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Background: A reliable physiological biomarker for Major Depressive Disorder is essential for developing and optimizing neuromodulatory treatment paradigms. This study investigates a passive electrophysiologic biomarker that tracks changes in depressive symptom severity on the order of minutes to hours., Methods: We analyze brief recordings from intracranial electrodes implanted deep in the brain during a clinical trial of deep brain stimulation for treatment-resistant depression in 5 human subjects (n female = 3, n male = 2). This surgical setting allows for precise temporal and spatial sensitivity in the ventromedial prefrontal cortex, a challenging area to measure. We focused on the aperiodic slope of the power spectral density, a metric reflecting the balance of activity across all frequency bands and serving as a proxy for excitatory/inhibitory balance in the brain., Results: Our findings demonstrate that shifts in aperiodic slope correlate with depression severity, with flatter (less negative) slopes indicating reduced depression severity. This significant correlation was observed in all N=5 subjects, particularly in the ventromedial prefrontal cortex., Conclusions: This biomarker offers a new way to track patient responses to Major Depressive Disorder treatment, paving the way for individualized therapies in both intracranial and non-invasive monitoring contexts., (Copyright © 2024. Published by Elsevier Inc.)

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally directed cognition. The present study employs stereo-EEG in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by a stronger increase in gamma band power (30-70 Hz) coupled with lower theta band power (4-8 Hz). The difference in activity between the two networks was especially strong during the mind wandering task. Within the DMN, we found that the tasks showed different dynamics, with the alternate uses task engaging the DMN more during the initial stage of the task, and mind wandering in the later stage. Gamma power changes were mainly driven by lateral DMN sites, while theta power displayed task-specific effects. During alternate uses task, theta changes did not show spatial differences within the DMN, while mind wandering was associated to an early lateral and late dorsomedial DMN engagement. Furthermore, causal manipulations of DMN regions using direct cortical stimulation preferentially decreased the originality of responses in the alternative uses task, without affecting fluency or mind wandering. Our results suggest that DMN activity is flexibly modulated as a function of specific cognitive processes and supports its causal role in divergent thinking. These findings shed light on the neural constructs supporting different forms of cognition and provide causal evidence for the role of DMN in the generation of original connections among concepts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Recent advances in stereotactic and functional neurosurgery have brought forth the stereo-electroencephalography approach which allows deeper interrogation and characterization of the contributions of deep structures to neural and affective functioning. We argue that this approach can and should be brought to bear on the notoriously intractable issue of defining the pathophysiology of refractory psychiatric disorders and developing patient-specific optimized stimulation therapies., Methods: We have developed a suite of methods for maximally leveraging the stereo-electroencephalography approach for an innovative application to understand affective disorders, with high translatability across the broader range of refractory neuropsychiatric conditions., Results: This article provides a roadmap for determining desired electrode coverage, tracking high-resolution research recordings across a large number of electrodes, synchronizing intracranial signals with ongoing research tasks and other data streams, applying intracranial stimulation during recording, and design choices for patient comfort and safety., Conclusion: These methods can be implemented across other neuropsychiatric conditions needing intensive electrophysiological characterization to define biomarkers and more effectively guide therapeutic decision-making in cases of severe and treatment-refractory disease., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of Congress of Neurological Surgeons.)

Understanding the neural basis of major depressive disorder (MDD) is vital to guiding neuromodulatory treatments. The available evidence supports the hypothesis that MDD is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neural systems lead to diminished emotion regulation and intrusive ruminations. Recent research also points towards network changes in the brain, especially within the prefrontal cortex (PFC), as primary sources of MDD etiology. However, due to limitations in spatiotemporal resolution and clinical opportunities for intracranial recordings, this hypothesis has not been directly tested. We recorded intracranial EEG from the dorsolateral (dlPFC), orbitofrontal (OFC), and anterior cingulate cortices (ACC) in neurosurgical patients with MDD. We measured daily fluctuations in self-reported depression severity alongside directed connectivity between these PFC subregions. We focused primarily on delta oscillations (1-3 Hz), which have been linked to GABAergic inhibitory control and intracortical communication. Depression symptoms worsened when connectivity within the left vs. right PFC became imbalanced. In the left hemisphere, all directed connectivity towards the ACC, from the dlPFC and OFC, was positively correlated with depression severity. In the right hemisphere, directed connectivity between the OFC and dlPFC increased with depression severity as well. This is the first evidence that delta oscillations flowing between prefrontal subregions transiently increase intensity when people are experiencing more negative mood. These findings support the overarching hypothesis that MDD worsens with prefrontal disinhibition.

Background: Single-pulse electrical stimulation (SPES) is an established technique used to map functional effective connectivity networks in treatment-refractory epilepsy patients undergoing intracranial-electroencephalography monitoring. While the connectivity path between stimulation and recording sites has been explored through the integration of structural connectivity, there are substantial gaps, such that new modeling approaches may advance our understanding of connectivity derived from SPES studies., New Method: Using intracranial electrophysiology data recorded from a single patient undergoing stereo-electroencephalography (sEEG) evaluation, we employ an automated detection method to identify early response components, C1, from pulse-evoked potentials (PEPs) induced by SPES. C1 components were utilized for a novel topology optimization method, modeling 3D electrical conductivity to infer neural pathways from stimulation sites. Additionally, PEP features were compared with tractography metrics, and model results were analyzed with respect to anatomical features., Results: The proposed optimization model resolved conductivity paths with low error. Specific electrode contacts displaying high error correlated with anatomical complexities. The C1 component strongly correlated with additional PEP features and displayed stable, weak correlations with tractography measures., Comparison With Existing Method: Existing methods for estimating neural signal pathways are imaging-based and thus rely on anatomical inferences., Conclusions: These results demonstrate that informing topology optimization methods with human intracranial SPES data is a feasible method for generating 3D conductivity maps linking electrical pathways with functional neural ensembles. PEP-estimated effective connectivity is correlated with but distinguished from structural connectivity. Modeled conductivity resolves connectivity pathways in the absence of anatomical priors., Competing Interests: Declaration of Competing Interest S.A.S. is a consultant for Boston Scientific, Neuropace, Koh Young, Zimmer Biomet, Varian Medical, and Sensoria Therapeutics and co-founder of Motif Neurotech. The authors declare no other competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Prefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown. Here, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS). We demonstrate a shared frontotemporal circuit consisting of the ventromedial prefrontal cortex, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found participant-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation. Our findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy., Competing Interests: SS has consulting agreements with Boston Scientific, Neuropace, Abbott, and Zimmer Biomet, Varian Medical and Sensoria Therapeutics and is a co-founder for Motif Neurotech. NP was a consultant for Second Sight Medical Products, Abbott Laboratories, Boston Scientific, and Sensoria Therapeutics. WG has received donated devices from Medtronic, has consulted for Biohaven Pharmaceuticals and receives royalties from Nview, LLC. SM was supported through the use of resources and facilities at the Michael E. Debakey VA Medical Center, Houston, Texas and receives support from The Menninger Clinic. SM has served as a consultant to Allergan, Alkermes, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, COMPASS Pathways, Eleusis, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, and Sunovion. He has received research support from Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, and VistaGen Therapeutics. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Allawala, Bijanki, Oswalt, Mathura, Adkinson, Pirtle, Shofty, Robinson, Harrison, Mathew, Goodman, Pouratian, Sheth and Borton.)

Background: Reconstructive surgery for upper extremity manifestations of cerebral palsy (CP) has been demonstrated to be safe and effective, yet many potential candidates are never evaluated for surgery. The purpose of this study was to determine barriers to upper extremity reconstruction for patients with CP in a cohort of upper extremity surgeons and nonsurgeons., Methods: We sent a questionnaire to 4167 surgeons and nonsurgeon physicians, aggregated responses, and analyzed for differences in perceptions regarding surgical efficacy, patient candidacy for surgery, compliance with rehabilitation, remuneration, complexity of care, and physician comfort providing care., Results: Surgeons and nonsurgeons did not agree on the literature support of surgical efficacy (73% vs 35% agree or strongly agree, respectively). Both surgeons and nonsurgeons felt that many potential candidates exist, yet there was variability in their confidence in identifying them. Most surgeons (59%) and nonsurgeons (61%) felt comfortable performing surgery and directing the associated rehabilitation, respectively. Neither group reported that patient compliance, access to rehabilitation services, and available financial resources were a major barrier, but surgeons were more likely than nonsurgeons to feel that remuneration for services was inadequate (37% vs 13%). Both groups agreed that surgical treatments are complex and should be performed in the setting of a multidisciplinary team., Conclusions: Surgeons and nonsurgeons differ in their views regarding upper extremity reconstructive surgery for CP. Barriers to reconstruction may be addressed by performing higher level research, implementing multispecialty educational outreach, developing objective referral criteria, increasing surgical remuneration, improving access to trained upper extremity surgeons, and implementing multidisciplinary CP clinics.

Background Brachial artery lacerations are limb-threatening injuries requiring emergent repair. Concomitant peripheral nerve symptoms are often only identified postoperatively. This study evaluated the prevalence of peripheral nerve deficits among this population as the indications for early nerve exploration have not been definitively established. Methods We reviewed all patients sustaining a brachial artery injury at one pediatric and two adult Level I Trauma Centers between January 1, 2007, and December 31, 2017. We recorded patient demographics, comorbidities, intoxication status, injury mechanism, concomitant injuries, type of repair, and intraoperative peripheral nerve exploration findings. Pre-and post-operative and long-term peripheral nerve function examination findings were analyzed. Differences between categorical variables were determined with Chi-square and Fisher's exact tests. Results Thirty-four patients sustained traumatic brachial artery lacerations requiring operative repair. Injury mechanisms included tidy (clean cut) laceration (n=11, 32%), gunshot wound (n=9, 26%), blunt trauma (n=8, 24%), and untidy laceration (n=6, 18%). Preoperatively, 15% had a normal peripheral nerve examination, 26% had localizable symptoms, 38% had non-localizable symptoms, and 21% were taken to the operating room without formal nerve assessment. Thirty-two percent underwent formal nerve exploration, and 81% underwent nerve repair. At an average follow-up of 2.5 years, 27% of patients underwent exploration, and 39% did not have localizable peripheral nerve deficits ( p =0.705). Conclusions Brachial artery injuries are associated with a clinically significant risk for long-term peripheral nerve symptoms. Early nerve exploration in patients with peripheral nerve symptoms after a brachial artery injury may be warranted, although there is no statistically significant likelihood for improved peripheral neurological outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Loewenstein et al.)

Background In this study, we sought to determine if postoperative physician phone calls following hand and wrist fracture surgery improve patient outcomes, satisfaction, and treatment adherence. Methodology We prospectively enrolled 24 consecutive adult patients who underwent outpatient surgery for isolated hand and wrist fractures at a single, metropolitan, safety-net hospital over one year to receive an additional physician phone call starting on postoperative day one. We measured preoperative and postoperative Brief Michigan Hand Questionnaire (bMHQ) composite score, overall satisfaction on a five-point Likert scale, compliance with treatment recommendations, presence of complications, discharge instructions reading level, and clarity of discharge and follow-up instructions. The surgical team was blinded to the treatment arm. Results The bMHQ score improved 26% after surgery; however, there was no difference in absolute score change between groups (12.2 vs. 6.5, p = 0.69). Most patients were satisfied throughout all stages of care, but postoperative satisfaction did not differ between groups (1.4 vs. 2.5, p = 0.21). There was a stronger correlation between patient hand function and satisfaction starting one month after surgery (R 2 = 0.502, p = 0.002) than preoperatively (R 2 = 0.252, p = 0.029). Immediately following surgery, most patients stated that discharge instructions were clear, and the average readability was below the average patient education level. Despite this, 13% removed their splint or Kirschner wires, 67% did not follow up within a week of recommendation, 62% did not complete postoperative treatment, and 33% had complications. Conclusions Postoperative phone calls by physicians did not improve compliance with recommendations, patient-rated outcome measures, or clinical outcomes among our hand and wrist fracture patient population., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Loewenstein et al.)

Background: Many patients with complete nerve lacerations after upper extremity trauma have a documented normal peripheral nerve examination at the time of initial evaluation. The purpose of this study was to determine whether physician-, patient-, and injury-related factors increase the risk of false-negative nerve examinations. Methods: A statewide health information exchange was used to identify complete upper extremity nerve lacerations subsequently confirmed by surgical exploration at 1 pediatric and 2 adult level I trauma centers in a single city from January 2013 to January 2017. Charts were manually reviewed to build a database that included Glasgow Coma Scale score, urine drug screen results, blood alcohol level, presence of concomitant trauma, type of injury, level of injury, laterality, initial provider examination, and initial specialist examination. Bivariate and multivariable analyses were performed to evaluate risk factors for a false-negative examination. Results: Two hundred eighty-eight patients met inclusion criteria. The overall false-negative examination rate was 32.5% at initial encounter, which was higher among emergency medicine physicians compared with extremity subspecialists ( P < .001) and among trauma surgeons compared with surgical subspecialists ( P = .002). The false-negative rate decreased to 8% at subsequent encounter ( P < .001). Risk factors for a false-negative nerve examination included physician specialty, a gunshot wound mechanism of injury, injury at the elbow, and age greater than 71 years. Conclusion: There is a high false-negative rate among upper extremity neurotmesis injuries. Patients with an injury pattern that may lead to nerve injury warrant prompt referral to an upper extremity specialist in an effort to optimize outcomes.

Quantification of the complexity of signals recorded concurrently from multivariate systems, such as the brain, plays an important role in the study and characterization of their state and state transitions. Multivariate analysis of the electroencephalographic signals (EEG) over time is conceptually most promising in unveiling the global dynamics of dynamical brain disorders such as epilepsy. We employed a novel methodology to study the global complexity of the epileptic brain en route to seizures. The developed measures of complexity were based on Multivariate Matching Pursuit (MMP) decomposition of signals in terms of time-frequency Gabor functions (atoms) and Shannon entropy. The measures were first validated on simulation data (Lorenz system) and then applied to EEGs from preictal (before seizure onsets) periods, recorded by intracranial electrodes from eight patients with temporal lobe epilepsy and a total of 42 seizures, in search of global trends of complexity before seizures onset. Out of five Gabor measures of complexity we tested, we found that our newly defined measure, the normalized Gabor entropy (NGE), was able to detect statistically significant ( p < 0.05) nonlinear trends of the mean global complexity across all patients over 1 h periods prior to seizures' onset. These trends pointed to a slow decrease of the epileptic brain's global complexity over time accompanied by an increase of the variance of complexity closer to seizure onsets. These results show that the global complexity of the epileptic brain decreases at least 1 h prior to seizures and imply that the employed methodology and measures could be useful in identifying different brain states, monitoring of seizure susceptibility over time, and potentially in seizure prediction.

A CD4-independent version of the X4 human immunodeficiency virus type 1 (HIV-1) HXBc2 envelope (Env) protein, termed 8x, mediates infection of CD4-negative, CXCR4-positive cells, binds directly to CXCR4 in the absence of CD4 due to constitutive exposure of a conserved coreceptor binding site in the gp120 subunit, and is more sensitive to antibody-mediated neutralization. To study the relationships between CD4 independence, neutralization sensitivity, and exposure of CD4-induced epitopes associated with the coreceptor binding site, we generated a large panel of Env mutants and chimeras between 8x and its CD4-dependent parent, HXBc2. We found that a frameshift mutation just proximal to the gp41 cytoplasmic domain in 8x Env was necessary but not sufficient for CD4 independence and led to increased exposure of the coreceptor binding site. In the presence of this altered cytoplasmic domain, single amino acid changes in either the 8x V3 (V320I) or V4/C4 (N386K) regions imparted CD4 independence, with other changes playing a modulatory role. The N386K mutation resulted in loss of an N-linked glycosylation site, but additional mutagenesis showed that it was the presence of a lysine rather than loss of the glycosylation site that contributed to CD4 independence. However, loss of the glycosylation site alone was sufficient to render Env neutralization sensitive, providing additional evidence that carbohydrate structures shield important neutralization determinants. Exposure of the CD4-induced epitope recognized by monoclonal antibody 17b and which overlaps the coreceptor binding site was highly sensitive to an R298K mutation at the base of the V3 loop and was often but not always associated with CD4 independence. Finally, while not all neutralization-sensitive Envs were CD4 independent, all CD4-independent Envs exhibited enhanced sensitivity to neutralization by HIV-1-positive human sera, indicating that the humoral immune response can exert strong selective pressure against the CD4-independent phenotype in vivo. Whether this can be used to advantage in designing more effective immunogens remains to be seen.

The renal excretion of uric acid was studied in nondiuretic (ND) male Wistar rats and in the same animals subsequently made diuretic (D) by the infusion of hypertonic saline. Clearances of endogenous urate and of inulin, determined chemically, were compared with the simultaneous clearance of 14C infused as [6(-14)C]urate or [2(-14)C]urate. In rats infused with [6(-14)C]urate the isotope/inulin clearance ratios were 0.29 +/- 0.09 (ND) and 0.31 +/- 0.11 (D) ml/min; the simultaneous urate (chemical)/inulin ratios were 0.21 +/- 0.07 (ND) and 0.24 +/- 0.08 (D) ml/min. In rats infused with [2(-14)C]urate the isotope/inulin clearance ratios were 1.02 +/- 0.5 (ND) and 1.13 +/- 0.9 ml/min (D); the simultaneous urate (chemical)/inulin clearance ratios were much lower-0.19 +/- 0.09 (ND) and 0.32 +/- 0.19 (D) ml/min. Thin-layer chromatography of urine after [6(-14)C]urate inl uric acid. In contrast, a similar analysis of urinary radioactivity after [2(-14)C]urate infusion revealed that more than 70% of the 14C was excreted as allantoin and not as uric acid.