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The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome. These "multiomic" foundations are poorly understood in humans, perhaps in part because most modern studies that characterize the molecular state of the human PFC use tissue obtained when neurotransmission and higher-order brain functions have ceased (i.e., the postmortem state). Here, analyses are presented on data generated for the Living Brain Project (LBP) to investigate whether PFC tissue from individuals with intact higher-order brain function has characteristic multiomic foundations. Two complementary strategies were employed towards this end. The first strategy was to identify in PFC samples obtained from living study participants a signature of RNA transcript expression associated with neurotransmission measured intracranially at the time of PFC sampling, in some cases while participants performed a task engaging higher-order brain functions. The second strategy was to perform multiomic comparisons between PFC samples obtained from individuals with intact higher-order brain function at the time of sampling (i.e., living study participants) and PFC samples obtained in the postmortem state. RNA transcript expression within multiple PFC cell types was associated with fluctuations of dopaminergic, serotonergic, and/or noradrenergic neurotransmission in the substantia nigra measured while participants played a computer game that engaged higher-order brain functions. A subset of these associations - termed the "transcriptional program associated with neurotransmission" (TPAWN) - were reproduced in analyses of brain RNA transcript expression and intracranial neurotransmission data obtained from a second LBP cohort and from a cohort in an independent study. RNA transcripts involved in TPAWN were found to be (1) enriched for RNA transcripts associated with measures of neurotransmission in rodent and cell models, (2) enriched for RNA transcripts encoded by evolutionarily constrained genes, (3) depleted of RNA transcripts regulated by common DNA sequence variants, and (4) enriched for RNA transcripts implicated in higher-order brain functions by human population genetic studies. In PFC excitatory neurons of living study participants, higher expression of the genes in TPAWN tracked with higher expression of RNA transcripts that in rodent PFC samples are markers of a class of excitatory neurons that connect the PFC to deep brain structures. TPAWN was further reproduced by RNA transcript expression patterns differentiating living PFC samples from postmortem PFC samples, and significant differences between living and postmortem PFC samples were additionally observed with respect to (1) the expression of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression. Taken together, this report highlights that studies of brain tissue obtained in a safe and ethical manner from large cohorts of living individuals can help advance understanding of the multiomic foundations of brain function.
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Dopamine (DA) signals originating from substantia nigra (SN) neurons are centrally involved in the regulation of motor and reward processing. DA signals behaviorally relevant events where reward outcomes differ from expectations (reward prediction errors, RPEs). RPEs play a crucial role in learning optimal courses of action and in determining response vigor when an agent expects rewards. Nevertheless, how reward expectations, crucial for RPE calculations, are conveyed to and represented in the dopaminergic system is not fully understood, especially in the human brain where the activity of DA neurons is difficult to study. One possibility, suggested by evidence from animal models, is that DA neurons explicitly encode reward expectations. Alternatively, they may receive RPE information directly from upstream brain regions. To address whether SN neuron activity directly reflects reward expectation information, we directly examined the encoding of reward expectation signals in human putative DA neurons by performing single-unit recordings from the SN of patients undergoing neurosurgery. Patients played a two-armed bandit decision-making task in which they attempted to maximize reward. We show that neuronal firing rates (FR) of putative DA neurons during the reward expectation period explicitly encode reward expectations. First, activity in these neurons was modulated by previous trial outcomes, such that FR were greater after positive outcomes than after neutral or negative outcome trials. Second, this increase in FR was associated with shorter reaction times, consistent with an invigorating effect of DA neuron activity during expectation. These results suggest that human DA neurons explicitly encode reward expectations, providing a neurophysiological substrate for a signal critical for reward learning.
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Depression is prevalent in epilepsy patients and their intracranial brain activity recordings can be used to determine the types of brain activity that are associated with comorbid depression. We performed case-control comparison of spectral power and phase amplitude coupling (PAC) in 34 invasively monitored drug resistant epilepsy patients' brain recordings. The values of spectral power and PAC for one-minute segments out of every hour in a patient's study were correlated with pre-operative assessment of depressive symptoms by Beck Depression Inventory-II (BDI). We identified an elevated PAC signal (theta-alpha-beta phase (5-25 Hz)/gamma frequency (80-100 Hz) band) that is present in high BDI scores but not low BDI scores adult epilepsy patients in brain regions implicated in primary depression, including anterior cingulate cortex, amygdala and orbitofrontal cortex. Our results showed the application of PAC as a network-specific, electrophysiologic biomarker candidate for comorbid depression and its potential as treatment target for neuromodulation.
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Ondas Encefálicas , Epilepsia , Adulto , Humanos , Depressão/diagnóstico , Depressão/etiologia , Epilepsia/complicações , Epilepsia/diagnóstico , Encéfalo , Ondas Encefálicas/fisiologia , Córtex Pré-Frontal , EletroencefalografiaRESUMO
Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson's disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value-akin to reward prediction errors-whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia's main output structures reflect distinct social context and value signals.
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Dopamina , Doença de Parkinson , Serotonina , Substância Negra , Humanos , Serotonina/metabolismo , Dopamina/metabolismo , Substância Negra/metabolismo , Masculino , Feminino , Doença de Parkinson/metabolismo , Pessoa de Meia-Idade , Idoso , Comportamento Social , RecompensaRESUMO
Social decision making requires the integration of reward valuation and social cognition systems, both dependent on the orbitofrontal cortex (OFC). How these two OFC functions interact is largely unknown. We recorded intracranial activity from the OFC of ten patients making choices in a social context where reward inequity with a social counterpart varied and could be either advantageous or disadvantageous. We find that OFC high-frequency activity (HFA; 70-150 Hz) encodes self-reward, consistent with previous reports. We also observe encoding of the social counterpart's reward, as well as the type of inequity being experienced. Additionally, we find evidence of inequity-dependent reward encoding: depending on the type of inequity, electrodes rapidly and reversibly switch between different reward-encoding profiles. These results provide direct evidence for encoding of self- and other rewards in the human OFC and highlight the dynamic nature of encoding in the OFC as a function of social context.
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Neurônios , Córtex Pré-Frontal , Humanos , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , RecompensaRESUMO
Flexible behavior requires gating mechanisms that encode only task-relevant information in working memory. Extant literature supports a theoretical division of labor whereby lateral frontoparietal interactions underlie information maintenance and the striatum enacts the gate. Here, we reveal neocortical gating mechanisms in intracranial EEG patients by identifying rapid, within-trial changes in regional and inter-regional activities that predict subsequent behavioral outputs. Results first demonstrate information accumulation mechanisms that extend prior fMRI (i.e., regional high-frequency activity) and EEG evidence (inter-regional theta synchrony) of distributed neocortical networks in working memory. Second, results demonstrate that rapid changes in theta synchrony, reflected in changing patterns of default mode network connectivity, support filtering. Graph theoretical analyses further linked filtering in task-relevant information and filtering out irrelevant information to dorsal and ventral attention networks, respectively. Results establish a rapid neocortical theta network mechanism for flexible information encoding, a role previously attributed to the striatum.
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Encéfalo , Memória de Curto Prazo , Humanos , Encéfalo/diagnóstico por imagem , Corpo Estriado , Neostriado , Imageamento por Ressonância Magnética , Mapeamento Encefálico/métodosRESUMO
Computational psychiatry, a relatively new yet prolific field that aims to understand psychiatric disorders with formal theories about the brain, has seen tremendous growth in the past decade. Despite initial excitement, actual progress made by computational psychiatry seems stagnant. Meanwhile, understanding of the human brain has benefited tremendously from recent progress in intracranial neuroscience. Specifically, invasive techniques such as stereotactic electroencephalography, electrocorticography, and deep brain stimulation have provided a unique opportunity to precisely measure and causally modulate neurophysiological activity in the living human brain. In this review, we summarize progress and drawbacks in both computational psychiatry and invasive electrophysiology and propose that their combination presents a highly promising new direction-invasive computational psychiatry. The value of this approach is at least twofold. First, it advances our mechanistic understanding of the neural computations of mental states by providing a spatiotemporally precise depiction of neural activity that is traditionally unattainable using noninvasive techniques with human subjects. Second, it offers a direct and immediate way to modulate brain states through stimulation of algorithmically defined neural regions and circuits (i.e., algorithmic targeting), thus providing both causal and therapeutic insights. We then present depression as a use case where the combination of computational and invasive approaches has already shown initial success. We conclude by outlining future directions as a road map for this exciting new field as well as presenting cautions about issues such as ethical concerns and generalizability of findings.
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Simulação por Computador , Neurociências , Psiquiatria , Psiquiatria/instrumentação , Psiquiatria/métodos , Psiquiatria/tendências , Humanos , Neurociências/instrumentação , Neurociências/métodos , Neurociências/tendências , Crânio , Neurofisiologia/instrumentação , Neurofisiologia/métodos , Neurofisiologia/tendências , Depressão/fisiopatologia , Depressão/terapia , Modelos Neurológicos , Eletrofisiologia/instrumentação , AlgoritmosRESUMO
Objective: Non-literal expressions such as sarcasm, metaphor and simile refer to words and sentences that convey meanings or intentions that are different and more abstract than literal expressions. Neuroimaging studies have shown activations in a variety of frontal, parietal and temporal brain regions implicated in non-literal language processing. However, neurophysiological correlates of these brain areas underlying non-literal processing remain underexplored. Methods: To address this, we investigated patterns of intracranial EEG activity during non-literal processing by leveraging a unique patient population. Seven neurosurgical patients with invasive electrophysiological monitoring of superficial brain activity were recruited. Intracranial neural responses were recorded over the temporal-parietal junction (TPJ) and its surrounding areas while patients performed a language task. Participants listened to vignettes that ended with non-literal or literal statements and were then asked related questions to which they responded verbally. Results: We found differential neurophysiological activity during the processing of non-literal statements as compared to literal statements, especially in low-Gamma (30-70 Hz) and delta (1-4 Hz) bands. In addition, we found that neural responses related to non-literal processing in the high-gamma band (>70 Hz) were significantly more prominent at TPJ electrodes as compared to non-TPJ (i.e., control) electrodes in most subjects. Moreover, in half of patients, high-gamma activity related to non-literal processing was accompanied by delta-band modulation. Conclusion: These results suggest that both low- and high-frequency electrophysiological activities in the temporal-parietal junction play a crucial role during non-literal language processing in the human brain. The current investigation, utilizing better spatial and temporal resolution of human intracranial electrocorticography, provides a unique opportunity to gain insights into the localized brain dynamics of the TPJ during the processing of non-literal language expressions.
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BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease (PD). While the success of DBS is dependent on careful patient selection and accurate lead placement, programming parameters play a pivotal role in tailoring therapy on the individual level. Various algorithms have been developed to streamline the initial programming process, but the relationship between pre-operative patient characteristics and post-operative device settings is unclear. In this study, we investigated how PD severity correlates with DBS settings. METHODS: We conducted a retrospective review of PD patients who underwent DBS of the subthalamic nucleus at one US tertiary care center between 2014 and 2018. Pre-operative patient characteristics and post-operative programming data at various intervals were collected. Disease severity was measured using the Unified Parkinson's Disease Rating Scale score (UPDRS) as well as levodopa equivalent dose (LED). Correlation analyses were conducted looking for associations between pre-operative disease severity and post-operative programming parameters. RESULTS: Fifty-six patients were analyzed. There was no correlation between disease severity and any of the corresponding programming parameters. Pre-operative UPDRS scores on medication were similar to post-operative scores with DBS. Settings of amplitude, frequency, and pulse width increased significantly from 1 to 6 months post-operatively. Stimulation volume, inferred by the distance between contacts used, also increased significantly over time. CONCLUSIONS: Interestingly, we found that patients with more advanced disease responded to electrical stimulation similarly to patients with less advanced disease. These data provide foundational knowledge of DBS programming parameters used in a single cohort of PD patients over time.
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Estimulação Encefálica Profunda , Doença de Parkinson , Núcleo Subtalâmico , Humanos , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Despite increased awareness of the lack of gender equity in academia and a growing number of initiatives to address issues of diversity, change is slow, and inequalities remain. A major source of inequity is gender bias, which has a substantial negative impact on the careers, work-life balance, and mental health of underrepresented groups in science. Here, we argue that gender bias is not a single problem but manifests as a collection of distinct issues that impact researchers' lives. We disentangle these facets and propose concrete solutions that can be adopted by individuals, academic institutions, and society.
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Equidade de Gênero , Pesquisadores , Sexismo , Universidades/organização & administração , Feminino , Humanos , Masculino , Pesquisa/organização & administraçãoRESUMO
BACKGROUND: One in three patients with epilepsy are medication-refractory and may benefit from investigations and operative treatment at a comprehensive epilepsy center. However, while these centers have capabilities for advanced seizure monitoring and surgical intervention, they are not required to have a functional neurosurgeon who is primarily focused in epilepsy surgery. Therefore, the objective of this study is to determine the impact of having a sub-specialized, epilepsy-focused functional neurosurgeon on patient outcomes. METHODS: We conducted a retrospective chart review for all patients who underwent surgical intervention for medically refractory epilepsy at a Level 4 comprehensive Epilepsy Center from 2008 through 2019. Data was divided into two groups: group 1 comprised patients who had surgery before the hiring of a dedicated epilepsy-focused functional neurosurgeon in 2016, and group 2 was afterwards. We compared surgical procedures, significant complications, and seizure outcomes. RESULTS: A total of 101 patients underwent 105 operations (52 in group 1 and 53 in group 2), not including intracranial EEG insertion. Compared to group 1, group 2 had more surgeries performed per year (15.1 vs. 6.5), and a significantly lower Engel score at last follow-up (1.78 vs. 2.57; p < 0.001). There was no difference in percentage of cases undergoing iEEG, and no difference in complication rates. CONCLUSIONS: In this series, the hiring of a sub-specialized functional neurosurgeon dedicated to epilepsy surgery in a comprehensive epilepsy center was associated with an increase in surgical volume and improved seizure outcomes.
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Estado Terminal , Solução Salina , Adulto , Criança , Estado Terminal/terapia , Soluções Cristaloides , Humanos , RessuscitaçãoRESUMO
BACKGROUND: Stereotactic electroencephalography (SEEG) has largely become the preferred method for intracranial seizure localization in epileptic patients due to its low morbidity and minimally invasive approach. While robotic placement is gaining popularity, many centers continue to use manual frame-based and frameless methods for electrode insertion. However, it is unclear how these methods compare in regard to accuracy, precision, and safety. Here, we aim to compare frame-based insertion using a CRW frame (Integra®) and frameless insertion using the StealthStation™ S7 (Medtronic®) navigation system for common temporal SEEG targets. METHODS: We retrospectively examined electrode targets in SEEG patients that were implanted with either frame-based or frameless methods at a level 4 epilepsy center. We focused on two commonly used targets: amygdala and hippocampal head. Stealth station software was used to merge pre-operative MR with post-operative CT images for each patient, and coordinates for each electrode tip were calculated in relation to the midcommissural point. These were compared to predetermined ideal coordinates in regard to error and directional bias. RESULTS: A total of 81 SEEG electrodes were identified in 23 patients (40 amygdala and 41 hippocampal head). Eight of 45 electrodes (18%) placed with the frameless technique and 0 of 36 electrodes (0%) placed with the frame-based technique missed their target and were not clinically useful. The average Euclidean distance comparing actual to ideal electrode tip coordinates for frameless vs. frame-based techniques was 11.0 mm vs. 7.1 mm (p < 0.001) for the amygdala and 12.4 mm vs. 8.5 mm (p < 0.001) for the hippocampal head, respectively. There were no hemorrhages or clinical complications in either group. CONCLUSIONS: Based on this series, frame-based SEEG insertion is significantly more accurate and precise and results in more clinically useful electrode contacts, compared to frameless insertion using a navigation guidance system. This has important implications for centers not currently using robotic insertion.
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Neuronavegação/métodos , Hemorragia Pós-Operatória/epidemiologia , Adolescente , Adulto , Tonsila do Cerebelo/cirurgia , Eletrodos Implantados/efeitos adversos , Feminino , Hipocampo/cirurgia , Humanos , Masculino , Neuronavegação/efeitos adversos , Neuronavegação/normas , Hemorragia Pós-Operatória/etiologiaRESUMO
BACKGROUND: Deep brain stimulation (DBS) is an effective therapy for a variety of refractory movement disorders. Accurate lead placement in the target nucleus is critical to ensure therapeutic effects and to minimize side effects, and intraoperative computed tomography (iCT) scan has been used to target and confirm lead position. The objective of this study is to compare the accuracy of determining the x, y, and z coordinates of final lead placement using iCT scan relative to postoperative magnetic resonance imaging (MRI). METHODS: We conducted a retrospective study on 83 patients who underwent insertion of 145 DBS leads from 2015 to 2017 at a single institution. iCT scan was merged with the preoperative MRI to determine lead coordinates on both magnetic resonance and computed tomography images independently, and the absolute differences between the x, y, and z coordinates between the 2 scans along with the Euclidean vectors were calculated. RESULTS: The mean absolute differences ± standard error of the mean between iCT scan and postoperative MRI coordinates were as follows: x = 0.01 ± 0.09 mm (P = 0.89), y = 1.67 ± 0.14 mm (P < 0.001), and z = 2.75 ± 0.15 mm (P < 0.001). The average Euclidean vector difference was 3.21 ± 0.15 mm (P < 0.001). CONCLUSIONS: Significant differences exist between iCT scan and postoperative MRI DBS y and z lead coordinates, but not with x coordinates. Based on this series, iCT scan is more accurate when confirming x coordinates, and less accurate for confirming y and z coordinates during DBS operations.
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Encéfalo/diagnóstico por imagem , Estimulação Encefálica Profunda , Transtornos dos Movimentos/cirurgia , Neuroimagem/métodos , Tomografia Computadorizada por Raios X/métodos , Encéfalo/cirurgia , Eletrodos Implantados , Humanos , Período Intraoperatório , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Técnicas EstereotáxicasRESUMO
Obtaining a position as an independent investigator is a daunting prospect, and often requires skill sets that are not emphasized during graduate or postdoctoral training. Here, we present insight from a seminar series designed to guide young researchers looking to "make the jump", covering the fundamental steps of the job search (preparation of an application package, Skype/remote interview, campus visit, and negotiations). We summarize the many useful insights distilled throughout these roundtable sessions with the goal of providing information and guidance to a broader community of researchers on the best way to prepare for and tackle the faculty job market.
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Docentes , Pesquisadores , HumanosRESUMO
BACKGROUND: Fluid therapy is one of the main interventions provided for critically ill patients, although there is no general consensus regarding the type of solution. Among crystalloid solutions, 0.9% saline is the most commonly administered. Buffered solutions may offer some theoretical advantages (less metabolic acidosis, less electrolyte disturbance), but the clinical relevance of these remains unknown. OBJECTIVES: To assess the effects of buffered solutions versus 0.9% saline for resuscitation in critically ill adults and children. SEARCH METHODS: We searched the following databases to July 2018: CENTRAL, MEDLINE, Embase, CINAHL, and four trials registers. We checked references, conducted backward and forward citation searching of relevant articles, and contacted study authors to identify additional studies. We imposed no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) with parallel or cross-over design examining buffered solutions versus intravenous 0.9% saline in a critical care setting (resuscitation or maintenance). We included studies on participants with critical illness (including trauma and burns) or undergoing emergency surgery during critical illness who required intravenous fluid therapy. We included studies of adults and children. We included studies with more than two arms if they fulfilled all of our inclusion criteria. We excluded studies performed in persons undergoing elective surgery and studies with multiple interventions in the same arm. DATA COLLECTION AND ANALYSIS: We used Cochrane's standard methodological procedures. We assessed our intervention effects using random-effects models, but when one or two trials contributed to 75% of randomized participants, we used fixed-effect models. We reported outcomes with 95% confidence intervals (CIs). MAIN RESULTS: We included 21 RCTs (20,213 participants) and identified three ongoing studies. Three RCTs contributed 19,054 participants (94.2%). Four RCTs (402 participants) were conducted among children with severe dehydration and dengue shock syndrome. Fourteen trials reported results on mortality, and nine reported on acute renal injury. Sixteen included trials were conducted in adults, four in the paediatric population, and one trial limited neither minimum or maximum age as an inclusion criterion. Eight studies involving 19,218 participants were rated as high methodological quality (trials with overall low risk of bias according to the domains: allocation concealment, blinding of participants/assessors, incomplete outcome data, and selective reporting), and in the remaining trials, some form of bias was introduced or could not be ruled out.We found no evidence of an effect of buffered solutions on in-hospital mortality (odds ratio (OR) 0.91, 95% CI 0.83 to 1.01; 19,664 participants; 14 studies; high-certainty evidence). Based on a mortality rate of 119 per 1000, buffered solutions could reduce mortality by 21 per 1000 or could increase mortality by 1 per 1000. Similarly, we found no evidence of an effect of buffered solutions on acute renal injury (OR 0.92, 95% CI 0.84 to 1.00; 18,701 participants; 9 studies; low-certainty evidence). Based on a rate of 121 per 1000, buffered solutions could reduce the rate of acute renal injury by 19 per 1000, or result in no difference in the rate of acute renal injury. Buffered solutions did not show an effect on organ system dysfunction (OR 0.80, 95% CI 0.40 to 1.61; 266 participants; 5 studies; very low-certainty evidence). Evidence on the effects of buffered solutions on electrolyte disturbances varied: potassium (mean difference (MD) 0.09, 95% CI -0.10 to 0.27; 158 participants; 4 studies; very low-certainty evidence); chloride (MD -3.02, 95% CI -5.24 to -0.80; 351 participants; 7 studies; very low-certainty evidence); pH (MD 0.04, 95% CI 0.02 to 0.06; 200 participants; 3 studies; very low-certainty evidence); and bicarbonate (MD 2.26, 95% CI 1.25 to 3.27; 344 participants; 6 studies; very low-certainty evidence). AUTHORS' CONCLUSIONS: We found no effect of buffered solutions on preventing in-hospital mortality compared to 0.9% saline solutions in critically ill patients. The certainty of evidence for this finding was high, indicating that further research would detect little or no difference in mortality. The effects of buffered solutions and 0.9% saline solutions on preventing acute kidney injury were similar in this setting. The certainty of evidence for this finding was low, and further research could change this conclusion. Patients treated with buffered solutions showed lower chloride levels, higher levels of bicarbonate, and higher pH. The certainty of evidence for these findings was very low. Future research should further examine patient-centred outcomes such as quality of life. The three ongoing studies once published and assessed may alter the conclusions of the review.
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Estado Terminal , Hidratação/métodos , Solução Salina/uso terapêutico , Adulto , Criança , Cuidados Críticos , Mortalidade Hospitalar , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Soluções para ReidrataçãoRESUMO
PURPOSE: Oral squamous cell carcinoma (OSCC) is a highly prevalent type of immunogenic cancer with a low survival rate in patients with comorbidities owing to toxic habits. MATERIALS AND METHODS: A retrospective cohort study was conducted of patients with resectable OSCC at a tertiary Spanish hospital from 2011 to 2014. The primary predictor variables were comorbidity and immune biomarkers. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) and scored from 1 to 3 (mild to severe decompensation, respectively). The immune biomarkers were neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). The primary outcome variable was 5-year overall survival (OS). Other study variables were stage, margin, and neck management. Receiver operating characteristic curves were built for each ratio. For the survey of immune biomarkers, area under the curve was computed to determine cutoff points and investigate their association with OS. Kaplan-Meier estimates of survival and Cox proportional hazards models were used for longitudinal analysis. RESULTS: Overall 215 patients were identified (median age, 67 yr; range, 32 to 96 yr; median follow-up, 31 months; range, 7 to 78 months); 159 patients had at least 1 comorbid condition. Results showed that a severe comorbidity (according to the ACE-27) increased the risk of death by 4 times in patients with OSCC regardless of stage. NLR, dNLR, LMR, and PLR were associated with OS in the univariate study. Cutoff points to predict increased mortality were 3, 1.9, 2.6, and 66 for NLR, dNLR, LMR, and PLR, respectively. Age, comorbidity, stage, margins, and management of the neck were important independent predictors of decreased OS in OSCC. PLR was marginally associated with OS in the multivariate model. CONCLUSION: These results suggest that comorbidity and NLR, dNLR, LMR, and PLR are associated with 5-year OS in patients with resectable OSCC.
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Carcinoma de Células Escamosas , Neoplasias Bucais , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Comorbidade , Humanos , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Neutrófilos , Prognóstico , Estudos RetrospectivosRESUMO
Despite decades of research, our understanding of epilepsy, including how seizures are generated and propagate, is incomplete. However, there is growing recognition that epilepsy is more than just the occurrence of seizures, with patients often experiencing comorbid deficits in cognition that are poorly understood. In addition, the available therapies for treatment of epilepsy, from pharmaceutical treatment to surgical resection and seizure prevention devices, often exacerbate deficits in cognitive function. In this review, we discuss the hypothesis that seizure generation and cognitive deficits have a similar pathological source characterized by, but not limited to, deficits in theta oscillations and their influence on interneurons. We present a new framework that describes oscillatory states in epilepsy as alternating between hyper- and hypo-synchrony rather than solely the spontaneous transition to hyper-excitability characterized by the seizures. This framework suggests that as neural oscillations, specifically in the theta range, vary their tempo from a slowed almost adagio tempo during interictal periods to faster, more rhythmic allegretto tempo preictally, they impact the function of interneurons, modulating their ability to control seizures and their role in cognitive processing. This slow wave oscillatory framework may help explain why current therapies that work to reduce hyper-excitability do not completely eliminate seizures and often lead to exacerbated cognitive deficits.
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Cognição/fisiologia , Epilepsia/fisiopatologia , Interneurônios/fisiologia , Ritmo Teta/fisiologia , Animais , HumanosRESUMO
Brain-machine interface-once the stuff of science fiction novels-is coming to a computer near you. The only question is: How soon? While the technology is in its infancy, it is already helping people with spinal cord injuries. Our authors examine its potential to be the ultimate game changer for any number of neurodegenerative diseases, as well as behavior, learning, and memory. They take the temperature of where the technology is, where it is going, and the inevitable ethical and regulatory implications.
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Human orbitofrontal cortex (OFC) has long been implicated in value-based decision making. In recent years, convergent evidence from human and model organisms has further elucidated its role in representing reward-related computations underlying decision making. However, a detailed description of these processes remains elusive due in part to (1) limitations in our ability to observe human OFC neural dynamics at the timescale of decision processes and (2) methodological and interspecies differences that make it challenging to connect human and animal findings or to resolve discrepancies when they arise. Here, we sought to address these challenges by conducting multi-electrode electrocorticography (ECoG) recordings in neurosurgical patients during economic decision making to elucidate the electrophysiological signature, sub-second temporal profile, and anatomical distribution of reward-related computations within human OFC. We found that high-frequency activity (HFA) (70-200 Hz) reflected multiple valuation components grouped in two classes of valuation signals that were dissociable in temporal profile and information content: (1) fast, transient responses reflecting signals associated with choice and outcome processing, including anticipated risk and outcome regret, and (2) sustained responses explicitly encoding what happened in the immediately preceding trial. Anatomically, these responses were widely distributed in partially overlapping networks, including regions in the central OFC (Brodmann areas 11 and 13), which have been consistently implicated in reward processing in animal single-unit studies. Together, these results integrate insights drawn from human and animal studies and provide evidence for a role of human OFC in representing multiple reward computations.