit clinically meaningful tic reduction while reducing side effects and increasing battery life. Here, we evaluate scheduled DBS applied to TS at two-year follow-up. METHODS: Five patients underwent bilateral centromedian thalamic (CM) region DBS. A cranially contained constant-current device delivering stimulation on a scheduled duty cycle, as opposed to the standard continuous DBS paradigm was utilized. Baseline vs. 24-month outcomes were collected and analyzed, and a responder analysis was performed. A 40% improvement in the Modified Rush Tic Rating Scale (MRTRS) total score or Yale Global Tic Severity Scale (YGTSS) total score defined a full responder. RESULTS: Three of the 4 patients followed to 24 months reached full responder criteria and had a mean stimulation time of 1.85 h per day. One patient lost to follow-up evaluated at the last time point (month 18) was a non-responder. Patients exhibited improvements in MRTRS score beyond the improvements previously reported for the 6 month endpoint; on average, MRTRS total score was 15.6% better at 24 months than at 6 months and YGTSS total score was 14.8% better. Combining the patients into a single cohort revealed significant improvements in the MRTRS total score (-7.6 [5.64]; p = 0.02). CONCLUSION: Electrical stimulation of the centromedian thalamic region in a scheduled paradigm was effective in suppressing tics, particularly phonic tics. Full responders were able to achieve the positive DBS effect with a mean of 2.3 ± 0.9 (SEM) hours of DBS per day.

Pioglitazone increases PGC1-α signaling within chronically ischemic myocardium.

The peroxisome proliferator-activated receptor (PPAR)-γ drug pioglitazone (PIO) has been shown to protect tissue against oxidant stress. In a swine model of chronic myocardial ischemia, we tested whether PIO increases PGC1-α signaling and the expression of mitochondrial antioxidant peptides. Eighteen pigs underwent a thoracotomy with placement of a fixed constrictor around the LAD artery. At 8 weeks, diet was supplemented with either PIO (3 mg/kg) or placebo for 4 weeks. Regional myocardial function and blood flow were determined at the time of the terminal study. PGC1-α expression was quantified from nuclear membranes by gels and respiration, oxidant stress markers and proteomics by iTRAQ were determined from isolated mitochondria. In the chronically ischemic LAD region, wall thickening from the PIO and control groups was 42 ± 6 and 45 ± 5 %, respectively (NS) with no intergroup differences in basal blood flow (0.72 ± 0.04 versus 0.74 ± 0.04 ml/min g, respectively; NS). In the PIO group, the expression of nuclear bound PGC1-α was higher (11.3 ± 2.6 versus 4.4 ± 1.4 AU; P < 0.05) and the content of mitochondrial antioxidant peptides including superoxide dismutase 2, aldose reductase, glutathione S-transferase and thioredoxin reductase were greater than controls. Although isolated mitochondria from the PIO group showed lower state 3 respiration (102 ± 13 versus 161 ± 22 nmol/min mg; P < 0.05), no differences in oxidant stress were noted by protein carbonyl (1.7 ± 0.7 versus 1.1 ± 0.1 nmol/mg). Chronic pioglitazone does not reduce regional myocardial blood flow or function in a swine model of chronic myocardial ischemia, but may have an important role in increasing expression of antioxidant proteins through PGC1-α signaling.

Cardiac Strain in a Swine Model of Regional Hibernating Myocardium: Effects of CoQ10 on Contractile Reserve Following Bypass Surgery.

There is conflicting clinical evidence whether administration of coenzyme Q10 (CoQ10) improves function following coronary artery bypass graft surgery (CABG). Using a swine model of hibernating myocardium, we tested whether daily CoQ10 would improve contractile function by MRI at 4-week post-CABG. Twelve pigs underwent a thoracotomy and had a constrictor placed on the left anterior descending (LAD). At 12 weeks, they underwent off-pump bypass and received daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo. At 4-week post-CABG, circumferential strain measurements in the hibernating LAD region from placebo and CoQ10 groups were not different and increased to a similar extent with dobutamine (-14.7 ± 0.6 versus -14.8 ± 0.1, respectively (NS)). Post-sacrifice, oxidant stress markers were obtained in the mitochondrial isolates and protein carbonyl in the placebo, and CoQ10 groups were 6.14 ± 0.36 and 5.05 ± 0.32 nmol/mg, respectively (NS). In summary, CoQ10 did not improve contractile reserve or reduce oxidant stress at 4-week post-CABG.

Interdisciplinary Parkinson's Disease Deep Brain Stimulation Screening and the Relationship to Unintended Hospitalizations and Quality of Life.

OBJECTIVE: To investigate the impact of pre-operative deep brain stimulation (DBS) interdisciplinary assessments on post-operative hospitalizations and quality of life (QoL). BACKGROUND: DBS has been utilized successfully in Parkinson's disease (PD) for the treatment of tremor, rigidity, bradykinesia, off time, and motor fluctuations. Although DBS is becoming a more common management approach there are no standardized criteria for selection of DBS candidates, and sparse data exist to guide the use of interdisciplinary evaluations for DBS screening. We reviewed the outcomes of the use of an interdisciplinary model which utilized seven specialties to pre-operatively evaluate potential DBS candidates. METHODS: The University of Florida (UF) INFORM database was queried for PD patients who had DBS implantations performed at UF between January 2011 and February 2013. Records were reviewed to identify unintended hospitalizations, falls, and infections. Minor and major concerns or reservations from each specialty were previously documented and quantified. Clinical outcomes were assessed through the use of the Parkinson disease quality of life questionnaire (PDQ-39), and the Unified Parkinson's Disease Rating Score (UPDRS) Part III. RESULTS: A total of 164 cases were evaluated for possible DBS candidacy. There were 133 subjects who were approved for DBS surgery (81%) following interdisciplinary screening. There were 28 cases (21%) who experienced an unintended hospitalization within the first 12 months following the DBS operation. The patients identified during interdisciplinary evaluation with major or minor concerns from any specialty service had more unintended hospitalizations (93%) when compared to those without concerns (7%). When the preoperative "concern" shifted from "major" to "minor" to "no concerns," the rate of hospitalization decreased from 89% to 33% to 3%. A strong relationship was uncovered between worsened PDQ-39 at 12 months and increased hospitalization. CONCLUSIONS: Unintended hospitalizations and worsened QOL scores correlated with the number and severity of concerns raised by interdisciplinary DBS evaluations. The data suggest that detailed screenings by interdisciplinary teams may be useful for more than just patient selection. These evaluations may help to stratify risk for post-operative hospitalization and QoL outcomes.

Long-Term Outcomes of Patients Who Had Cardiac Arrest After Cardiac Operations.

BACKGROUND: Cardiac arrest after cardiac procedures has a case fatality rate of approximately 60%. However, the long-term risk of death and outcomes among survivors of postoperative cardiac arrest is less clear. METHODS: We examined the mortality and outcomes of 6,979 consecutive patients who underwent cardiac operations from 1991 to 2014 in the Minneapolis Veterans Affairs Health Care System. RESULTS: Cardiac arrest occurred in 182 patients (2.6%) at a median of 3 days (range, 0 to 39 days) after the operation. Of these, 93 (51%) died during the same hospitalization, and an additional 24 (13%) died within 1 year. Mortality at 30 days (51% vs 1.9%; p < 0.0001), at 1 year (64% vs 6%; p < 0.0001), and after a mean follow-up of 7.5 ± 5.5 years (81% vs 34%; p < 0.0001), was higher in those with vs without cardiac arrest. After adjusting for age, sex, year, and type of operation, an in-hospital cardiac arrest was associated with a 4.7-times (95% confidence interval [CI], 3.9 to 5.6; p < 0.0001) higher risk of long-term death in the entire cohort, 2.0-times (95% CI, 1.6 to 2.7; p < 0.0001) higher risk among those who survived 30 days, and 1.3-times (95% CI, 0.9 to 1.9; p = 0.14) higher risk among those who survived 1 year after the operation. Being discharged to a facility (hazard ratio, 3.97; 95% CI, 1.52 to 10.32; p = 0.005) and renal dysfunction (hazard ratio, 3.35; 95% CI, 1.42 to 7.89; p = 0.006) were independent predictors of death amongst cardiac arrest survivors. CONCLUSIONS: Long-term mortality remains high in patients discharged alive after postoperative cardiac arrest. Discharge disposition and renal dysfunction after cardiac arrest have important prognostic implications.

Impact of an Interdisciplinary Deep Brain Stimulation Screening Model on Post-Surgical Complications in Essential Tremor Patients.

OBJECTIVE: To investigate the relationship of our interdisciplinary screening process on post-operative unintended hospitalizations and quality of life. BACKGROUND: There are currently no standardized criteria for selection of appropriate Deep Brain Stimulation candidates and little hard data exists to support the use of any singular method. METHODS: An Essential Tremor cohort was selected from our institutional Deep Brain Stimulation database. The interdisciplinary model utilized seven specialties who pre-operatively screened all potential Deep Brain Stimulation candidates. Concerns for surgery raised by each specialty were documented and classified as none, minor, or major. Charts were reviewed to identify unintended hospitalizations and quality of life measurements at 1 year post-surgery. RESULTS: Eighty-six percent (44/51) of the potential screened candidates were approved for Deep Brain Stimulation. Eight (18%) patients had an unintended hospitalization during the follow-up period. Patients with minor or major concerns raised by any specialty service had significantly more unintended hospitalizations when compared to patients without concerns (75% vs. 25%, p < 0.005). The rate of hospitalization revealed a direct relationship to the "level of concern"; ranging from 100% if major concerns, 42% if minor concerns, and 7% if no concerns raised, p = 0.001. Quality of life scores significantly worsened in patients with unintended hospitalizations at 6 (p = 0.046) and 12 months (p = 0.027) when compared to baseline scores. No significant differences in tremor scores between unintended and non-unintended hospitalizations were observed. CONCLUSIONS: The number and level of concerns raised during interdisciplinary Deep Brain Stimulation screenings were significantly related to unintended hospitalizations and to a reduced quality of life. The interdisciplinary evaluation may help to stratify risk for these complications. However, data should be interpreted with caution due to the limitations of our study. Further prospective comparative and larger studies are required to confirm our results.

The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease.

Clinicians often use the term "hibernating myocardium" in reference to patients with ischemic heart disease and decreased function within viable myocardial regions. Because the term is a descriptor of nature's process of torpor, we provide a comparison of the adaptations observed in both conditions. In nature, hearts from hibernating animals undergo a shift in substrate preference in favor of fatty acids, while preserving glucose uptake and glycogen. Expression of electron transport chain proteins in mitochondria is decreased while antioxidant proteins including uncoupling protein-2 are increased. Similarly, hibernating hearts from patients have a comparable metabolic signature, with increased glucose uptake and glycogen accumulation and decreased oxygen consumption. In contrast to nature however, patients with hibernating hearts are at increased risk for arrhythmias, and contractility does not fully recover following revascularization. Clearly, additional interventions need to be advanced in patients with coronary artery disease and hibernating myocardium to prevent refractory heart failure.

Expression of uncoupling protein-2 remains increased within hibernating myocardium despite successful coronary artery bypass grafting at 4 wk post-revascularization.

BACKGROUND: We have previously shown that mitochondrial uncoupling protein-2 (UCP-2) is increased in a swine model of hibernating myocardium (HM). Although UCP-2 reduces oxidant stress, it can promote inefficiency of the electron transport chain. In this study, we tested whether UCP-2 remains increased in revascularized HM (RHM) after coronary artery bypass grafting (CABG). METHODS: Seven swine underwent thoracotomy with placement of a constrictor on the left anterior descending artery (LAD). Twelve weeks later, a left internal mammary artery graft was placed on the distal LAD. Four weeks post-CABG, computed tomography angiography documented patent grafts and function. At the terminal study, blood flow to the LAD and remote territories were assessed during high dose dobutamine and mitochondria isolated from both regions for analysis. Comparisons were made to a group of swine with HM who underwent constrictor placement without bypass grafting (n = 4). RESULTS: During dobutamine infusion, RHM demonstrated lower blood flows (2.44 ± 0.23 versus 3.43 ± 0.30 mL/min/g; P < 0.05) and reduced wall thickening (33 ± 9% versus 52 ± 13%; P < 0.05) compared with remote regions. RHM had lower respiratory control indices (3.7 ± 0.3 versus 4.3 ± 0.4; P < 0.05) with persistently increased UCP-2 content. CONCLUSIONS: Despite patent grafts, RHM demonstrates a submaximal response to dobutamine infusion and increased mitochondrial UCP-2 expression. These data support the notion that recovery of the mitochondria in RHM is delayed early post-CABG and may contribute to impaired oxygen consumption and contractile reserve during catecholamine challenges.