Search

Background: We previously demonstrated that deep brain stimulation (DBS) of lateral cerebellar nucleus (LCN) can enhance motor recovery and functional reorganization of perilesional cortex in rodent models of stroke or TBI., Objective: Considering the treatment-related neuroplasticity observed at the perilesional cortex, we hypothesize that chronic LCN DBS-enhanced motor recovery observed will carry-over even after DBS has been deactivated., Methods: Here, we directly tested the enduring effects of LCN DBS in male Long Evans rats that underwent controlled cortical impact (CCI) injury targeting sensorimotor cortex opposite their dominant forepaw followed by unilateral implantation of a macroelectrode into the LCN opposite the lesion. Animals were randomized to DBS or sham treatment for 4 weeks during which the motor performance were characterize by behavioral metrics. After 4 weeks, stimulation was turned off, with assessments continuing for an additional 2 weeks. Afterward, all animals were euthanized, and tissue was harvested for further analyses., Results: Treated animals showed significantly greater motor improvement across all behavioral metrics relative to untreated animals during the 4-week treatment, with functional gains persisting across 2-week post-treatment. This motor recovery was associated with the increase in CaMKIIα and BDNF positive cell density across perilesional cortex in treated animals., Conclusions: LCN DBS enhanced post-TBI motor recovery, the effect of which was persisted up to 2 weeks beyond stimulation offset. Such evidence should be considered in relation to future translational efforts as, unlike typical DBS applications, treatment may only need to be provided until such time as a new function plateau is achieved., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs. Machado and Baker have intellectual property and distribution rights in Enspire DBS Therapy, Inc., which is a spin-off of the Cleveland Clinic. Drs. Machado and Baker serve on the Scientific Advisory Board of Enspire DBS Therapy, Inc. Dr. Machado holds a patent titled as “Methods of treating medical conditions by neuromodulation of the cerebellar pathways.” US 7,640,063.

Early exposure to stressors affects how the organism reacts to stimuli, its emotional state throughout life, and how it deals with emotional memories. Consequently, it may affect susceptibility to psychopathology later in life. We used an animal model of early stress by maternal separation to study its potential impact on the extinction of aversive memories and anxiety-like behavior in adulthood, as well as its effects on mitochondrial functionality, inflammatory and astrocytic markers in the amygdala. We also assessed whether a diet enriched with linseed oil, known for its high content in omega-3 fats, could be used to attenuate the behavioral and neurochemical effects of early stress. Litters of Wistar rats were divided into controls (intact) or subjected to maternal separation (MS). They were subdivided into two groups receiving isocaloric diets enriched in soy or linseed oils at weaning. In adulthood, the animals were exposed to the open field and the elevated plus maze, to evaluate exploratory activity and anxiety-like behavior. They were also trained in a context of fear conditioning, and afterward subjected to an extinction session, followed by a test session to evaluate the extinction memory. Amygdalae were evaluated for inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumor-necrose factor (TNF)-alpha), mitochondrial functionality, and astrocyte markers (glial fibrillary acidic protein - GFAP, S100B, and glutamine synthetase activity). MS induced anxiety-like behavior in the elevated plus-maze, which was reversed by a diet enriched in linseed oil offered from weaning. When testing the memory of an extinction session of fear conditioning, MS animals showed more freezing behavior. MS males receiving a linseed oil-enriched diet had lower functional mitochondria in the amygdala. In addition, MS led to increased inflammatory cytokines, particularly IL-1beta, and the diet enriched in linseed oil further increased these levels in MS animals. MS also increased S100B levels. These results point to a higher emotionality presented by MS animals, with higher levels of inflammatory cytokines and S100B. While a diet enriched in linseed oil attenuated anxiety-like behavior, it further altered amygdala IL-1beta and reduced mitochondria functionality, particularly in males. MS also increased glutamine synthetase activity in the amygdala, and this effect was higher when the animals received a diet enriched in linseed oil, particularly in females. In conclusion, these results point to MS effects on emotional behavior, and neurochemical alterations in the amygdala, with sex-specific effects. Although a diet enriched in linseed oil appears to be able to reverse some of MS behavioral effects, these results must be considered with caution, since biochemical parameters could be worsened in MS animals receiving a linseed oil-enriched diet. This knowledge is important for the understanding of mechanisms of action of strategies aiming to reverse early stress effects, and future studies are warranted to determine possible interventions to promote resilience., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: Deep brain stimulation (DBS) is an established neurosurgical treatment of a variety of neurological disorders. DBS is considered a safe and effective neurosurgical procedure; however, surgical complications are inevitable, and clinical outcomes may vary. The aim of this study was to describe DBS complications at a large clinical center in the United States and to investigate the relationship between patients' baseline characteristics, surgical technique, and operative complications., Methods: We identified all patients who underwent DBS lead implantation at our center between 1st January 2012 and 1st January 2020. We extracted relevant information regarding patient demographics, surgical details, clinical complications, and clinical outcomes from the electronic medical records., Results: A total of 859 leads were implanted in 481 patients (153 men, 328 women). The mean patient age at the time of the surgery was 65 years, with the mean disease duration of 13.3 years. There were no mortalities and 57 readmissions within 30 days (mean = 14.2 days). The most common complications included pneumocephalus (n = 661), edema (n = 78), altered mental state (n = 35), implantable pulse generator discomfort (n = 34), hemorrhage (n = 26), and infection (n = 23). Most notably, the use of general anesthesia, hypertension, heart disease, and depression were associated with significantly longer postoperative stay. High preoperative body mass index was associated with higher rates of surgery-related infections and lead revision/explantation. The intraoperative mean arterial pressure, anesthesia type, and frame apparatus were all important predictors of postoperative pneumocephalus., Conclusion: In this report, we described the rates and types of complications associated with DBS surgery at a large neurosurgical center in the United States. The novel insights highlighted in this study present an opportunity to further improve the clinical outcomes and patient selection in DBS surgery., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low-density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood-brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr -/- ) mice. We noticed that microgliosis was more severe in the hippocampus of middle-aged LDLr -/- mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr -/- mice already showed increased microgliosis and decreased immunocontent of claudin-5 in the prefrontal cortex (PFC). Subsequently, 6-month-old male C57BL/6 wild-type and LDLr -/- mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr -/- mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non-treated LDLr -/- mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region-specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6-month-old LDLr -/- mice exhibited a slight but not significant increase in IBA-1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr -/- mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH., (© 2023 International Society for Neurochemistry.)

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS., (Copyright © 2024 the authors.)

Objectives: Evaluate the bleaching efficacy (BE) and tooth sensitivity (TS) of in-office bleaching using different application tips., Methods: Forty-eight participants were selected (split-mouth), one to receive bleaching with an attached brush tip and one with a conventional tip. The procedure was performed with Whiteness Automixx Plus 35%. The BE was evaluated at the beginning, weekly, one and 12 months post-bleaching with a Vita Easyshade spectrophotometer (ΔE* ab , ΔE 00 , and WI D ) and with Vita classical A1-D4 and Vita Bleachedguide shade guides units (ΔSGU). Absolute risk and intensity of TS were recorded using the Visual Analogue Scale. The equivalence of BE was analyzed using the two one-sided t-tests for paired samples. The absolute risk of TS was evaluated using the McNemar test, and the TS intensity was measured with the paired t test (α = 0.05)., Results: The equivalence of BE was observed for both groups in all color evaluations (p > 0.05). A lower absolute risk and intensity of TS were observed for the attached brush tip when compared with the conventional tip (p < 0.003 and p < 0.0001)., Conclusion: Using an attached brush tip showed the same BE as a conventional tip. However, for the attached brush tip, there was a reduction in TS., Clinical Significance: The applicator-attached brush tip is recommended for in-office dental bleaching, because of the possible reduction in risk and intensity of TS., (© 2024 Wiley Periodicals LLC.)

Objective: The aim of this study was 1) to describe the rate of intrathecal baclofen (ITB)-associated complications at a large tertiary center, and 2) to evaluate the impact of patient-related factors on the likelihood of developing such complications., Methods: A retrospective single-center study was carried out. A total of 301 eligible patients were included in the analysis. Univariate regression models were used to evaluate the impact of age, sex, diagnosis, ambulation status, modified Ashworth scale score, body mass index, diabetes status, and pain level on the likelihood of developing a device-related infection, pump malfunction, catheter malfunction, and other clinically significant complications., Results: Overall, 27% of patients experienced an ITB-related complication. The most common complications included infection (6%, 18/301), pump malfunction (7.3%, 22/301), and catheter malfunction (14%, 42/301). The univariate analyses revealed that the patient's ambulatory status had a significant impact on the likelihood of developing a catheter-related malfunction. Furthermore, a trend toward significance was identified between patients' preoperative body mass index and device-related infection. Finally, the risk of suffering any ITB-related complications was statistically correlated with the number of years that had passed since the initial pump implantation., Conclusions: The authors' analysis reveals a previously underrecognized association between ambulatory status at the time of ITB pump implantation and the incidence of catheter-related complications, and confirms the impact of time since surgery on the risk of developing any ITB-related complication. The patient's age, sex, diagnosis, diabetes status, or pain level at baseline were not associated with the risk of complications. Collectively, these insights contribute novel information to the existing literature, providing practical value for physicians in guiding patient selection for ITB therapy.

Despite great advances in acute care and rehabilitation, stroke remains the leading cause of motor impairment in the industrialized world. We have developed a deep brain stimulation (DBS)-based approach for post-stroke rehabilitation that has shown reproducible effects in rodent models and has been recently translated to humans. Mechanisms underlying the rehabilitative effects of this novel therapy have been largely focused on the ipsilesional cortex, including cortical reorganization, synaptogenesis, neurogenesis and greater expression of markers of long-term potentiation. The role of subcortical structures on its therapeutic benefits, particularly the striatum, remain unclear. In this study, we compared the motor rehabilitative effects of deep cerebellar stimulation in two rodent models of cerebral ischemia: a) cortical ischemia; and b) combined striatal and cortical ischemia. All animals underwent the same procedures, including implantation of the electrodes and tethered connections for stimulation. Both experimental groups received four weeks of continuous lateral cerebellar nucleus (LCN) DBS and each was paired with a no stimulation, sham, group. Fine motor function was indexed using the pasta matrix task. Brain tissue was harvested for histology and immunohistochemical analyses. In the cortical-only ischemia, the average pasta matrix performance of both sham and stimulated groups reduced from 19 to 24 pieces to 7-8 pieces following the stroke induction. At the end of the four-week treatment, the performance of stimulated group was significantly greater than that of sham group (14 pieces vs 7 pieces, p < 0.0001). Similarly, in the combined cortical and striatal ischemia, the performance of both sham and stimulated groups reduced from 29 to 30 pieces to 7-11 pieces following the stroke induction. However, at the end of the four-week treatment, the performance of stimulated group was not significantly greater than that of sham group (15 pieces vs 11 pieces, p = 0.452). In the post-mortem analysis, the number of cells expressing CaMKIIα at the perilesional cortical and striatum of the LCN DBS treated animals receiving cortical-only stroke elevated but not those receiving cortical+striatal stroke. The current findings suggested that the observed, LCN DBS-enhanced motor recovery and perilesional plasticity may involve striatal mechanisms., Competing Interests: Declaration of competing interest Drs. Machado and Baker have intellectual property and distribution rights in Enspire DBS Therapy, Inc., which is a spin-off of the Cleveland Clinic. Drs. Machado and Baker serve on the Scientific Advisory Board of Enspire DBS Therapy, Inc. Dr. Machado holds a patent titled as “Methods of treating medical conditions by neuromodulation of the cerebellar pathways.”, US 7,640,063., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The primary aim of this study is to report long-term outcomes associated with deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) performed at our institution. We further aimed to elicit the factors associated with loss of efficacy and to discuss the need for exploring and establishing reliable rescue targets., Methods: To study long-term outcomes, we performed a retrospective chart review and extracted tremor scores of 43 patients who underwent VIM DBS lead implantation for essential tremor at our center. We further evaluated factors that could influence outcomes over time, including demographics, body mass index, duration of follow-up, degree of parenchymal atrophy indexed by the global cortical atrophy scale, and third ventricular width., Results: In this cohort, tremor scores on the latest follow-up (median 52.7 months) were noted to be worse than initial postoperative scores in 56% of DBS leads. Furthermore, 14% of leads were associated with clinically significant loss of benefit. Factors including the length of time since the lead implantation, age at the time of surgery, sex, body mass index, preoperative atrophy, and third ventricular width were not predictive of long-term outcomes., Conclusions: Our study identified a substantial subgroup of VIM-DBS patient who experienced a gradual decline in treatment efficacy over time. We propose that this phenomenon can be attributed primarily to habituation and disease progression. Furthermore, we discuss the need to establish reliable and effective rescue targets for this subpopulation of patients, with ventral-oralis complex and dentate nucleus emerging as potential candidates., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Functional neuroimaging methods like fMRI and PET are vital in neuroscience research, but require that subjects remain still throughout the scan. In animal research, anesthetic agents are typically applied to facilitate the acquisition of high-quality data with minimal motion artifact. However, anesthesia can have profound effects on brain metabolism, selectively altering dynamic neural networks and confounding the acquired data. To overcome the challenge, we have developed a novel head fixation device designed to support awake rat brain imaging. A validation experiment demonstrated that the device effectively minimizes animal motion throughout the scan, with mean absolute displacement and mean relative displacement of 0.0256 (SD: 0.001) and 0.009 (SD: 0.002), across eight evaluated subjects throughout fMRI image acquisition (total scanning time per subject: 31 min, 12 s). Furthermore, the awake scans did not induce discernable stress to the animals, with stable physiological parameters throughout the scan (Mean HR: 344, Mean RR: 56, Mean SpO 2 : 94 %) and unaltered serum corticosterone levels (p = 0.159). In conclusion, the device presented in this paper offers an effective and safe method of acquiring functional brain images in rats, allowing researchers to minimize the confounding effects of anesthetic use., Competing Interests: Declaration of competing interest This project has received funding through grants from NIH NINDS [R01NS116384]. Additionally, the innovative device described in this report has obtained a provisional patent (Serial No.: 63/461,932), and its commercial prospects are currently under evaluation by the Cleveland Clinic innovations department., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cerebellum shares robust di-synaptic dentato-thalamo-cortical (DTC) connections with the contralateral motor cortex. Preclinical studies have shown that DTC are excitatory in nature. Structural integrity of DTC is associated with better upper extremity (UE) motor function in people with stroke, indicating DTC are important for cerebellar influences on movement. However, there is a lack of understanding of physiologic influence of DTC in humans, largely due to difficulty in accessing the dentate nucleus., Objective: Characterize DTC physiology using dentate nucleus deep brain stimulation (DBS) combined with transcranial magnetic stimulation (TMS) in stroke., Methods: Nine chronic stroke survivors with moderate-to-severe UE impairment (Fugl-Meyer 13-38) underwent a paired DBS-TMS experiment before receiving experimental dentate nucleus DBS in our first-in-human phase I trial (Baker et al., 2023, Nature Medicine). Conditioning DBS pulses were given to dentate nucleus 1 to 10 ms prior to supra-threshold TMS pulses given to ipsilesional motor cortex. Effects were assessed on motor evoked potentials (MEPs). Size of DBS-conditioned MEPs was expressed relative to TMS MEPs, where values >1 indicate facilitation., Results: Dentate nucleus DBS led to facilitation of MEPs at short-latency intervals (3.5 and 5 ms, P  = .049 and .021, respectively), a phenomenon we have termed dentato-cortical facilitation (DCF). Higher DCF was observed among patients with more severe UE impairment. Diffusion tensor imaging revealed microstructure of thalamo-cortical portion of DTC was related to higher corticomotor excitability., Conclusions: Our in vivo investigation reveals for the first time in humans the intrinsic excitatory properties of DTC, which can serve as a novel therapeutic target for post-stroke motor recovery., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Andre G. Machado is a consultant and has intellectual property licensed to Enspire DBS. Kenneth B. Baker is a consultant to Enspire DBS. Enspire DBS funded part of the clinical trial. The remaining authors report no competing interests.

Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.ClinicalTrials.gov identifier: NCT02881151 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Transcranial direct current stimulation (tDCS) targeting the primary motor cortex is modestly effective for promoting upper-limb motor function following stroke. The premotor cortex (PMC) represents an alternative target based on its higher likelihood of survival and dense motor-network connections. Objective: The objective of this study was to determine whether ipsilesional PMC tDCS affects motor network functional connectivity (FC) in association with reduction in motor impairment, and to determine whether this relationship is influenced by baseline motor severity. Methods: Participants with chronic stroke were randomly assigned to receive active-PMC or sham-tDCS with rehabilitation for 5 weeks. Resting-state functional magnetic resonance imaging was acquired to characterize change in FC across motor-cortical regions. Results: Our results indicated that moderate-to-severe participants who received active-tDCS had greater increases in PMC-to-PMC interhemispheric FC compared to those who received sham; this increase was correlated with reduction in proximal motor impairment. There was also an increase in intrahemispheric dorsal premotor cortex-primary motor cortex FC across participants regardless of severity or tDCS group assignment; this increase was correlated with a reduction in proximal motor impairment in only the mild participants. Conclusions: Our findings have significance for developing targeted brain stimulation approaches. While participants with milder impairments may inherently recruit viable substrates within the ipsilesional hemisphere, stimulation of PMC may enhance interhemispheric FC in association with recovery in more impaired participants. Trial Registration: ClinicalTrials.gov Identifier: NCT01539096; Registration date: February 21, 2012.

Objective: High accuracy and precision are essential in stereotactic neurosurgery, as targeting errors can significantly affect clinical outcomes. Image registration is a vital step in stereotaxis, and understanding the error associated with different image registration methods is important to inform the choice of equipment and techniques in stereotactic neurosurgery. The authors aimed to quantify the test-retest reliability and stereotactic accuracy of cone-beam CT (CBCT) compared with the current clinical gold-standard technique (i.e., CT)., Methods: Two anthropomorphic phantom models with 40 independent unique steel spheres were developed to compare CBCT frame and stereotactic space registration with the clinical gold standard (CT). The cartesian coordinates of each sphere were compared between the imaging modalities for test-retest reliability and overall accuracy., Results: Both imaging modalities showed similar levels of fiducial deviation from the expected geometry. The equivalence test demonstrated mean differences between CT and CBCT registration of -0.082 mm (90% CI -0.27 to 0.11), -0.045 mm (90% CI -0.43 to 0.34), and -0.041 mm (90% CI -0.064 to 0.018) for coordinates in the x-, y-, and z-axes, respectively. The mean euclidean distance difference between the two modalities was 0.28 mm (90% CI 0.27-0.29)., Conclusions: Accuracy and precision were comparable between CBCT and CT image registrations. These findings suggest that CBCT registration can be used as a clinically equivalent substitute to gold-standard CT acquisition.

Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorganization of ipsilesional cortex in 12 individuals with persistent (1-3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: NCT02835443 ., (© 2023. The Author(s).)

Introduction: The therapeutic efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) may be limited for some patients by the presence of stimulation-related side effects. Such effects are most often attributed to electrical current spread beyond the target region. Prior computational modeling studies have suggested that changing the degree of asymmetry of the individual phases of the biphasic, stimulus pulse may allow for more selective activation of neural elements in the target region. To the extent that different neural elements contribute to the therapeutic vs. side-effect inducing effects of DBS, such improved selectivity may provide a new parameter for optimizing DBS to increase the therapeutic window., Methods: We investigated the effect of six different pulse geometries on cortical and myogenic evoked potentials in eight patients with PD whose leads were temporarily externalized following STN DBS implant surgery. DBS-cortical evoked potentials were quantified using peak to peak measurements and wavelets and myogenic potentials were quantified using RMS., Results: We found that the slope of the recruitment curves differed significantly as a function of pulse geometry for both the cortical- and myogenic responses. Notably, this effect was observed most frequently when stimulation was delivered using a monopolar, as opposed to a bipolar, configuration., Discussion: Manipulating pulse geometry results in differential physiological effects at both the cortical and neuromuscular level. Exploiting these differences may help to expand DBS' therapeutic window and support the potential for incorporating pulse geometry as an additional parameter for optimizing therapeutic benefit., Competing Interests: AM was a consultant and had intellectual property licensed to Enspire DBS, had distribution rights in Ceraxis, and was a consultant to Abbott. KB was a consultant for Enspire DBS. AM and KB had intellectual property and distribution rights in Cardionomics. SN consulted for Abbott and was a speaker for Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Campbell, Favi Bocca, Tiefenbach, Hogue, Nagel, Rammo, Escobar Sanabria, Machado and Baker.)

We aim to provide a comprehensive review of the current scientific evidence supporting the use of invasive neurostimulation in the treatment of deficits associated with traumatic brain injury (TBI), as well as to identify future directions for research and highlight important questions that remain unaddressed. Neurostimulation is a treatment modality with expanding applications in modern medical practice. Targeted electrical stimulation of specific brain regions has been shown to increase synaptogenesis and enhance structural reorganization of neuronal networks. This underlying therapeutic effect might be of high value for patients suffering from TBI because it could modulate neuronal connectivity and function of areas that are partially or completely spared after injury. The current published literature exploring the application of invasive neurostimulation for the treatment of functional deficits associated with TBI is scarce but promising. Rodent models have shown that targeted stimulation of the hippocampus or connecting structures can result in significant cognitive recovery, while stimulation of the motor cortex and deep cerebellar nuclei is associated with motor improvements. Data from clinical studies are extremely limited; single-patient reports and case series found neurostimulation to be effective in relieving motor symptoms, improving visuospatial memory, and supporting emotional adjustment. Looking forward, it will be important to identify stimulation targets and paradigms that can maximize improvement over multiple functional domains. It will also be important to corroborate the observed behavioral improvements with histological, electrophysiological, and radiological evidence. Finally, the impact of biological variables such as sex and age on the treatment outcomes needs to be explored., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Methods: and results: Pregnant Wistar rats received diets enriched in soybean oil (SO) or OO during gestation/lactation. At birth, litters were subdivided into MS or intact groups. After weaning, the pups received standard chow until adulthood, when they were subjected to behavioral tasks. At PND90 biochemical analyses were performed. Maternal OO-enriched diet prevented MS-induced higher weight gain, and decreased MS-induced anhedonic behavior. Increased latency to immobility and shorter immobility time were observed in the maternal OO-enrich diet groups. Maternal OO-enrich diet groups also presented reduced reactive oxygen species and increased activity of antioxidant enzymes. In addition, this diet showed sex-specific effects, by decreasing mitochondrial mass and potential, reducing AMPK activation, and increasing synaptophysin and PSD-95 immunocontent in the DH of male rats. Early stress, on the other hand, decreased production of free radicals and decreased levels of SIRT1 in the DH of male rats. In females, OO prevented the anhedonic behavior induced by MS., Conclusions: Maternal OO-enrich diet attenuated MS-induced depressive behavior in both sexes. In addition, it affected energy metabolism in the DH of male rats, favored synaptic plasticity, and contributed to reducing pathophysiological conditions.

The impact of pulse timing is an important factor in our understanding of how to effectively modulate the basal ganglia thalamocortical (BGTC) circuit. Single pulse low-frequency DBS-evoked potentials generated through electrical stimulation of the subthalamic nucleus (STN) provide insight into circuit activation, but how the long-latency components change as a function of pulse timing is not well-understood. We investigated how timing between stimulation pulses delivered in the STN region influence the neural activity in the STN and cortex. DBS leads implanted in the STN of five patients with Parkinson's disease were temporarily externalized, allowing for the delivery of paired pulses with inter-pulse intervals (IPIs) ranging from 0.2 to 10 ms. Neural activation was measured through local field potential (LFP) recordings from the DBS lead and scalp EEG. DBS-evoked potentials were computed using contacts positioned in dorsolateral STN as determined through co-registered post-operative imaging. We quantified the degree to which distinct IPIs influenced the amplitude of evoked responses across frequencies and time using the wavelet transform and power spectral density curves. The beta frequency content of the DBS evoked responses in the STN and scalp EEG increased as a function of pulse-interval timing. Pulse intervals <1.0 ms apart were associated with minimal to no change in the evoked response. IPIs from 1.5 to 3.0 ms yielded a significant increase in the evoked response, while those >4 ms produced modest, but non-significant growth. Beta frequency activity in the scalp EEG and STN LFP response was maximal when IPIs were between 1.5 and 4.0 ms. These results demonstrate that long-latency components of DBS-evoked responses are pre-dominantly in the beta frequency range and that pulse interval timing impacts the level of BGTC circuit activation., Competing Interests: AM and KB have intellectual property and distribution rights in Enspire and Cardionomics. AM has distribution rights in ATI and is a consultant to Abbott. SN consults for Abbott and is a speaker for Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Campbell, Favi Bocca, Escobar Sanabria, Almeida, Rammo, Nagel, Machado and Baker.)

Functional outcome following traumatic brain injury (TBI) varies greatly, with approximately half of those who survive suffering long-term motor and cognitive deficits despite contemporary rehabilitation efforts. We have previously shown that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) enhances rehabilitation of motor deficits that result from brain injury. The objective of the present study was to evaluate the efficacy of LCN DBS on recovery from rodent TBI that uniquely models the injury location, chronicity and resultant cognitive symptoms observed in most human TBI patients. We used controlled cortical impact (CCI) to produce an injury that targeted the medial prefrontal cortex (mPFC-CCI) bilaterally, resulting in cognitive deficits. Unilateral LCN DBS electrode implantation was performed 6 weeks post-injury. Electrical stimulation started at week eight post-injury and continued for an additional 4 weeks. Cognition was evaluated using baited Y-maze, novel object recognition task and Barnes maze. Post-mortem analyses, including Western Blot and immunohistochemistry, were conducted to elucidate the cellular and molecular mechanisms of recovery. We found that mPFC-CCI produced significant cognitive deficits compared to pre-injury and naïve animals. Moreover, LCN DBS treatment significantly enhanced the long-term memory process and executive functions of applying strategy. Analyses of post-mortem tissues showed significantly greater expression of CaMKIIα, BDNF and p75 NTR across perilesional cortex and higher expression of postsynaptic formations in LCN DBS-treated animals compared to untreated. Overall, these data suggest that LCN DBS is an effective treatment of cognitive deficits that result from TBI, possibly by activation of ascending, glutamatergic projections to thalamus and subsequent upregulation of thalamocortical activity that engages neuroplastic mechanisms for facilitation of functional re-organization. These results support a role for cerebellar output neuromodulation as a novel therapeutic approach to enhance rehabilitation for patients with chronic, post-TBI cognitive deficits that are unresponsive to traditional rehabilitative efforts., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) is a well-established therapy for the motor symptoms of Parkinson's disease (PD), but there remains an opportunity to improve symptom relief. The temporal pattern of stimulation is a new parameter to consider in DBS therapy, and we compared the effectiveness of Temporally Optimized Patterned Stimulation (TOPS) to standard DBS at reducing the motor symptoms of PD. Twenty-six subjects with DBS for PD received three different patterns of stimulation (two TOPS and standard) while on medication and using stimulation parameters optimized for standard DBS. Side effects and motor symptoms were assessed after 30 min of stimulation with each pattern. Subjects experienced similar types of side effects with TOPS and standard DBS, and TOPS were well-tolerated by a majority of the subjects. On average, the most effective TOPS was as effective as standard DBS at reducing the motor symptoms of PD. In some subjects a TOPS pattern was the most effective pattern. Finally, the TOPS pattern with low average frequency was found to be as effective or more effective in about half the subjects while substantially reducing estimated stimulation energy use. TOPS DBS may provide a new programing option to improve DBS therapy for PD by improving symptom reduction and/or increasing energy efficiency. Optimizing stimulation parameters specifically for TOPS DBS may demonstrate further clinical benefit of TOPS DBS in treating the motor symptoms of Parkinson's disease., Competing Interests: WG was Co-Founder, Chief Scientific Officer, and share owner in Deep Brain Innovations, LLC. He is an inventor on licensed patents on temporal patterns of brain stimulation and receives royalties therefrom. AK served as a consultant for Deep Brain Innovations, LLC and was the clinical project manager for this study. AM served as a consultant for St. Jude (Abbott), had distribution rights from IP for Enspire DBS and Cardionomics, and received fellowship support from Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Okun, Hickey, Machado, Kuncel and Grill.)

Deep brain stimulation (DBS) of the deep cerebellar nuclei has been shown to enhance perilesional cortical excitability and promote motor rehabilitation in preclinical models of cortical ischemia and is currently being evaluated in patients with chronic, post-stroke deficits. Understanding the effects of cerebellar DBS on contralateral sensorimotor cortex may be key to developing approaches to optimize stimulation delivery and treatment outcomes. Using the naïve rat model, we characterized the effects of DBS of the lateral cerebellar nucleus (LCN) on somatosensory evoked potentials (SSEPs) and evaluated their potential use as a surrogate index of cortical excitability. SSEPs were recorded concurrently with continuous 30 Hz or 100 Hz LCN DBS and compared to the DBS OFF condition. Ratios of SSEP peak to peak amplitude during 100 Hz LCN DBS to DBS OFF at longer latency peaks were significantly>1, suggesting that cortical excitability was enhanced as a result of LCN DBS. Although changes in SSEP peak to peak amplitudes were observed, they were modest in relation to previously reported effects on motor cortical excitability. Overall, our findings suggest that LCN output influences thalamocortical somatosensory pathways, however further work is need to better understand the potential role of SSEPs in optimizing therapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To assess use of directional stimulation in Parkinson's disease and essential tremor patients programmed in routine clinical care., Materials and Methods: Patients with Parkinson's disease or essential tremor implanted at Cleveland Clinic with a directional deep brain stimulation (DBS) system from November 2017 to October 2019 were included in this retrospective case series. Omnidirectional was compared against directional stimulation using therapeutic current strength, therapeutic window percentage, and total electrical energy delivered as outcome variables., Results: Fifty-seven Parkinson's disease patients (36 males) were implanted in the subthalamic nucleus (105 leads) and 33 essential tremor patients (19 males) were implanted in the ventral intermediate nucleus of the thalamus (52 leads). Seventy-four percent of patients with subthalamic stimulation (65% of leads) and 79% of patients with thalamic stimulation (79% of leads) were programmed with directional stimulation for their stable settings. Forty-six percent of subthalamic leads and 69% of thalamic leads were programmed on single segment activation. There was no correlation between the length of microelectrode trajectory through the STN and use of directional stimulation., Conclusions: Directional programming was more common than omnidirectional programming. Substantial gains in therapeutic current strength, therapeutic window, and total electrical energy were found in subthalamic and thalamic leads programmed on directional stimulation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naïve, parkinsonian, and pharmacologically treated parkinsonian states. To advance cortical potentials as possible biomarkers for DBS programming., Materials and Methods: Serial electrocorticographic (ECoG) recordings were made more than nine months from a single non-human primate instrumented with bilateral ECoG grids spanning anterior parietal to prefrontal cortex. Cortical evoked potentials (CEPs) were generated through time-lock averaging of the ECoG recordings to DBS pulses delivered unilaterally in the STN region using a chronically implanted, six-contact, scaled DBS lead. Recordings were made across the naïve followed by mild and moderate parkinsonian conditions achieved by staged injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin. In addition to characterizing the spatial distribution and stability of the response within each state, changes in the amplitude and latency of CEP components as well as in the frequency content were examined in relation to parkinsonian severity and dopamine replacement., Results: In the naïve state, the STN DBS CEP presented as a multiphase response maximal over M1 cortex, with components attributable to physiological activity distinguishable from stimulus artifact as early as 0.45-0.75 msec poststimulation. When delivered using therapeutically effective parameters in the parkinsonian state, the CEP was highly stable across multiple recording sessions within each behavioral state. Across states, significant differences were present with respect to both the latency and amplitude of individual response components, with greater differences present for longer-latency components (all p < 0.05). Power spectral density analysis revealed a high-beta peak within the evoked response, with significant changes in power between disease states across multiple frequency bands., Conclusions: Our findings underscore the spatiotemporal specificity and relative stability of the DBS-CEP associated with different disease states and with therapeutic benefit. DBS-CEP may be a viable biomarker for therapeutic programming., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

The robust, reciprocal anatomic connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscore the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, poststroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in participants (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigated the excitability of ipsilesional cortex, DN, and their interaction as a function of motor impairment and performance. Our results indicate the following: (1) event-related oscillations in the ipsilesional cortex and DN were significantly correlated at movement onset in the low beta band, with moderately and severely impaired participants showing desynchronization and synchronization, respectively; and (2) significant CCC was observed during the isometric hold period in the low beta band, which was critical for maintaining task accuracy. Our findings support a strong coupling between ipsilesional cortex and DN in the low beta band during motor control across all impairment levels, which encourages the exploitation of the cerebello-thalamo-cortical pathway as a neuromodulation target to promote rehabilitation. SIGNIFICANCE STATEMENT Cerebral infarct because of stroke can lead to lasting reduction in cerebellar metabolism, resulting in poor rehabilitative outcomes. Thorough investigation of the cerebellar electrophysiology, as well as cortico-cerebellar connectivity in humans that could provide key insights to facilitate the development of novel neuromodulatory technologies, has been lacking. As a part of the first in-human phase I trial investigating deep brain stimulation of the cerebellar dentate nucleus (DN) for chronic, poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG while stroke survivors performed a motor task. Our data indicate strong coupling between ipsilesional sensorimotor cortex and DN in the low beta band across all impairment levels encouraging the exploration of electrical stimulation of the DN., (Copyright © 2022 the authors.)

Longitudinal and behavioral preclinical animal studies generate complex data, which may not be well matched to statistical approaches common in this literature. Analyses that do not adequately account for complexity may result in overly optimistic study conclusions, with consequences for reproducibility and translational decision-making. Recent work interrogating methodological shortcomings in animal research has not yet comprehensively investigated statistical shortcomings in the analysis of complex longitudinal and behavioral data. To this end, the current cross-sectional meta-research study rigorously reviewed published mouse or rat controlled experiments for motor rehabilitation in three neurologic conditions to evaluate statistical choices and reporting. Medline via PubMed was queried in February 2020 for English-language articles published January 1, 2017- December 31, 2019. Included were articles that used rat or mouse models of stroke, Parkinson's disease, or traumatic brain injury, employed a therapeutic controlled experimental design to determine efficacy, and assessed at least one functional behavioral assessment or global evaluation of function. 241 articles from 99 journals were evaluated independently by a team of nine raters. Articles were assessed for statistical handling of non-independence, animal attrition, outliers, ordinal data, and multiplicity. Exploratory analyses evaluated whether transparency or statistical choices differed as a function of journal factors. A majority of articles failed to account for sources of non-independence in the data (74-93%) and/or did not analytically account for mid-treatment animal attrition (78%). Ordinal variables were often treated as continuous (37%), outliers were predominantly not mentioned (83%), and plots often concealed the distribution of the data (51%) Statistical choices and transparency did not differ with regards to journal rank or reporting requirements. Statistical misapplication can result in invalid experimental findings and inadequate reporting obscures errors. Clinician-scientists evaluating preclinical work for translational promise should be mindful of commonplace errors. Interventions are needed to improve statistical decision-making in preclinical behavioral neurosciences research., Competing Interests: the authors have declared that no competing interests exist.

Parkinson's disease is a neurological disease with cardinal motor signs including bradykinesia and tremor. Although beta-band hypersynchrony in the cortico-basal ganglia network is thought to contribute to disease manifestation, the resulting effects on network connectivity are unclear. We examined local field potentials from a non-human primate across the naïve, mild, and moderate disease states (model was asymmetric, left-hemispheric dominant) and probed power spectral density as well as cortico-cortical and cortico-subthalamic connectivity using both coherence and Granger causality, which measure undirected and directed effective connectivity, respectively. Our network included the left subthalamic nucleus (L-STN), bilateral primary motor cortices (L-M1, R-M1), and bilateral premotor cortices (L-PMC, R-PMC). Results showed two distinct peaks (Peak A at 5-20 Hz, Peak B at 25-45 Hz) across all analyses. Power and coherence analyses showed widespread increases in power and connectivity in both the Peak A and Peak B bands with disease progression. For Granger causality, increases in Peak B connectivity and decreases in Peak A connectivity were associated with the disease. Induction of mild disease was associated with several changes in connectivity: (1) the cortico-subthalamic connectivity in the descending direction (L-PMC to L-STN) decreased in the Peak A range while the reciprocal, ascending connectivity (L-STN to L-PMC) increased in the Peak B range; this may play a role in generating beta-band hypersynchrony in the cortex, (2) both L-M1 to L-PMC and R-M1 to R-PMC causalities increased, which may either be compensatory or a pathologic effect of disease, and (3) a decrease in connectivity occurred from the R-PMC to R-M1. The only significant change seen between mild and moderate disease was increased right cortical connectivity, which may reflect compensation for the left-hemispheric dominant moderate disease state., Competing Interests: AM and KB had potential financial conflict of interest with this research related to intellectual property or consulting and distribution rights in Enspire DBS. AM was a consultant to Abbott and Cleveland Clinic receives fellowship support from Medtronic. The Cleveland Clinic Conflict of Interest (COI) committee has approved a plan for managing these conflicts of interest. The authors have adhered to the management plan in the conduct and reporting of research findings. None of these entities had any role in the research or preparation of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bore, Toth, Campbell, Cho, Pucci, Hogue, Machado and Baker.)

Up to 50% of stroke survivors have persistent, severe upper extremity paresis even after receiving rehabilitation. Repetitive transcranial magnetic stimulation (rTMS) can augment the effects of rehabilitation by modulating corticomotor excitability, but the conventional approach of facilitating excitability of the ipsilesional primary motor cortex (iM1) fails to produce motor improvement in stroke survivors with severe loss of ipsilesional substrate. Instead, the undamaged, contralesional dorsal premotor cortex (cPMd) may be a more suitable target. CPMd can offer alternate, bi-hemispheric and ipsilateral connections in support of paretic limb movement. This pilot, randomized clinical trial seeks to investigate whether rTMS delivered to facilitate cPMd in conjunction with rehabilitation produces greater gains in motor function than conventional rTMS delivered to facilitate iM1 in conjunction with rehabilitation in severely impaired stroke survivors. Twenty-four chronic (≥6 months) stroke survivors with severe loss of ipsilesional substrate (defined by the absence of physiologic evidence of excitable residual pathways tested using TMS) will be included. Participants will be randomized to receive rTMS to facilitate cPMd or iM1 in conjunction with task-oriented upper limb rehabilitation given for 2 sessions/week for 6 weeks. Assessments of primary outcome related to motor impairment (upper extremity Fugl-Meyer [UEFM]), motor function, neurophysiology, and functional neuroimaging will be made at baseline and at 6-week end-of-treatment. An additional assessment of motor outcomes will be repeated at 3-month follow-up to evaluate retention. The primary endpoint is 6-week change in UEFM. This pilot trial will provide preliminary evidence on the effects and mechanisms associated with facilitating intact cPMd in chronic severe stroke survivors. The trial is registered on clinicaltrials.gov, NCT03868410., (© 2022 S. Karger AG, Basel.)

Introduction: Repetitive peripheral sensory stimulation (RPSS) followed by 4-hour task-specific training (TST) improves upper limb motor function in subjects with stroke who experience moderate to severe motor upper limb impairments. Here, we compared effects of RPSS vs sham followed by a shorter duration of training in subjects with moderate to severe motor impairments in the chronic phase after stroke., Methods: This single-center, randomized, placebo-controlled, parallel-group clinical trial compared effects of 18 sessions of either 1.5 h of active RPSS or sham followed by a supervised session that included 45 min of TST of the paretic upper limb. In both groups, subjects were instructed to perform functional tasks at home, without supervision. The primary outcome measure was the Wolf Motor Function Test (WMFT) after 6 weeks of treatment. Grasp and pinch strength were secondary outcomes., Results: In intention-to-treat analysis, WMFT improved significantly in both active and sham groups at 3 and 6 weeks of treatment. Grasp strength improved significantly in the active, but not in the sham group, at 3 and 6 weeks. Pinch strength improved significantly in both groups at 3 weeks, and only in the active group at 6 weeks., Conclusions: The between-group difference in changes in WMFT was not statistically significant. Despite the short duration of supervised treatment, WMFT improved significantly in subjects treated with RPSS or sham. These findings are relevant to settings that impose constraints in duration of direct contact between therapists and patients. In addition, RPSS led to significant gains in hand strength.Trial Registry Name: Peripheral Nerve Stimulation and Motor Training in Stroke Clinical Trials.gov identifier: NCT0265878 https://clinicaltrials.gov/ct2/show/NCT02658578.

This study compared the efficacy of XP-Endo Finisher R and R1-Clearsonic insert in removing filling material remnants from oval canals. Twelve pairs of contralateral premolars were treated and subsequently retreated with Reciproc 50. A supplementary procedure with XP-Endo Finisher R or R1-Clearsonic was performed. Micro-computed tomography was used to quantify the filling material volume in the full canal and apical segment lengths. Intragroup analyses revealed significant reduction of filling material after both procedures, not only in the full canal but also in the apical segment (P < 0.05). The amount of filling material removed with XP-Endo Finisher R and R1-Clearsonic was 47.9% and 52.2% in the apical segment (P > 0.05), and 82.1% and 64.6% in the full canal (P < 0.05). None of the instruments was effective in completely removing the filling material from the apical canal, but better results were obtained with XP-Endo Finisher R in the total canal length., (© 2020 Australian Society of Endodontology Inc.)

Stroke is a leading cause of disability in the Western world. Current post-stroke rehabilitation treatments are only effective in approximately half of the patients. Therefore, there is a pressing clinical need for developing new rehabilitation approaches for enhancing the recovery process, which requires the use of appropriate animal models. Here, we demonstrate the use of nonlinear microscopy of calcium sensors in the rat brain to study the effects of ischemic stroke injury on cortical activity patterns. We longitudinally recorded from thousands of neurons labeled with a genetically-encoded calcium indicator before and after an ischemic stroke injury in the primary motor cortex. We show that this injury has an effect on the activity patterns of neurons not only in the motor and somatosensory cortices, but also in the more distant visual cortex, and that these changes include modified firing rates and kinetics of neuronal activity patterns in response to a sensory stimulus. Changes in neuronal population activity provided animal-specific, circuit-level information on the post-stroke cortical reorganization process, which may be essential for evaluating the efficacy of new approaches for enhancing the recovery process., Competing Interests: The authors declare no conflicts of interest., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

The aim of the study was to evaluate the accuracy of microcomputed tomography (mCT) to detect dentinal cracks when compared with scanning electron microscopy (SEM) and operating microscopy (OM). Different conditions of pixel size (10 or 17  μ m), sample moisture (dry/moist), and transillumination (with/without) were evaluated. Additionally, the influence of the dentinal defect width on its detection was analyzed. The root canals of human mandibular incisors were prepared with the Reciproc R40 instrument (VDW, Munich, Germany). The roots were sectioned 5 and 10 mm from the apex, and mCT scans of middle and apical segments were performed at two pixel sizes: 10  μ m and 17  μ m, under dry and moist conditions (groups: 10dry, 10moist, 17dry, and 17moist). The operating microscope was used with and without transillumination (groups: OMTrans and OM). Findings showed that accuracy was moderate for the 10dry, 10moist, and OMTrans groups, poor for OM and very poor for 17dry and 17moist. The thickness of the dentin crack significantly influenced its detection by mCT using the resolution of 10  μ m in both dry and wet conditions ( P = .002), 17  μ m in the dry condition ( P = .002), and by the operating microscope using transillumination ( P = .009). Some cracks visualized in SEM were not detected by mCT and an operating microscope. Not only the mCT resolution but also the sample moisture condition and the dentinal crack width can significantly influence its detection., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Andrea F. Campello et al.)

Background: Intrathecal baclofen (ITB) is traditionally reserved for non-ambulatory patients., Objective: To investigate outcomes of ITB in ambulatory multiple sclerosis (MS) patients., Methods: Changes in outcome measures were estimated by a mixed effect model, while the complication rate was calculated using a logistic regression. Predictors of non-ambulatory status were identified by Cox model., Results: In all, 256 patients received an ITB test injection and 170 underwent ITB surgery. Aggregate Modified Ashworth Scale (MAS) scores for the ambulatory ITB cohort decreased from 13.5 ± 6.96 to 4.54 ± 4.18 at 5 years ( p  < 0.001). There was no significant change in walking speed 1 year post ITB surgery (0.45 m/second ± 0.30 vs 0.38 m/second ± 0.39, p  = 0.80) with 77.8% of patients remaining ambulatory which decreased to 41.7% at year 5. Longer MS disease duration (hazard ratio (HR): 1.04; 95% confidence interval (CI): 1.01-1.07; p  = 0.018) and lower hip flexor strength (HR: 0.40; 95% CI: 0.27-0.57; p  < 0.001) predicted non-ambulatory status after surgery. Complications were more likely in the ambulatory cohort (odds ratio (OR): 3.30, 95% CI: 2.17-5.02; p  = 0.017)., Conclusion: ITB is effective for ambulatory MS patients without compromising short-term walking speed, although a higher complication rate was observed in this cohort.

Background: Managing cancer pain once it is refractory to conventional treatment continues to challenge caregivers committed to serving those who are suffering from a malignancy. Although neuromodulation has a role in the treatment of cancer pain for some patients, these therapies may not be suitable for all patients. Therefore, neuroablative procedures, which were once a mainstay in treating intractable cancer pain, are again on the rise. This guideline serves as a systematic review of the literature of the outcomes following neuroablative procedures., Objective: To establish clinical practice guidelines for the use of neuroablative procedures to treat patients with cancer pain., Methods: A systematic review of neuroablative procedures used to treat patients with cancer pain from 1980 to April 2019 was performed using the United States National Library of Medicine PubMed database, EMBASE, and Cochrane CENTRAL. After inclusion criteria were established, full text articles that met the inclusion criteria were reviewed by 2 members of the task force and the quality of the evidence was graded., Results: In total, 14 646 relevant abstracts were identified by the literature search, from which 189 met initial screening criteria. After full text review, 58 of the 189 articles were included and subdivided into 4 different clinical scenarios. These include unilateral somatic nociceptive/neuropathic body cancer pain, craniofacial cancer pain, midline subdiaphragmatic visceral cancer pain, and disseminated cancer pain. Class II and III evidence was available for these 4 clinical scenarios. Level III recommendations were developed for the use of neuroablative procedures to treat patients with cancer pain., Conclusion: Neuroablative procedures may be an option for treating patients with refractory cancer pain. Serious adverse events were reported in some studies, but were relatively uncommon. Improved imaging, refinements in technique and the availability of new lesioning modalities may minimize the risks of neuroablation even further.The full guidelines can be accessed at https://www.cns.org/guidelines/browse-guidelines-detail/guidelines-on-neuroablative-procedures-patients-wi., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Objective: Deep brain stimulation (DBS) for pain has largely been implemented in an uncontrolled manner to target the somatosensory component of pain, with research leading to mixed results. We have previously shown that patients with poststroke pain syndrome who were treated with DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) demonstrated a significant improvement in measures related to the affective sphere of pain. In this study, we sought to determine how DBS targeting the VS/ALIC modifies brain activation in response to pain., Materials and Methods: Five patients with poststroke pain syndrome who were blinded to DBS status (ON/OFF) and six age- and sex-matched healthy controls underwent functional magnetic resonance imaging (fMRI) measuring blood oxygen level-dependent activation in a block design. In this design, each participant received heat stimuli to the affected or unaffected wrist area. Statistical comparisons were performed using fMRI z-maps., Results: In response to pain, patients in the DBS OFF state showed significant activation (p < 0.001) in the same regions as healthy controls (thalamus, insula, and operculum) and in additional regions (orbitofrontal and superior convexity cortical areas). DBS significantly reduced activation of these additional regions and introduced foci of significant inhibitory activation (p < 0.001) in the hippocampi when painful stimulation was applied to the affected side., Conclusions: These findings suggest that DBS of the VS/ALIC modulates affective neural networks., (© 2020 International Neuromodulation Society.)

Deep brain stimulation (DBS) is one of the most important clinical therapies for neurological disorders. DBS also has great potential to become a great tool for clinical neuroscience research. Recently, the National Engineering Laboratory for Neuromodulation at Tsinghua University held an international Deep Brain Stimulation Initiative workshop to discuss the cutting-edge technological achievements and clinical applications of DBS. We specifically addressed new clinical approaches and challenges in DBS for movement disorders (Parkinson's disease and dystonia), clinical application toward neurorehabilitation for stroke, and the progress and challenges toward DBS for neuropsychiatric disorders. This review highlighted key developments in (1) neuroimaging, with advancements in 3-Tesla magnetic resonance imaging DBS compatibility for exploration of brain network mechanisms; (2) novel DBS recording capabilities for uncovering disease pathophysiology; and (3) overcoming global healthcare burdens with online-based DBS programming technology for connecting patient communities. The successful event marks a milestone for global collaborative opportunities in clinical development of neuromodulation to treat major neurological disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sui, Tian, Ko, Wang, Jia, Horn, De Ridder, Choi, Bari, Wang, Hamani, Baker, Machado, Aziz, Fonoff, Kühn, Bergman, Sanger, Liu, Haber and Li.)

Objectives: We are in the process of designing and testing an intradural stimulation device that will shorten the distance between the location of the electrode array and the targeted neural tissue, thus improving the efficacy of electrical current delivery. Identifying a biomarker that accurately reflects the response to this intervention is highly valued because of the potential to optimize interventional parameters or predict a response before it is clinically measurable. In this report, we summarize the findings pertaining to the study of biomarkers so that we and others will have an up-to-date reference that critically evaluates the current approaches and select one or several for testing during the development of our device., Materials and Methods: We have conducted a broad survey of the existing literature to catalogue the biomarkers that could be coupled to intradural spinal cord stimulation. We describe in detail some of the most promising biomarkers, existing limitations, and suitability to managing chronic pain., Results: Chronic, intractable pain is an all-encompassing condition that is incurable. Many treatments for managing chronic pain are nonspecific in action and intermittently administered; therefore, patients are particularly susceptible to large fluctuations in pain control over the course of a day. The absence of a reliable biomarker challenges assessment of therapeutic efficacy and contributes to either incomplete and inconsistent pain relief or, alternatively, intolerable side effects. Fluctuations in metabolites or inflammatory markers, signals captured during dynamic imaging, and genomics will likely have a role in governing how a device is modulated., Conclusions: Efforts to identify one or more biomarkers are well underway with some preliminary evidence supporting their efficacy. This has far-reaching implications, including improved outcomes, fewer adverse events, harmonization of treatment and individuals, performance gains, and cost savings. We anticipate that novel biomarkers will be used widely to manage chronic pain., (© 2020 International Neuromodulation Society.)

Objective:  To evaluate the presence of residual disease in the uterine specimen after hysteroscopic polypectomy or polyp biopsy in patients with endometrioid endometrial cancer (EC)., Methods:  We analyzed a series of 104 patients (92 cases from the Hospital AC Camargo and 12 from the Hospital do Servidor Público Estadual de São Paulo) with polyps that were diagnosed by hysteroscopy, showing endometrioid EC associated with the polyp or in the final pathological specimen. Patients underwent a surgical approach for endometrial cancer from January 2002 to January 2017. Their clinical and pathological data were retrospectively retrieved from the medical records., Results:  In 78 cases (75%), the polyp had EC, and in 40 (38.5%), it was restricted to the polyp, without endometrial involvement. The pathologic stage was IA in 96 cases (92.3%) and 90 (86.5%) had histologic grade 1 or 2. In 18 cases (17.3%), there was no residual disease in the final uterine specimen, but only in 9 of them the hysteroscopy suggested that the tumor was restricted to the polyp. In 5 cases (4.8%) from the group without disease outside of the polyp during hysteroscopy, myometrial invasion was noted in the final uterine specimen. This finding suggests the possibility of disease extrapolation through the base of the polyp., Conclusion:  Patients with endometrioid EC associated with polyps may have the tumor completely removed during hysteroscopy, but the variables shown in the present study could not safely predict which patient would have no residual disease., Competing Interests: The authors have no conflict of interests to declare., (Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Objectives: The aim of this study was to evaluate the corrosion resistance of heat-treated (Reciproc and WaveOne) and non-heat-treated (ProTaper and Mtwo) superelastic nickel-titanium endodontic files when immersed in a 5.25% sodium hypochlorite solution., Materials and Methods: Anodic polarization curves were obtained with potential sweeps that began at the open circuit potential or corrosion potential (E corr ). The pitting potential (E pit ) was identified on the anodic polarization curve as the potential at which a sudden increase in current was observed. The micromorphology of the 28 tested files was analyzed before and after the electrochemical assay using scanning electron microscope (SEM). The data were analyzed using 1-way analysis of variance with the post hoc Bonferroni test (for E corr ) and the Student t -test for independent samples (for E pit )., Results: The mean E corr values were 0.506 V for ProTaper, 0.348 V for Mtwo, 0.542 V for Reciproc, and 0.321 V for WaveOne files. Only WaveOne and Protaper files exhibited pitting corrosion, with E pit values of 0.879 V and 0.904 V, respectively. On the SEM images of the ProTaper and WaveOne files, cavities suggestive of pitting corrosion were detected., Conclusions: Signs of corrosion were observed in both heat-treated and non-heat-treated files. Of the evaluated files, WaveOne (a heat-treated file) and ProTaper (a non-heat-treated file) exhibited the lowest corrosion resistance., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2021. The Korean Academy of Conservative Dentistry.)

Neural oscillatory changes within and across different frequency bands are thought to underlie motor dysfunction in Parkinson's disease (PD) and may serve as biomarkers for closed-loop deep brain stimulation (DBS) approaches. Here, we used neural oscillatory signals derived from chronically implanted cortical and subcortical electrode arrays as features to train machine learning algorithms to discriminate between naive and mild PD states in a nonhuman primate model. Local field potential (LFP) data were collected over several months from a 12-channel subdural electrocorticography (ECoG) grid and a 6-channel custom array implanted in the subthalamic nucleus (STN). Relative to the naive state, the PD state showed elevated primary motor cortex (M1) and STN power in the beta, high gamma, and high-frequency oscillation (HFO) bands and decreased power in the delta band. Theta power was found to be decreased in STN but not M1. In the PD state there was elevated beta-HFO phase-amplitude coupling (PAC) in the STN. We applied machine learning with support vector machines with radial basis function (SVM-RBF) kernel and k -nearest neighbors (KNN) classifiers trained by features related to power and PAC changes to discriminate between the naive and mild states. Our results show that the most predictive feature of parkinsonism in the STN was high beta (∼86% accuracy), whereas it was HFO in M1 (∼98% accuracy). A feature fusion approach outperformed every individual feature, particularly in the M1, where ∼98% accuracy was achieved with both classifiers. Overall, our data demonstrate the ability to use various frequency band power to classify the clinical state and are also beneficial in developing closed-loop DBS therapeutic approaches. NEW & NOTEWORTHY Neurophysiological biomarkers that correlate with motor symptoms or disease severity are vital to improve our understanding of the pathophysiology in Parkinson's disease (PD) and for the development of more effective treatments, including deep brain stimulation (DBS). This work provides direct insight into the application of these biomarkers in training classifiers to discriminate between brain states, which is a first step toward developing closed-loop DBS systems.

Considerable variability exists in the publication of clinical research study procedures related to study enrollment and participant exit from clinical trials. Despite recent efforts to encourage research data sharing and greater transparency regarding research outcomes, reporting of research procedures remains inconsistent. Transparency about study procedures has important implications for the interpretation of study outcomes and the consistent implementation of best practices in clinical trial design and conduct. This review of publications from clinical trials of deep brain stimulation (DBS) using the MEDLINE database examines the frequency and consistency of publication of research procedures and data related to exit from DBS research. Related considerations, such as device explant or continued use, battery and other device hardware replacements, and post-trial follow-up care are also reviewed. This review finds significant variability in the publication and reporting of study exit procedures. Of the 47 clinical trials included in this review, 19% (9) disclosed procedures related to exit from research. Reporting of other exit-related data and study procedures examined in this review was identified in fewer than half of the included clinical trials. The rate of participant retention and duration of follow-up was reported more than any other category of data included in this review. Results inform efforts to improve consistency in research design, conduct, and publication of results from clinical trials in DBS and related areas of clinical research., (Copyright © 2020 Sankary, Nallapan, Hogue, Machado and Ford.)

Introduction: The introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges., Methods: A review of the available literature relevant to this topic was performed, with particular focus on the pertinent neuroanatomy and uses of spinal cord stimulation systems in the treatment of malignant and nonmalignant gastrointestinal, genitourinary, and chronic pelvic pain., Results: To date, there have been multiple off-label reports testing SCS for refractory gastrointestinal and genitourinary conditions. Though some findings have been favorable for these organs and systems, there is insufficient evidence to make this practice routine. The unique configuration and layout of the pelvic pain pathways may not be ideally treated using traditional SCS implantation techniques, and intradural stimulation may be a viable alternative., Conclusions: Despite the prevalence of visceral pain, the application of neuromodulation therapies, a standard approach for other painful conditions, has received far too little attention, despite promising outcomes from uncontrolled trials. Detailed descriptions of visceral pain pathways may offer several clues that could be used to implement devices tailored to this unique anatomy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: A recent "bimodal-balance recovery" model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships., Methods: Twenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5-week rehabilitation (n = 21)., Results: Relationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40-46). Patients less impaired than UEFM = 43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM = 43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n = 14), more-impaired patients showed further IHI reduction., Conclusions: A criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation., Significance: The criterion may be used to stratify patients to design targeted, precision treatments., Competing Interests: Declaration of Competing Interest Andre G. Machado has the following conflicts of interest: ATI, Enspire and Cardionomics (distribution rights from intellectual property), St Jude (consultant) and Medtronic (Fellowship support). Other authors declare that there is no conflict of interest associated with this work. Specifically, there are no financial or personal relationships with other people or organizations that could inappropriately influence or bias this work., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Neuromodulation for trigeminal pain syndromes such as trigeminal neuropathic pain (TNP) necessitates accurate localization of foramen ovale (FO). The Härtel-type approach is very well-established and safe, ideal for temporary cannulation of the FO for ablative procedures such as balloon microcompression. A key shortcoming of the Hartel approach for placement of neuromodulation leads is the limited opportunity for secure anchoring. The aim of this study is to introduce a novel surgical approach for the treatment of TNP by investigating key osseous landmarks and their spatial relationships to the FO., Materials and Methods: Sixteen sides of cadaver heads were dissected to investigate a surgical route of the FO via transoral gingival buccal approach. Alveolar arch of the maxilla and zygomaticomaxillary suture were selected to serve as an osseous landmark for the surgical guidance to the FO. Through the intraoral route, a needle simulating electrode was traversed to aim the FO from the inferior lateral to the superior medial direction to target specific fibers of the aimed division of the nerve., Results: Visual identification and access to the trigeminal nerve at the external opening of FO was successful in all 16 hemifacial cadavers. A needle successfully targeted different regions of the trigeminal nerve by changing the angle of the trajectory allowing the needle to reach a specific division of the trigeminal nerve., Conclusions: This study provides a novel means of approaching the FO via transoral gingival buccal access., (© 2020 International Neuromodulation Society.)

We investigated the effect of a chronic palatable diet rich in simple sugars on memory of different degrees of emotionality in male adult rats, and on hippocampal plasticity markers in different stages of development. On postnatal day (PND) 21, 45 male Wistar rats were divided in two groups, according to their diet: (1-Control) receiving standard lab chow or (2-Palatable Diet) receiving both standard chow plus palatable diet ad libitum. At PND 60, behavioral tests were performed to investigate memory in distinct tasks. Hippocampal plasticity markers were investigated at PND 28 in half of the animals, and after the behavioral tests. Palatable diet consumption induced an impairment in memory, aversive or not, and increased Na + , K + -ATPase activity, both at PND 28, and in the adulthood. Synaptophysin, brain-derived neurotrophic factor (BDNF), and protein kinase B (AKT), and phosphorylated AKT were reduced in the hippocampus at PND 28. However, at PND 75, this diet consumption led to increased hippocampal levels of synaptophysin, spinophilin/neurabin-II, and decreased BDNF and neuronal nitric oxide synthase. These results showed a strongly association of simple sugars-rich diet consumption during the development with memory impairments. Plasticity markers are changed, with results that depend on the stage of development evaluated., (© 2020 International Society for Developmental Neuroscience.)

Objective: Despite the widespread use of spinal cord stimulation (SCS) for chronic pain management, its neuromodulatory effects remain poorly understood. Computational models provide a valuable tool to study SCS and its effects on axonal pathways within the spinal cord. However, these models must include sufficient detail to correlate model predictions with clinical effects, including patient-specific data. Therefore, the goal of this study was to investigate axonal activation at clinically relevant SCS parameters using a computer model that incorporated patient-specific anatomy and electrode locations., Methods: We developed a patient-specific computer model for a patient undergoing SCS to treat chronic pain. This computer model consisted of two main components: 1) finite element model of the extracellular voltages generated by SCS and 2) multicompartment cable models of axons in the spinal cord. To determine the potential significance of a patient-specific approach, we also performed simulations with standard canonical models of SCS. We used the computer models to estimate axonal activation at clinically measured sensory, comfort, and discomfort thresholds., Results: The patient-specific and canonical models predicted significantly different axonal activation. Relative to the canonical models, the patient-specific model predicted sensory threshold estimates that were more consistent with the corresponding clinical measurements. These results suggest that it is important to account for sources of interpatient variability (e.g., anatomy, electrode locations) in model-based analysis of SCS., Conclusions: This study demonstrates the potential for patient-specific computer models to quantitatively describe the axonal response to SCS and to address scientific questions related to clinical SCS., (© 2019 International Neuromodulation Society.)