Neurobiology of Disease

BackgroundDeep Brain Stimulation (DBS) is an established and effective treatment for patients with Parkinsons disease (PD). Over recent decades, several brain targets have been explored for DBS, including the subthalamic nucleus (STN) and the globus pallidus internus (GPi). However, the relative efficacy of these targets in controlling tremor remains a subject of debate. This study aimed to systematically compare tremor outcomes between STN-DBS and GPi-DBS in patients with PD. MethodsA prospectively registered protocol guided a comprehensive search of PubMed, Embase, Scopus and Web of science for randomized and controlled studies comparing tremor outcomes between STN-DBS and GPi-DBS. Standardized mean differences (Hedges g) in tremor reduction were extracted and synthesized using a random-effects model. The primary outcomes included the overall magnitude of tremor improvement, inter-study heterogeneity, and inter-individual variability in short-term response. ResultsBoth STN-DBS and GPi-DBS yielded substantial and durable tremor reductions, typically ranging from 70% to 90% improvement from baseline. Meta-analytic pooling revealed no significant long-term difference between targets (Hedges g = -0.08; 95% CI, -0.53 to 0.38; p = 0.74), with minimal inter-study heterogeneity (I{superscript 2} = 0%). However, short-term postoperative data indicated a modest but consistent early advantage for STN-DBS in achieving faster tremor relief. Importantly, clinical follow-up findings revealed considerable variability in the magnitude and timing of tremor improvement across individual patients, independent of target. ConclusionsSTN-DBS and GPi-DBS are equally effective for long-term tremor control in PD. Nevertheless, the transient early benefit observed with STN stimulation and the pronounced individual variability in treatment response emphasize the importance of personalized DBS planning. Tailoring target selection and programming to patient-specific clinical profiles may optimize both short- and long-term outcomes

BackgroundDeep brain stimulation of the fornix (DBS-f) has emerged as a potential strategy for Alzheimers disease (AD), based on evidence that stimulating the Papez circuit may enhance hippocampal metabolism, increase hippocampal volume, and modulate large-scale memory networks. However, studies vary substantially in design, stimulation parameters, sample size, and disease stage, and the consistency of cognitive and motor effects remains unclear. ObjectiveTo systematically review and meta-analyze the cognitive outcome associated with fornix-targeted DBS in Alzheimers disease. MethodsThis systematic review followed PRISMA-2020 guidelines, and the protocol was registered in PROSPERO (ID: CRD420251175724). A comprehensive search was conducted in PubMed, Scopus, Embase, Web of Science (WOS) and Cochrane Database of Systematic reviews (CDSR) included randomized controlled trials (RCTs), cohort studies,and case series. Ten eligible studies were analyzed, including mild, moderate, and severe AD cohorts. Meta-analyses were performed for ADAS-Cog and MMSE outcomes using random-effects models. Subgroup analysis (observational vs RCT), trim-and-fill publication bias, sensitivity analysis, and meta-regression (age 63-65 years) were conducted. Structural and metabolic data (hippocampal volumetry and FDG-PET) and motor outcomes (FIM, ADL, Barthel Index) were narratively synthesized. ResultsAcross included studies, cognitive outcomes showed highly variable short-term responses but no sustained improvement in controlled settings. Severe-AD cohorts demonstrated early gains, MMSE and MoCA improved in 1.5-3 months (Mao 2018), and dual-target fornix + NBM DBS yielded significantly higher MMSE at 3 months (p=0.002) and MoCA at 3 (p=0.003) and 12 months (p=0.010) (Xu 2024). In contrast, mild-AD RCTs showed no clinically meaningful benefit. Meta-analysis demonstrated a null pooled effect for cognition: ADAS-Cog: SMD = 0.05 (95% CI spanning null), robust to trim-and-fill (k =1). MMSE: pooled SMD near zero, stable on leave-one-out sensitivity analysis. Subgroup comparisons (RCT vs observational) showed no differences ({chi}{superscript 2}=0.04-0.05, p>0.80), and meta-regression revealed no association between effect size and age ({beta} = -0.04, p=0.33; {tau}{superscript 2}=0), confirming minimal between-study variance. Structural and metabolic findings consistently showed biological activation despite weak clinical response. Two patients demonstrated bilateral hippocampal volume increase at 12 months, and FDG-PET studies reported widespread metabolic increases across frontal-temporal-parietal-striatal-thalamic and frontal-temporal-parietal-occipital-hippocampal networks. Higher baseline metabolism and increased metabolism at one year correlated with less cognitive decline. Motor outcomes showed no sustained improvements. FIM scores improved significantly more in the DBS group at 3 months (p<0.05) but not at 12 months (p=0.968). ADL and Barthel scores showed mixed responses in small severe-AD samples. DBS parameters were heterogeneous (1-7 V; 60-210 s; 130 Hz in most studies), and programming duration varied markedly, underscoring a lack of standardized neuromodulatory protocol. ConclusionFornix DBS reliably activates limbic and memory-related circuits at a physiological level but does not provide consistent or sustained cognitive or motor benefits at currently used parameters. Evidence suggests age- and severity-dependent effects, with older or more advanced patients showing transient improvements, while mild AD patients do not benefit. Future research should prioritize precision targeting, biomarker-driven patient selection, optimized stimulation paradigms, and multi-target neuromodulation approaches.

Essential tremor (ET), the most common movement disorder in adults, presents with involuntary shaking of the arms during postural hold and kinetic tasks linked to dysfunction in the cerebello-thalamo-cortical (CTC) network. Recently, transcutaneous afferent patterned stimulation (TAPS), applied through a wrist-worn device, has emerged as a non-invasive therapy for medication refractory ET. However, its mechanism remains unclear. We hypothesize that TAPS reduces tremor through modulation of the VIM thalamus in the CTC network. Employing refractory ET patients seeking VIM deep brain stimulation (DBS), we quantified clinical tremor improvement following TAPS treatment in a pre-operative setting, followed by intra-operative, microelectrode recording of the contralateral thalamus with concurrent TAPS treatment on and off. After one preoperative session, TAPS significantly reduces upper limb tremor, with asymmetric effect favoring the treated limb and greatest improvement tending to kinetic tremor. The magnitude of TAPS-related tremor reduction demonstrates a positive correlation with the modulation of alpha and beta band LFPs in the VIM. TAPS also modulated spiking activity in the VIM, though it was uncorrelated with the degree of tremor reduction. Of note, TAPS related modulation of LFPs and spiking activity was greatest near the optimal placement location for DBS lead in treating ET. In sum, TAPS likely reduces tremor in ET by modulating the VIM and connected nodes in the cerebello-thalamo-cortical pathway.

Preclinical data from the peculiar animal model of "synthetic torpor" (ST), a reversible hypothermic condition resembling natural torpor but pharmacologically induced in rats (a non-hibernating mammal), suggest that in hypothermic conditions the neuroprotective effects of melatonin are strongly enhanced. As a protection technique, during aortic-arch surgery patients are induced a hypothermia similar to ST. Since in ST systemic melatonin was found particularly high, our aim was to assay serum melatonin in patients (N=8) undergoing aortic surgery, either during hypothermia and in the following four recovery days. Serum markers of blood-brain barrier (BBB) integrity (the astrocytic protein S100B) and neuronal damage (neuronal-specific enolase, NSE) were also measured. Results show that, in contrast to what observed in ST, in hypothermic patients melatonin was dramatically reduced in respect to the pre-anesthesia level, slowly recovering during the post-surgery period. Also, S100B and NSE raised during surgery, indicating highly leaking BBB and some ongoing neuronal damage, though both markers returned closer to pre-anesthesia levels within recovery period. Together, present results show that, in aortic-arch surgery, hypothermic patients totally lack the systemic melatonin peak that was observed in ST, the BBB was temporarily compromised and some acute neuronal damage occurred. A main implication of this work is that, exploiting the low BBB efficiency that makes easier to reach brain parenchyma, by administering melatonin during the hypothermic stage of the surgery the observed gap could be filled, possibly triggering the neuroprotective mechanism seen in preclinical observations and leading to better neurological outcomes for this surgical procedure. HighlightsO_LIDuring hypothermia induced in aortic-surgery systemic melatonin was low C_LIO_LISerum biomarkers enlighten transient blood-brain barrier and neuronal sufferings C_LIO_LIGiving melatonin during aortic-surgery hypothermia may improve neurological outcome C_LI

IntroductionTreatment-refractory obsessive-compulsive disorder (trOCD) is a complex network disorder that may require personalized treatment strategies due to disease heterogeneity. A multi-site, multi-stage, double-blinded, randomized crossover clinical trial is underway, using stereo electroencephalography (sEEG) to guide selection of multi-nodal targets for deep brain stimulation (DBS) for trOCD. ObjectivesTo describe the clinical trial design, emphasizing personalized surgical targeting strategies that ensure the feasibility and precision of sEEG electrode placement, and enable adequate sampling of relevant targets in trOCD for network evaluation and modulation. MethodsAdults with severe trOCD (Yale-Brown Obsessive Compulsive Scale [&ge;] 28) who meet eligibility criteria are enrolled in this three-stage clinical trial (NCT05623306). Stage 1 involves SEEG electrode implantation in trOCD implicated regions and inpatient evaluation. Individualized probabilistic-tractography-guided target refinement is performed for surgical planning. Multimodal recordings are taken while participants stay in the psychiatric monitoring unit for 12 days. In stage 2, up to four permanent DBS electrodes are implanted followed by stimulation optimization. Stage 3 is the randomized, double blinded cross over phase. Expected OutcomesSafety, feasibility and preliminary efficacy will be assessed in this ongoing study. We anticipate that the use of sEEG to guide selection of multi-nodal targets for DBS will be safe, feasible and result in clinically meaningful improvements in symptom severity and functional impairment in trOCD. DiscussionWe present the clinical protocol of sEEG-guided investigation of brain networks involved in trOCD and describe our tractography-guided surgical targeting strategy designed to optimize individualized network engagement and neuromodulation.

IntroductionCurrently, sub-second monitoring of neurotransmitter release in humans can only be performed during standard of care invasive procedures like DBS electrode implantation. The procedure requires acute insertion of a research probe and additional time in surgery, which may increase infection risk. We sought to determine the impact of our research procedure, particularly the extended time in surgery, on infection risk. MethodsWe screened 607 DBS electrode implantation procedures performed at Wake Forest Baptist Medical Center between January 2011 through October 2020 using International Classification of Diseases (ICD) codes for infection. During this period, 116 cases included an IRB approved 30-minute research protocol, during the DBS electrode implantation surgery, to monitor sub-second neurotransmitter release. We used Fishers Exact test (FET) to determine if there was a significant change in the infection rate following DBS electrode implantation procedures that included, versus those that did not include, the neurotransmitter monitoring research protocol. ResultsWithin 30-days following DBS electrode implantation, infection was observed in 7 (1.43%) out of 491 procedures that did not include the research procedure and 2 (1.72%) of the 116 procedures that did include the research procedure. Total infection rates (i.e., not constrained by 30-day time window) for all non-research cases was 28/491 (5.70%) and only 4/116 (3.45%) for research inclusive cases. Notably, all types of infection observed were typical of those expected for DBS electrode implantation. ConclusionTotal infection rates are not statistically different in patients who performed the research procedure (3.45% vs. 5.70%; p = 0.4872, FET) and not statistically different across research and non-research groups within 30-days following the research procedure (1.72% vs. 1.43%; p = 0.684, FET). Our results demonstrate that the research procedures used for sub-second monitoring of neurotransmitter release in humans can be performed without increasing the rate of infection.

ObjectiveThe Globus Pallidus pars interna (GPi) is one of the main targets for Deep Brain Stimulation (DBS) therapies for dystonia and other movement disorders. Still, a complete picture of the spiking dynamics of the nucleus is far from being achieved. Microelectrode recordings (MER) provide a unique brain window opportunity to shed light on GPi organization, which might support intraoperative DBS target localization, as previously done for the Subthalamic nucleus (STN). ApproachHere we propose a novel procedure to analyze explorative MERs from DBS implants in dystonic patients. The procedure identifies the neural activity markers discriminating neurons in the GPi from those in the neighbouring structures, as well as the markers discriminating neurons located in different regions within the GPi. Main resultsThe identification of the borders of the GPi based on neural markers was a difficult task, due to internal inhomogeneities in GPi firing dynamics. However, the procedure was able to exploit these inhomogeneities to characterize the internal electrophysiological structure of the GPi. In particular, we found a reliable dorsolateral gradient in firing activity and regularity. SignificanceOverall, we characterized the spatial distribution of neural activity markers in the dystonic GPi, paving the way for the use of these markers for DBS target localization. The procedure we developed to achieve this result could be easily extended to MER performed for other disorders and in other areas.

BackgroundPancreaticoduodenectomy (PD) is an operation performed for several indications, including pancreatic and biliary malignancies. Delayed gastric emptying (DGE) is a common post-operative complication and the underlying pathophysiology remains poorly understood. This study aimed to evaluate the gastric electrophysiology, symptoms and quality of life following PD, using the novel non-invasive Gastric Alimetry System. MethodsPD patients with index operations between 2017-2022 were assessed using the Gastric Alimetry System(R), comprising a stretchable 8x8 electrode array, wearable Reader, and validated symptom logging app. A 30-minute pre-prandial and a 4-hour post-prandial recording was performed. Outcomes included Principal Gastric Frequency, BMI-adjusted amplitude, Gastric Alimetry Rhythm Index, meal response, symptoms, and quality of life (QOL) questionnaires (PAGI-SYM, PAGI-QOL). Data was compared to a validated reference range and matched healthy controls. Results19 patients and 19 matched controls were recruited. There were no differences in any gastric parameters between PD patients and matched controls (all p>0.05). Gastric electrophysiology parameters lay outside normative reference intervals in 8/19 cases, generally being only minor deviations, while significant symptoms occurred in 8/19 (42%); which did not correlate (p=0.43). PD patients had worse quality of life scores than controls (p<0.01), however, no correlations were identified between electrophysiological parameters and QOL. DiscussionModerate to severe upper GI symptoms are common after PD with worse QOL compared to the controls. Gastric electrical activity generally recovers well long-term following PD, indicating that other factors contribute to symptoms. Further studies should now assess acute changes in gastric function after PD.

BackgroundAdverse gastric symptoms persist in up to 20% of fundoplication surgeries completed for gastroesophageal reflux disease, causing significant morbidity, and driving the need for revisional procedures. Non-invasive techniques to assess the mechanisms of persistent postoperative symptoms are lacking. We aimed to investigate gastric myoelectrical abnormalities and symptoms in patients after fundoplication using a novel non-invasive body surface gastric mapping (BSGM) device. MethodsPatients with previous fundoplication surgery and ongoing significant gastroduodenal symptoms, and matched controls were included. BSGM using Gastric Alimetry (Alimetry, New Zealand) was employed, consisting of a high resolution 64-channel array, validated symptom-logging App, and wearable reader. Results16 patients with significant chronic symptoms post-fundoplication were recruited, with 16 matched controls. Overall, 6/16 (37.5%) patients showed significant spectral abnormalities defined by unstable gastric myoelectrical activity (n = 2), abnormally high gastric frequencies (n = 3) or high gastric amplitudes (n = 1). Those with spectral abnormalities had higher Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index scores (3.2 [2.8 to 3.6] vs 2.3 [2.2 to 2.8]; p =0.024). 7/16 patients (43.8%) had Gastric Alimetry tests suggestive of gut-brain axis contributions, and without myoelectrical dysfunction. Increasing Principal Gastric Frequency deviation, and decreasing Rhythm Index were associated with symptom severity (r>0.40, p<0.05). ConclusionA significant number of patients with persistent post-fundoplication symptoms display abnormal gastric function on Gastric Alimetry testing, which correlates with symptom severity. These findings advance the pathophysiological understanding of post-fundoplication disorders which may inform diagnosis and patient selection for medical therapy and revisional surgery.

Changes to spatiotemporal gait metrics in gait-altering conditions are characteristic of the pathology. This data can be interpreted by machine learning (ML) models which have recently emerged as an adjunct to clinical medicine. However, the literature is undecided regarding its utility in diagnosing pathological gait and is heterogeneous in its approach to applying ML techniques. This study aims to address these gaps in knowledge. This was a prospective observational study involving 32 patients with Parkinsons disease and 88 normative subjects. Spatiotemporal gait metrics were gathered from all subjects using the MetaMotionC inertial measurement unit and data obtained were used to train and evaluate the performance of 10 machine learning models. Principal component analysis and Genetic Algorithm were amongst the feature selection techniques used. Classification models included Logistic Regression, Support Vector Machine, Naive - Bayes, Random Forest, and Artificial Neural Networks. ML algorithms can accurately distinguish pathological gait in Parkinsons disease from that of normative controls. Two models which used the Random Forest classifier with Principal Component analysis and Genetic Algorithm feature selection techniques separately, were 100% accurate in its predictions and had an F1 score of 1. A third model using principal component analysis and Artificial neural networks was equally as successful (100% accuracy, F1 = 1). We conclude that ML algorithms can accurately distinguish pathological gait from normative controls in Parkinsons Disease. Random Forest classifiers, with Genetic Algorithm feature selection are the preferred ML techniques for this purpose as they produce the highest performing model. Author summaryThe way humans walk, are emblematic of their overall health status. These walking patterns, otherwise, can be captured as gait metrics from small and portable wearable sensors. Data gathered from these sensors can be interpreted by machine learning algorithms which can then be used to accurately distinguish healthy and non-healthy patients based on their gait or walking pattern. The applications of this technology are many and varied. Firstly, it can be used to simply aid in diagnosis as explored in this paper. In future, researchers may use their understanding of normal and pathological gait, and their differences to quantify how severely ones gait is affected in a disease state. This data can be used to track, and quantify, improvements or further deteriorations post treatment, whether these be medication-based or interventions like surgery. Retrospective analyses on data such as this can be used to judge the value of an intervention in reducing a patients disability, and advise health related expenditure.

IntroductionRadiofrequency (RF) induced tissue heating around deep brain stimulation (DBS) leads is a well-known safety risk during magnetic resonance imaging (MRI), resulting in strict imaging guidelines and limited allowable protocols. The implanted leads trajectory and its orientation with respect to the MRI electric fields contribute to variations in the magnitude of RF heating across patients. Currently, there are no consistent requirements for surgically implanting the extracranial portion of the DBS lead. This produces substantial variations in clinical DBS lead trajectories and hinders RF heating predictions. Recent studies showed that incorporating concentric loops in the extracranial trajectory of the lead can reduce RF heating, but the optimal positioning of the loop remains unknown. In this study, we systematically evaluated the RF heating of 244 unique lead trajectories to elucidate the characteristics of the trajectory that minimize RF heating during MRI at 3 T. We also presented the first surgical implementation of these modified trajectories and compared their RF heating to the RF heating of unmodified trajectories. MethodsWe performed phantom experiments to assess the maximum temperature increase, {Delta}Tmax, of 244 unique lead trajectories. We systematically interrogated the effect of three characteristics related to the extracranial portion of the lead trajectory, namely, the number of concentric loops, the size of the loops, and the position of the loops on the skull. Experiments were performed in an anthropomorphic phantom implanted with a commercial DBS system, and RF exposure was generated by applying a high-SAR sequence (T1-weighted turbo spin echo dark fluid pulse sequence, B1+rms = 2.7 T). Test-retest experiments were conducted to assess the reliability of measurements. Additionally, we determined the effect of imaging landmark and perturbations to the DBS device configuration on the efficacy of low-heating lead trajectories. Finally, recommended modified trajectories were implanted in patients by two neurosurgeons and their RF heating was characterized in comparison with non-modified trajectories. ResultsOur search protocol elicited lead trajectories with {Delta}Tmax from 0.09 - 7.34 {degrees}C. Interestingly, increasing the number of loops and positioning them near the surgical burr hole--especially for the contralateral lead--substantially reduced RF heating. Trajectory specifications based on the results from the phantom experiments were easily adopted during the surgical procedure and generated nearly a 4-fold reduction in RF heating. Discussion/ConclusionSurgically modifying the extracranial portion of the DBS lead trajectory can substantially mitigate RF heating during MRI at 3 T. Simple adjustments to the leads configuration can be readily adopted during DBS lead implantation by implementing small concentric loops near the surgical burr hole.

BackgroundWhile most gastric bypass patients recover well, some experience long-term complications, including nausea, pain, stricture, and dumping. This study aimed to evaluate symptoms and quality of life (QoL) together with remnant stomach function using the novel Gastric Alimetry(R) system. MethodGastric bypass and conversion-to-bypass patients were recruited. The Gastric Alimetry system (Auckland, NZ) was employed, comprising a high-resolution electrode Array, and validated symptom logging App. The protocol comprised 30-minute fasting baseline, a 218kCal meal stimulus, and 4-hours of post-prandial recordings. Symptoms and QoL were evaluated using validated PAGI questionnaires. Remnant gastric electrophysiology evaluation included frequency, BMI-adjusted amplitude, and Gastric Alimetry Rhythm Index (GA-RI; reflecting pacemaker stability), with comparison to matched controls. Results38 participants were recruited with mean time from bypass 46.8 {+/-} 28.6 months. One third of patients showed moderate to severe post-prandial symptoms, with patients PAGI-SYM 28 {+/-} 19 vs controls 9 {+/-} 17; PAGI-QoL 37 {+/-} 31 vs 135 {+/-} 22 (p<0.01). Remnant gastric function was markedly degraded shown by undetectable frequencies in 84% (vs 0% in controls), and low GA-RI (0.18 {+/-} 0.08 vs 0.51 {+/-} 0.22 in controls; p<0.0001). Impaired GA-RI and amplitude were correlated with worse PAGI-SYM and PAGI-QOL scores. ConclusionOne third of post-bypass patients suffered significant upper GI symptoms with reduced QoL. The bypassed remnant stomach shows highly deranged electrophysiology, reflecting disuse degeneration. These derangements correlated with QoL, although causality was not addressed.

Recent advances in deep brain stimulation (DBS) devices have enabled the ability to capture continuous neural recordings concurrently with stimulation therapy in the background of everyday life. These recordings provide the opportunity to investigate neural biomarkers of various behaviors or clinical status. However, they are susceptible to artifacts that can obscure and limit our ability to interpret neural signals. In a cohort of 23 patients who underwent DBS for obsessive-compulsive disorder (OCD) with the Medtronic Percept device, we identified an artifact in longitudinal neural recordings that occurs when the detected voltage exceeds the devices maximum sensing capabilities. When such an event occurs, the device inserts a flag value in the neural power stream. We found that overvoltage events are significantly more common in patients implanted with legacy Medtronic 3387 leads than those with newer Medtronic SenSight leads. We demonstrate a best practice, principled strategy for correcting samples affected by overvoltage events to preserve the ability to analyze the data. Finally, in a subset of patients who wore an Oura Ring concurrently with neural recordings (N=14), we found that overvoltage events were more likely during physical activity, suggesting that movement artifacts may elevate low-frequency power regardless of lead model.

Personality changes following neurosurgical procedures pose a major concern for patients and remain poorly understood both by clinicians and neuroscientists. Here we report a case of a female patient in her 50s who underwent resection of a large sagittal sinus meningioma with bilateral extension, including resection and ligation of the superior sagittal sinus, that resulted in borderline personality disorder and symptoms resembling the Gastaut-Geschwind syndrome. Clinical observations were further reflected and experimentally quantified with a series of behavioral and neuroimaging tasks assessing self-other voice discrimination, one of the established markers for self-consciousness. In all tasks, the patient consistently confused self- and other voices - i.e., she misattributed other-voice stimuli to herself and self-voice stimuli to others. Moreover, behavioral findings were corroborated with scalp EEG results. Specifically, the same EEG microstate, that was in healthy participants associated with hearing their own voice, in this patient occurred more often for other-voice stimuli. We hypothesize that the patients preexisting psychological problems were significantly aggravated by postoperative decompensation of a fragile steady-state combination of direct frontal lobe compression and preoperative development of a large venous collateral hemodynamic network that followed gradual occlusion of the superior sagittal sinus. Resection of the sagittal sinus together with the tumor impacted venous drainage of brain areas associated with self-consciousness. These findings are of high relevance for developing experimental biomarkers of post-surgical personality alterations.

ObjectivePeriventricular Nodular Heterotopia (PVNH) is the most common neuronal heterotopia, frequently resulting in pharmaco-resistant epilepsy. PVNH has a deep location which renders localization of seizure onsets and traditional surgical therapy challenging and of limited success. Here we characterize variables that predict good epilepsy outcomes following surgical intervention using SEEG-informed MRgLITT. MethodsA prospectively compiled surgical epilepsy database from a single high-volume epilepsy referral center was used to identify patients who underwent SEEG evaluation for PVNH and characterize the intervention on outcomes. ResultsThirty-nine patients underwent SEEG-informed MRgLITT. Associated imaging abnormalities-- mesial temporal sclerosis (MTS) or polymicrogyria (PMG) were treated based on SEEG. SEEG-guided MRgLITT of the seizure onset zone (SoZ) in PVNH and associated epileptic tissue was carried out. PVNH and PMG were densely sampled--mean 16.5(SD=2)/209.4(SD=36.9) SEEG probes/recording contacts. A single trajectory was used in 18, two in 13, and three or more in eight patients. Volumetric analyses revealed a high percentage of PVNH SoZ ablation (96.6%, SD=5.3%) in unilateral and bilateral (92.9%, SD=7.2%) cases. Mean follow-up duration was 31.4 months (SD=20.9). Seizure freedom was excellent overall: unilateral PVNH without other imaging abnormalities--80%; PVNH with MTS or PMG--63%; Bilateral PVNH--50%. SoZ ablation percentage significantly impacted surgical outcomes (p<0.001). InterpretationPVNH plays a central role in seizure genesis. MRgLITT represents a transformative technological advance in PVNH-associated epilepsy with seizure control outcomes consistent with those seen in focal lesional epilepsies. In localized unilateral cases and otherwise normal imaging, performing PVNH ablation without invasive recordings may be reasonable.

Distal injuries in human fingertips can regenerate almost fully, yet the process of human fingertip regeneration has hardly been characterized on a cellular and molecular level. A silicone finger cap, comprising a puncturable reservoir, was used to treat 22 human fingertip amputations. In all patients, subcutaneous tissue, nailbed and skin regenerated with excellent outcomes. Through the clinical assessment of the wounds, the regenerative process was divided into four distinct phases. Proteomic data from wound fluid samples collected at regular intervals, confirmed robust and unbiasedly distinct proteomic signatures, characteristic processes, and active regulatory networks in each phase. Moreover, this human dataset provides important insights, showing clear divergences from findings in regenerative animal models. The longitudinal and comprehensive analysis presented here unveils the complex orchestration of four clinically and proteomically-distinct phases of human fingertip regeneration. Further analyses of this proteomic data will allow for the identification of candidates orchestrating human fingertip regeneration and serving as a framework for comparative and regenerative medicine studies.

AO_SCPLOWBSTRACTC_SCPLOWDeep brain stimulation (DBS) within the subcallosal cingulate cortex (SCC) alleviates symptoms of depression through an unclear therapeutic mechanism. Precise stimulation of SCC white matter (SCCwm) is thought to be necessary to achieve therapeutic response, and clinical recordings can now be used to test this hypothesis. In this paper we characterized the where, what, and how of SCCwm-DBS immediate effects, its network action, at therapeutic stimulation frequencies. First, using simultaneous LFP and EEG, we determined whether the effects of SCCwm-DBS are local at the SCC and/or remote at downstream cortical regions. We then charactized the spatial pattern effected by DBS across high-density EEG, finding multi-oscillatory response modes. Finally, we demonstrated that these modes are spatially consistent with white matter tracts targeted during surgical implantation. These results clarify the immediate actions of SCCwm-DBS as broad low-frequency power increases in brain regions downstream to stimulated white matter. This quantitative characterization of SCCwm-DBS network action has implications for future clinical trials, and may accelerate adaptive therapy optimization.

BackgroundThe anterior cingulate cortex (ACC) plays an important role in the cognitive and emotional processing of pain. Prior studies have used deep brain stimulation (DBS) to treat chronic pain, but results have been inconsistent. This may be due to network adaptation over time and variable causes of chronic pain. Identifying patient-specific pain network features may be necessary to determine patient candidacy for DBS. HypothesisCingulate stimulation would increase patients hot pain thresholds if non-stimulation 70-150 Hz activity encoded psychophysical pain responses. MethodsIn this study, four patients who underwent intracranial monitoring for epilepsy monitoring participated in a pain task. They placed their hand on a device capable of eliciting thermal pain for five seconds and rated their pain. We used these results to determine the individuals thermal pain threshold with and without electrical stimulation. Two different types of generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. ResultsThe pain threshold for each patient was determined from the psychometric probability density function. Two patients had a higher pain threshold with stimulation than without, while the other two patients had no difference. We also evaluated the relationship between neural activity and pain responses. We found that patients who responded to stimulation had specific time windows where high-frequency activity was associated with increased pain ratings. ConclusionStimulation of cingulate regions with increased pain-related neural activity was more effective at modulating pain perception than stimulating non-responsive areas. Personalized evaluation of neural activity biomarkers could help identify the best target for stimulation and predict its effectiveness in future studies evaluating DBS.

ObjectiveThe general objective of this study is to map the current knowledge in DNA methylation in Pituitary Adenomas, and in particular focus on genetic and epigenetic findings and the translation into a clinical setting. IntroductionPituitary tumorigenesis is currently under major investigation. The current research has turned to epigenomic analysis, investigating whether several epigenetic components like DNA methylation and histone modification can be used as markers for tumorigenesis. Several studies report genes involved in relation to hypo/hypermethylated sites. Others describe differential methylated probes/regions (DMR or DMP) and show subclassification traits. Furthermore, most recent studies aim to cluster samples based on full methylome data (unsupervised cluster analysis), while others chose to assess the most different probes (example 2000 probes) and perform the same data-analysis. Inclusion criteriaIn this review, we will include all primary studies on pituitary adenomas analyzed by DNA methylation. No review studies will be included. All papers describing DNA methylation in pituitary adenomas in humans will be included. In addition, all languages will be included. However, both title and abstract needs to be written in English. MethodsPapers will be identified via systematic search using the bibliographic databases: Medline, Embase, Cochrane Library and Scopus. Two reviewers will screen all papers based on title and abstract. All relevant papers will be included for further assessment by the same two reviewers. Full texts from each selected paper will be read, and if relevant regarding the eligibility criteria, papers will be included in the review. Disputes between these reviewers, the paper/papers will be discussed in the entire research-group. 5. FundingNo external funding for this review, funded by in-house resources.

A critical challenge in endocrine neurosurgery is intraoperative discrimination between normal pituitary tissue and pituitary neuroendocrine tumors (PitNETs). Suggesting the universal persistence of near-infrared autofluorescence (NIRAF) in endocrine organs and inspired by routine clinical use of NIRAF for parathyroid gland identification, we discovered that pituitary NIRAF can be employed for label-free transsphenoidal surgery guidance. Ex vivo confocal spectral imaging of 33 specimens identified secretory granules as the dominant long-wavelength fluorescence source and showed that normal pituitary had higher granule content than PitNETs. For the first time, we made use of the pituitary NIRAF during surgery and assessed its performance for pituitary/adenoma separation in vivo for 27 surgeries and showed near-perfect separability between pituitary and non-pituitary measurement sites with ROC-AUC of 0.98. The obtained results clearly demonstrate that the suggested method, based on the solid microscopic background, has the potential for clinical translation and paves the way for enhanced gland preservation during resection.