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PubMed2005

Contrasting roles for beta1, beta2 and beta3-adrenoceptors in memory formation in the chick.

Noradrenaline plays distinct roles in the modulation and consolidation of memory for one-trial, discriminated, avoidance learning in the chick. We have previously shown that activation of beta2-, beta3- and alpha1-adrenoceptors (ARs) by injection into the multimodal forebrain association region (intermediate medial hyperstriatum ventrale [IMHV] or intermediate medial mesopallium [IMM]) is involved in the consolidation of memory 30 min after training and that activation of alpha2-ARs in the caudate putamen plays a role in the reinforcement of memory leading to consolidation in the IMM (IMHV). In this paper we provide evidence that noradrenaline acts at beta1-ARs in the basal ganglia (lobus parolfactorius or medial striatum) in short-term memory processing immediately post-training and demonstrate inhibition of memory by selective AR antagonists at particular times in the sequential memory processing sequence after training. These results support separate roles for beta2- and beta3-ARs in memory consolidation. Our studies suggest that, as a consequence of the learning experience, noradrenaline acts in different brain regions and at different times in memory processing, to enhance memory through distinct populations of ARs.

Adrenergic beta-Agonists↗
PubMed1994

Dissociation between conditioned taste aversion and radial maze learning following seizure-induced multifocal brain damage: quantitative tests of serial vs. parallel circuit models of memory.

Multivariate analyses between conditioned taste aversion (CTA) and radial maze acquisition (RMA) scores and percentages of neuronal dropout within thalamic and telencephalic structures were completed for rats in which overt seizures had been evoked following a single systemic injection of lithium/pilocarpine. Despite multifocal damage, only the amount of damage within the hippocampus (CA1) and the basolateral amygdala was most strongly associated with attenuated CTA, whereas damage within the mediodorsal thalamus was primarily associated with RMA. There was no significant correlation between CTA or RMA. Multiple regression analyses for specific Paxinos and Watson structures and their traditional aggregates supported more precise delineation of neuronal substrates of learning/memory and a multimodal (parallel) model for these processes.

Animals↗
PubMedDate not supplied

Lake Superior Rural Cancer Care Project, part II: provider knowledge.

PURPOSE: The purpose of this article is to report the main learning outcomes of the Lake Superior Rural Cancer Care Project. DESCRIPTION OF STUDY: The authors designed and tested a multimodal intervention directed at rural providers and their healthcare systems in a large rural area in the north central United States. An experimental design was used to randomize rural providers at the group level. The intervention consisted of providing increased education for rural providers with a number of approaches, including the use of clinical opinion leaders. The main outcome of the intervention was knowledge scoring on discipline-specific cancer management tests. RESULTS: Knowledge scores for providers in the experimental group significantly increased from pretest to post-test: 66 to 79 for physicians (and physician assistants) (P=.02); 58 to 71 for nurses (P=.01); and 54 to 64 for pharmacists (P=.01). At post-test, participating providers in the experimental group performed significantly better on the knowledge tests (P <.01) than those in the control groups. CLINICAL IMPLICATIONS: This study may be the first to test educational interventions to improve rural providers' knowledge about cancer practice using an experimental design. The intervention may possibly change provider practice behaviors and, thus, patient outcomes, data that will be reported in a future issue. Finally, this educational intervention may prove useful for providers in other rural areas.

Humans↗
PubMed1994

Group and family treatment of post-traumatic stress disorder.

A central feature of PTSD is its effect on social relationships. Trauma affects groups of people, not just individuals. Family systems, neighborhoods, and even whole generations may feel the results of psychological trauma. Because of the social nature of the effects of trauma, post-trauma treatment must address an individual's relationship to others. Group and family psychotherapy are ideally suited to this and are important components of a multimodal approach to PTSD treatment. Group and family psychotherapies provide superb opportunities for social support, social reintegration, and interpersonal learning. As with any powerful technique, these methods must be carefully applied. Although not all patients are appropriate for exposure-based treatments, improved interpersonal coping skills will likely be beneficial to many PTSD patients. Patients should be carefully evaluated for treatment types and assessed for treatment response. Although group and family therapies currently provide relief and growth for PTSD patients, many considerations remain for the future. For example, how can patients be matched with various treatments for optimal results? How should acute and chronic PTSD treatments be similar and different? What is the effectiveness of group and family therapies for PTSD? What are the social and legal implications of a prolonged course of treatment for a victim whose children meanwhile are being traumatized by the parent's relatively poor parenting skills secondary to their inadequacies and disabilities? Finally, at a global level, how do we improve systems therapy technology to enable us more radically, effectively, and quickly to bring about total systems change? Because families and groups are the "cells" that compose the "vital organs" we call nations, and these nations in turn make the total body of humankind, the answers to these questions may have a significant determining effect on the future survival of us all.

Adult↗
PubMedDate not supplied

A prospective study of alexithymia in obsessive-compulsive patients treated with multimodal cognitive-behavioral therapy.

BACKGROUND: Alexithymia as a predictor of treatment outcome in psychotherapy has often been discussed but rarely evaluated in prospective studies. The present study evaluated the absolute and relative stability of alexithymia in patients with obsessive-compulsive disorder (OCD), and the predictive value of alexithymia for the outcome of treatment. METHODS: We conducted a prospective study with 42 inpatients receiving intensive, multimodal cognitive-behavioral therapy (CBT). Patients were assessed for alexithymia at pre- and post-treatment with the 20-item Toronto Alexithymia Scale (TAS-20), for obsessive-compulsive symptoms and depression with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the 21-item Hamilton Depression Rating Scale (HDRS). RESULTS: OCD and comorbid depression showed a highly significant symptom-reduction from pre- to post-treatment while no absolute changes in the TAS-20 total scores and its factors 1 and 3 occurred. Only factor 2 scores decreased significantly, but with a smaller effect size than the effect sizes for the changes in Y-BOCS and HDRS. Alexithymia scores at pre-treatment correlated significantly with alexithymia scores at the end of treatment, indicating its relative stability. In the linear regression analyses, no variables were identified that predicted significantly the outcome of treatment. CONCLUSIONS: Our findings support the view that alexithymia is a stable personality trait rather than a state-dependent phenomenon in obsessive-compulsive patients. Alexithymia scores do not predict response to multimodal CBT in OCD. It might be an effect of CBT that patients could at least partly regain or newly learn the capability to describe their feelings.

Adult↗
PubMed2026

Beyond Morphology: Reframing Lymph-Node Metastasis Prediction Through Clonal Ecology-Decades-Long Genomic Instability and Polyclonal-to-Monoclonal Transitions as the Missing Dimension in Cancer.

Recent whole-genome, lineage-tracing, single-cell, and spatial studies have reshaped our understanding of tumor evolution, revealing that cancers can arise from polyclonal populations, undergo decades-long genomic instability before clinical detection, and progress through dynamic changes in subclonal composition, cellular state, and ecological organization. These findings challenge the assumption underlying morphology-based prediction models that metastatic risk can be inferred from static histological features alone. Here, we revisit lymph-node metastasis prediction in colorectal cancer through clonal ecology, integrating computational pathology with evolutionary oncology. Drawing on the subclonal switchboard model proposed in 2012 and subsequent artificial intelligence (AI)-enabled approaches for tracking dominant and dormant subclones, we synthesize evidence that metastatic potential reflects clonal ancestry, evolutionary timing, spatial niche architecture, cellular plasticity, intercellular interactions, dormancy, and treatment-driven shifts in subclonal fitness. We define five complementary methodological pillars for operationalizing clonal ecology: single-cell transcriptomics for resolving rare subclones, evolutionary trajectories, and adaptive cell states; lineage tracing and phylogenetics for reconstructing clonal ancestry and divergence; spatial transcriptomics and genomics for mapping subclonal geography and tumor-stromal-immune interactions; longitudinal liquid biopsy surveillance for monitoring residual disease, clonal turnover, and emerging resistance; and AI-enabled multimodal integration for connecting histopathology, genomics, spatial biology, and longitudinal data into predictive ecological-state models. Multiple-instance learning and pathology foundation models provide scalable computational foundations for evolution-aware prediction. Translationally, dormant subclones represent actionable reservoirs of recurrence. A longitudinal clinical and experimental study of KMT2A-rearranged acute myeloid leukemia further supports central predictions of the subclonal switchboard framework by demonstrating treatment-associated shifts in subclonal dominance, persistence of cryptic adaptive programs, and ecological rewiring during resistance and relapse. We propose clonal ecology as a measurable dimension for extending morphology-driven prediction toward integrative models that anticipate evolutionary transitions, identify therapeutic windows, and proactively constrain adaptive tumor ecosystems before resistant or metastatic subclones achieve clinical dominance.

Humans↗
PubMed2026

Artificial Intelligence for Colorectal Surgeons-Part II: Research Applications, Challenges in Adoption, and Practical Resources.

BACKGROUND: This is part II of a 2-part series examining artificial intelligence in colorectal surgery. Part I established foundational concepts and clinical applications. Implementation, however, requires understanding research methodologies, available resources, and the specific challenges currently limiting widespread adoption. These topics are the focus of part II. OBJECTIVE: To examine artificial intelligence's transformation of surgical research, provide practical implementation resources, address adoption challenges, and explore future directions in colorectal surgery. METHODS: Comprehensive literature review focusing on artificial intelligence research methodology, implementation barriers, educational resources, and emerging technologies relevant to colorectal surgeons. RESULTS: Artificial intelligence streamlines clinical trial design through predictive modeling and natural language processing, reducing enrollment challenges that contribute to failed or inadequate trial accrual. Machine learning enables heterogeneity analysis within clinical trials, identifying treatment-responsive subgroups. Foundation models unlock analysis of unstructured electronic health record data at scale. Professional societies and universities offer specialized artificial intelligence education programs, with open-access data sets facilitating research participation. However, implementation faces multifaceted challenges: technical infrastructure demands, with real-time processing requiring dedicated graphics processing unit clusters; regulatory frameworks struggling with continuously evolving algorithms; undefined liability distribution for artificial intelligence-assisted decisions; algorithmic bias risking health care disparities; and the "black box" problem limiting clinical trust. Economic barriers include substantial initial costs without clear reimbursement pathways. Future directions include multimodal artificial intelligence integrating imaging, genomics, and histopathology; cognitive robotic systems with real-time decision support; digital twin technology for patient-specific surgical simulation; and global surgical artificial intelligence networks enabling distributed learning across institutions. CONCLUSIONS: Although artificial intelligence offers transformative potential for colorectal surgery research and practice, successful implementation requires addressing technical, regulatory, ethical, and economic challenges. The surgeon's evolving role demands both traditional expertise and computational fluency. Future advances in multimodal integration, autonomous systems, and global collaboration will fundamentally reshape surgical practice but will require thoughtful implementation prioritizing patient benefit and clinical value.

Humans↗
PubMed2000

Incorporating the management of ADHD into your practice. Can it be done?

BACKGROUND: Management of children with learning and behavioural disorders has traditionally been the precinct of specialist paediatricians, psychiatrists, psychologists and teaching professionals. Networks and teams have not generally included general practitioners. In Geraldton a professional network of health and educational professionals were of the view that learning disorders including attention deficit hyperactivity disorder (ADHD) frequently went unrecognised or misdiagnosed. In 1996 the National Health and Medical Research Council recommended use of the DSM-IV American Psychiatric Association diagnostic criteria for ADHD. A multimodal model of shared care was considered optimal. In 1999 the US National Institute of Mental Health's Multimodal Treatment Study of Children with ADHD was released. OBJECTIVE: To outline the development of a program to educate and support local professionals (doctors, teachers, psychologists, nurses, counsellors) in the management of behavioural disorders in which specific goals were to: build capacity for accurate diagnosis and management of children with learning and behavioural disorders facilitate via the Midwest Division of General Practice, a network of professionals to assess and manage learning disorders, including ADHD create a model of shared care with potential for application elsewhere formalise shared care/coprescriber arrangements for stimulant medications between GPs and specialists, including fast-tracking of medication develop school networks for early identification, referral and support of ADHD cases. DISCUSSION: Our creation of a strong professional network enabling a GP case manager role has been very successful. Multiple treatment successes have created much community goodwill toward the Midwest Division of General Practice and my private practice has changed forever with the inclusion of 200 ADHD families. Colleagues considering entering this area need to recognise the potential for disruption to both their practice and their personal lives. A well organised practice with firm boundaries for difficult cases is essential.

Attention Deficit Disorder with Hyperactivity↗
PubMed2001

Pyrazine odour makes visually conspicuous prey aversive.

Unpalatable insects frequently adopt multimodal signals to ward off predators, incorporating sounds and odours into their colourful displays. Pyrazine is an odour commonly used in insect warning displays, and has previously been shown to elicit unlearned biases against common warning colours, e.g. yellow and red in naive predators. We designed two experiments to test for similar effects of pyrazine on the conspicuousness of prey, perhaps the most ubiquitous aspect of aposematic coloration. In the first experiment, we offered predators (Gallus gallus domesticus) a choice between conspicuous crumbs and cryptic crumbs in the presence or absence of pyrazine. In the second experiment, we manipulated the birds' experience of conspicuous prey during an initial training phase. Only in the presence of pyrazine did birds show a bias against conspicuously coloured food, and this occurred whether or not they had previously experienced food that contrasted with the background. This emergent behaviour relied upon the visual and odorous signal components being presented together. These unlearned, yet hidden, responses against conspicuousness demonstrate that there are initial benefits to prey being conspicuous when the multimodal nature of warning signals is accounted for.

Animals↗
PubMed2005

A process for developing community consensus regarding the diagnosis and management of attention-deficit/hyperactivity disorder.

There remain large discrepancies between pediatricians' practice patterns and the American Academy of Pediatrics (AAP) guidelines for the assessment and treatment of children with attention-deficit/hyperactivity disorder (ADHD). Several studies raise additional concerns about access to ADHD treatment for girls, blacks, and poorer individuals. Barriers may occur at multiple levels, including identification and referral by school personnel, parents' help-seeking behavior, diagnosis by the medical provider, treatment decisions, and acceptance of treatment. Such findings confirm the importance of establishing appropriate mechanisms to ensure that children of both genders and all socioeconomic, racial, and ethnic groups receive appropriate assessment and treatment. Publication of the AAP ADHD toolkit provides resources to assist with implementing the ADHD guidelines in clinical practice. These resources address a number of the barriers to office implementation, including unfamiliarity with Diagnostic and Statistical Manual of Mental Disorders criteria, difficulty identifying comorbidities, and inadequate knowledge of effective coding practices. Also crucial to the success of improved processes within clinical practice is community collaboration in care, particularly collaboration with the educational system. Such collaboration addresses other barriers to good care, such as pressures from parents and schools to prescribe stimulants, cultural biases that may prevent schools from assessing children for ADHD or may prevent families from seeking health care, and inconsistencies in recognition and referral among schools in the same system. Collaboration may also create efficiencies in collection of data and school-physician communications, thereby decreasing physicians' non-face-to-face (and thus nonreimbursable) elements of care. This article describes a process used in Guilford County, North Carolina, to develop a consensus among health care providers, educators, and child advocates regarding the assessment and treatment of children with symptoms of ADHD. The outcome, ie, a community protocol followed by school personnel and community physicians for >10 years, ensures communication and collaboration between educators and physicians in the assessment and treatment of children with symptoms of ADHD. This protocol has the potential to increase practice efficiency, improve practice standards for children with ADHD, and enhance identification of children in schools. Perhaps most importantly, the community process through which the protocol was developed and implemented has an educational component that increases the knowledge of school personnel about ADHD and its treatment, increasing the likelihood that referrals will be appropriate and increasing the likelihood that children will benefit from coordination of interventions among school personnel, physicians, and parents. The protocol reflects a consensus of school personnel and community health care providers regarding the following: (1) ideal ADHD assessment and management principles; (2) a common entry point (a team) at schools for children needing assessment because of inattention and classroom behavior problems, whether the problems present first to a medical provider, the behavioral health system, or the school; (3) a protocol followed by the school system, recognizing the schools' resource limitations but meeting the needs of community health care providers for classroom observations, psychoeducational testing, parent and teacher behavior rating scales, and functional assessment; (4) a packet of information about each child who is determined to need medical assessment; (5) a contact person or team at each physician's office to receive the packet from the school and direct it to the appropriate clinician; (6) an assessment process that investigates comorbidities and applies appropriate diagnostic criteria; (7) evidence-based interventions; (8) processes for follow-up monitoring of children after establishment of a treatment plan; (9) roles for central participants (school personnel, physicians, school nurses, and mental health professionals) in assessment, management, and follow-up monitoring of children with attention problems; (10) forms for collecting and exchanging information at every step; (11) processes and key contacts for flow of communication at every step; and (12) a plan for educating school and health care professionals about the new processes. A replication of the community process, initiated in Forsyth County, North Carolina, in 2001, offers insights into the role of the AAP ADHD guidelines in facilitating development of a community consensus protocol. This replication also draws attention to identification and referral barriers at the school level. The following recommendations, drawn from the 2 community processes, describe a role for physicians in the collaborative community care of children with symptoms of ADHD. (1) Achieve consensus with the school system regarding the role of school personnel in collecting data for children with learning and behavior problems; components to consider include (a) vision and hearing screening, (b) school/academic histories, (c) classroom observation by a counselor, (d) parent and teacher behavior rating scales (eg, Vanderbilt, Conner, or Achenbach scales), (e) consideration of speech/language evaluation, (f) screening intelligence testing, (g) screening achievement testing, (h) full intelligence and achievement testing if discrepancies are apparent in abbreviated tests, and (i) trials of classroom interventions. (2) Use pediatric office visits to identify children with academic or behavior problems and symptoms of inattention (history or questionnaire). (3) Refer identified children to the contact person at each child's school, requesting information in accordance with community consensus. (4) Designate a contact person to receive school materials for the practice. (5) Review the packet from the school and incorporate school data into the clinical assessment. (6) Reinforce with the parents and the school the need for multimodal intervention, including academic and study strategies for the classroom and home, in-depth psychologic testing of children whose discrepancies between cognitive level and achievement suggest learning or language disabilities and the need for an individualized educational plan (special education), consideration of the "other health impaired" designation as an alternate route to an individualized educational plan or 504 plan (classroom accommodations), behavior-modification techniques for targeted behavior problems, and medication trials, as indicated. (7) Refer the patient to a mental health professional if the assessment suggests coexisting conditions. (8) Use communication forms to share diagnostic and medication information, recommended interventions, and follow-up plans with the school and the family. (9) Receive requested teacher and parent follow-up reports and make adjustments in therapy as indicated by the child's functioning in targeted areas. (10) Maintain communication with the school and the parents, especially at times of transition (eg, beginning and end of the school year, change of schools, times of family stress, times of change in management, adolescence, and entry into college or the workforce).

Adolescent↗
PubMed1997

Future directions in lung cancer research and therapeutics.

Although immune and genetic approaches do not yet have substantial clinical exposure in NSCLC, it is hoped that the future will bring less toxic, more specific, and more effective methods to prevent the development of end-stage NSCLC. The principles of multitargeted and multimodality therapy to overcome tumor heterogeneity and resistance, and drug delivery issues have been developed over years of effort using chemotherapy. The lessons learned should not be forgotten, because they will remain applicable to newer biologic and genetic modalities.

Antineoplastic Agents↗
PubMed2026

Beyond antibiotics: artificial intelligence-enabled anti-infective ecosystems for next-generation precision therapeutics against antimicrobial resistance.

The rapid global expansion of antimicrobial resistance (AMR) threatens to undermine decades of progress in infectious disease management and highlights the limitations of conventional antibiotic-centered therapeutic strategies. Although emerging technologies-including antimicrobial peptides, bacteriophage therapy, CRISPR-based antimicrobials, microbiome therapeutics, anti-virulence approaches, nanotechnology-enabled drug delivery, and artificial intelligence (AI)-have individually demonstrated considerable promise, they are predominantly being developed as independent interventions rather than as coordinated components of an integrated therapeutic strategy. This Perspective proposes the Intelligent Anti-Infective Ecosystem (IAIE) as a conceptual systems-level framework that computationally integrates multimodal diagnostics, pathogen genomics, microbiome profiling, AI-assisted decision support, programmable precision therapeutics, ecological monitoring, and longitudinal clinical feedback within a continuously learning dynamically optimized workflow. Unlike existing paradigms that primarily optimize individual technologies or therapeutic decisions, IAIE emphasizes closed-loop coordination among complementary antimicrobial approaches to support precision-guided infection management while preserving microbiome integrity and mitigating resistance selection pressure. We further outline the core components, operational principles, translational challenges, and technology readiness of the major therapeutic platforms that could contribute to such an ecosystem, while distinguishing clinically established interventions from emerging experimental strategies. Importantly, IAIE should be interpreted as a prospective conceptual architecture rather than an existing clinical platform. Its proposed clinical value remains to be established through sequential computational, preclinical, and prospective clinical investigations using standardized microbiological, ecological, and patient-centered outcome measures. By framing antimicrobial innovation within an responsive systems perspective, IAIE provides a roadmap for future multidisciplinary research aimed at integrating artificial intelligence and systems microbiology to enable sustainable management of antimicrobial resistance.

Humans↗
PubMed1992

Evaluation of coma and vegetative states.

The Coma/Near-Coma (CNC) scale was designed to measure small clinical changes in patients with severe traumatic and nontraumatic brain injuries who were functioning at very low levels characteristic of near-vegetative and vegetative states. In 20 patients followed for 16 weeks the scale identified 25% who ultimately showed modest improvement. Interrater reliability was high (r = .95); validity was supported by significant correlations between CNC- and brain-multimodality evoked potential abnormality scores as well as between scores on the CNC and the Disability Rating Scale. The CNC scale was easily learned and it could be completed quickly and cost effectively. Staff found it useful in recognizing among relatively homogeneous low-level patients those most likely to respond to further rehabilitation care. The CNC appears to be useful for justifying ongoing intensive rehabilitation and for preventing premature transfer to lower levels of care.

Adolescent↗
PubMed2026

Biological Foundation Models for Complex Disease Research and Clinical Translation.

Complex diseases, including cancer, rare genetic disorders, neurodevelopmental and psychiatric conditions, and neurodegenerative diseases, arise from interactions among genetic variation, gene regulation, and cellular states that are difficult to capture using a single data type or biological scale. Biological foundation models address this challenge by treating nucleotides and genes as tokens and learning representations that can be transferred to downstream biomedical and clinical tasks. In this review, we examine two major model classes, genomic sequence foundation models and cell foundation models, and compare their tokenization strategies, model architectures, pretraining objectives, and adaptation methods. We summarize their emerging applications in regulatory variant interpretation, disease-associated cell-state analysis, drug-response prediction, and therapeutic target discovery across complex diseases. We distinguish applications supported by experimental or retrospective validation from those that remain primarily computational or conceptual. We further discuss key challenges to clinical translation, including multimodal data integration, model interpretability, benchmarking, patient-specific prediction, and privacy protection. We highlight future opportunities to integrate biological foundation models with emerging frameworks of medical digital twins, agentic AI, and federated learning. By linking model design to translational goals, this review provides a practical framework for evaluating biological foundation models and their readiness for complex disease research and clinical use.

biological foundation model↗
PubMed2005

Physiological and morphological development of the rat cerebellar Purkinje cell.

Cerebellar Purkinje cells integrate multimodal afferent inputs and, as the only projection neurones of the cerebellar cortex, are key to the coordination of a variety of motor- and learning-related behaviours. In the neonatal rat the cerebellum is undeveloped, but over the first few postnatal weeks both the structure of the cerebellum and cerebellar-dependent behaviours mature rapidly. Maturation of Purkinje cell physiology is expected to contribute significantly to the development of cerebellar output. However, the ontogeny of the electrophysiological properties of the Purkinje cell and its relationship to maturation of cell morphology is incompletely understood. To address this problem we performed a detailed in vitro electrophysiological analysis of the spontaneous and intracellularly evoked intrinsic properties of Purkinje cells obtained from postnatal rats (P0 to P90) using whole-cell patch clamp recordings. Cells were filled with neurobiotin to enable subsequent morphological comparisons. Three stages of physiological and structural development were identified. During the early postnatal period (P0 to approximately P9) Purkinje cells were characterized by an immature pattern of Na(+)-spike discharge, and possessed only short multipolar dendrites. This was followed by a period of rapid maturation (from approximately P12 to approximately P18), consisting of changes in Na(+)-spike discharge, emergence of repetitive bursts of Na(+) spikes terminated by Ca(2+) spikes (Ca(2+)-Na(+) bursts), generation of the trimodal pattern, and a significant expansion of the dendritic tree. During the final stage (> P18 to P90) there were minor refinements of cell output and a plateau in dendritic area. Our results reveal a rapid transition of the Purkinje cell from morphological and physiological immaturity to adult characteristics over a short developmental window, with a close correspondence between changes in cell output and dendritic growth. The development of Purkinje cell intrinsic electrophysiological properties further matches the time course of other measures of cerebellar structural and functional maturation.

Action Potentials↗
PubMed2026

AI-Supported, Integrative Prediction of Postoperative Delirium: Protocol for the CONFUSED Study.

BACKGROUND: Postoperative delirium (POD) is a frequent and serious complication in older surgical patients, characterized by acute cognitive dysfunction and fluctuating levels of consciousness. POD is associated with prolonged hospitalization, long-term cognitive decline, reduced quality of life, and increased mortality. Despite its clinical relevance, the underlying pathophysiological mechanisms remain poorly understood, and reliable biomarkers for early prediction and prevention are lacking. OBJECTIVE: The CONFUSED study aims to identify molecular and clinical predictors of POD by integrating clinical data with proteomic, transcriptomic, and epigenetic analyses. The primary objective is to develop predictive models for POD using multimodal data. Secondary objectives include the identification of delirium-associated genes, proteins, and epigenetic signatures, as well as the exploration of patient subgroups at increased risk for POD. METHODS: CONFUSED is a prospective observational cohort study conducted at a German university hospital. Adult patients undergoing major surgery under general anesthesia will be enrolled until 100 cases of POD have been observed, which is expected to require a total sample size of approximately 200 to 300 patients. Blood samples are collected at 4 predefined time points: before premedication, immediately after surgery, and on postoperative days 2 and 5. Samples undergo comprehensive proteomic profiling, transcriptomic analysis using RNA microarrays, DNA methylation analysis, and genotyping of selected polymorphisms. Clinical data, including demographics, comorbidities, perioperative variables, medications, and delirium assessments using the Confusion Assessment Method (CAM) and CAM for the intensive care unit, are systematically recorded. Statistical analyses include univariate and multivariate methods, as well as machine learning approaches such as random forests and support vector machines, to identify relevant biomarkers and develop predictive models. The study protocol follows STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) and TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) guidelines and was approved by the responsible ethics committees. RESULTS: The study was registered in the German Clinical Trials Register (DRKS00033854) on March 18, 2024. Recruitment started in January 2024 and is ongoing at the time of manuscript submission. As of now, 135 patients have been enrolled. Sample collection and laboratory analyses are ongoing. Data analysis began in January 2026, with first results anticipated in July 2026. Final data lock is anticipated after the completion of recruitment. CONCLUSIONS: By integrating multimodal molecular data with clinical parameters and applying advanced machine learning techniques, the CONFUSED study aims to improve the prediction and understanding of POD. The results are expected to support the development of personalized preventive strategies and contribute to improved perioperative care for patients at risk of POD.

Humans↗
PubMed1995

Amygdala role in conditioned associative learning.

Amygdala role in emotion was reviewed in reference to recent amygdala lesion studies and neuronal responses in the rat amygdala to conditioned stimuli. Extensive lesion studies suggest that the amygdala is crucial in various kinds of motivated and emotional behavior, and related autonomic responses. These amygdala functions critically depend on learning and memory. Amygdala lesions, both before and after training of conditioned associative learning, impaired emotional expression without simple sensory-motor deficits. Pharmacological experiments indicated neurotransmission in the amygdala is mediated through NMDA and AMPA receptors. These results strongly suggest the amygdala involvement in acquiring and storing associative memory (i.e. stimulus-affect association), by which animals recognize and evaluate the biological significance of a stimulus. This information is then transferred to the brainstem executing system. In the neurophysiological experiments, there were topographic distributions of sensory-responsive neurons within the amygdala, which were well correlated to anatomical data. The responses of rat amygdala neurons changed plastically during learning. Furthermore, more sensory-responsive neurons were encountered in the amygdala of rats trained to associate the sensory stimuli with a reinforcement than in the amygdala of rats that were not trained. In trained rats, multimodal neurons that responded to conditioned and unconditioned stimuli were frequently found in the basolateral and central nuclei of the amygdala. The results suggest that basolateral and central nuclei are foci where various sensory modalities converge, and which might perform critical functions in acquiring and storing long-term associative memory to link between sensory information and affective significance.

Amygdala↗