The plasticity of pyramidal neurons in the behaving brain.

Neurons are plastic. That is, they change their activity according to different behavioural conditions. This endows pyramidal neurons with an incredible computational power for the integration and processing of synaptic inputs. Plasticity can be investigated at different levels of investigation within a single neuron, from spines to dendrites, to synaptic input. Although most of our knowledge stems from the in vitro brain slice preparation, plasticity plays a vital role during behaviour by providing a flexible substrate for the execution of appropriate actions in our ever-changing environment. Owing to advances in recording techniques, the plasticity of neurons and the neural networks in which they are embedded is now beginning to be realized in the in vivo intact brain. This review focuses on the structural and functional synaptic plasticity of pyramidal neurons, with a specific focus on the latest developments from in vivo studies. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

LINE-1 retrotransposons contribute to mouse PV interneuron development.

Retrotransposons are mobile DNA sequences duplicated via transcription and reverse transcription of an RNA intermediate. Cis-regulatory elements encoded by retrotransposons can also promote the transcription of adjacent genes. Somatic LINE-1 (L1) retrotransposon insertions have been detected in mammalian neurons. It is, however, unclear whether L1 sequences are mobile in only some neuronal lineages or therein promote neurodevelopmental gene expression. Here we report programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV) interneuron development. Mouse PV interneurons permit L1 mobilization in vitro and in vivo, harbor unmethylated L1 promoters and express full-length L1 mRNAs and proteins. Using nanopore long-read sequencing, we identify unmethylated L1s proximal to PV interneuron genes, including a novel L1 promoter-driven Caps2 transcript isoform that enhances neuron morphological complexity in vitro. These data highlight the contribution made by L1 cis-regulatory elements to PV interneuron development and transcriptome diversity, uncovered due to L1 mobility in this milieu.

A thalamocortical pathway controlling impulsive behavior.

Planning and anticipating motor actions enables movements to be quickly and accurately executed. However, if anticipation is not properly controlled, it can lead to premature impulsive actions. Impulsive behavior is defined as actions that are poorly conceived and are often risky and inappropriate. Historically, impulsive behavior was thought to be primarily controlled by the frontal cortex and basal ganglia. More recently, two additional brain regions, the ventromedial (VM) thalamus and the anterior lateral motor cortex (ALM), have been shown to have an important role in mice. Here, we explore this newly discovered role of the thalamocortical pathway and suggest cellular mechanisms that may be involved in driving the cortical activity that contributes to impulsive behavior.

Cocaine regulates sensory filtering in cortical pyramidal neurons.

Exposure to cocaine leads to robust changes in the structure and function of neurons within the mesocorticolimbic pathway. However, little is known about how cocaine influences the processing of information within the sensory cortex. We address this by using patch-clamp and juxtacellular voltage recordings and two-photon Ca2+ imaging in vivo to investigate the influence of acute cocaine exposure on layer 2/3 (L2/3) pyramidal neurons within the primary somatosensory cortex (S1). Here, cocaine dampens membrane potential state transitions and decreases spontaneous somatic action potentials and Ca2+ transients. In contrast to the uniform decrease in background spontaneous activity, cocaine has a heterogeneous influence on sensory encoding, increasing tactile-evoked responses in dendrites that do not typically encode sensory information and decreasing responses in those dendrites that are more reliable sensory encoders. Combined, these findings suggest that cocaine acts as a filter that suppresses background noise to selectively modulate incoming sensory information.

High synaptic threshold for dendritic NMDA spike generation in human layer 2/3 pyramidal neurons.

Neurons receive synaptic input primarily onto their dendrites. While we know much about the electrical properties of dendrites in rodents, we have only just started to describe their properties in the human brain. Here, we investigate the capacity of human dendrites to generate NMDA-receptor-dependent spikes (NMDA spikes). Using dendritic glutamate iontophoresis, as well as local dendritic synaptic stimulation, we find that human layer 2/3 pyramidal neurons can generate dendritic NMDA spikes. The capacity to evoke NMDA spikes in human neurons, however, was significantly reduced compared with that in rodents. Simulations in morphologically realistic and simplified models indicated that human neurons have a higher synaptic threshold for NMDA spike generation primarily due to the wider diameter of their dendrites. In summary, we find reduced NMDA spike generation in human compared with rodent layer 2/3 pyramidal neurons and provide evidence that this is due to the wider diameter of human dendrites.

Dendritic Mechanisms for In Vivo Neural Computations and Behavior.

Dendrites receive the vast majority of a single neuron's inputs, and coordinate the transformation of these signals into neuronal output. Ex vivo and theoretical evidence has shown that dendrites possess powerful processing capabilities, yet little is known about how these mechanisms are engaged in the intact brain or how they influence circuit dynamics. New experimental and computational technologies have led to a surge in interest to unravel and harness their computational potential. This review highlights recent and emerging work that combines established and cutting-edge technologies to identify the role of dendrites in brain function. We discuss active dendritic mediation of sensory perception and learning in neocortical and hippocampal pyramidal neurons. Complementing these physiological findings, we present theoretical work that provides new insights into the underlying computations of single neurons and networks by using biologically plausible implementations of dendritic processes. Finally, we present a novel brain-computer interface task, which assays somatodendritic coupling to study the mechanisms of biological credit assignment. Together, these findings present exciting progress in understanding how dendrites are critical for in vivo learning and behavior, and highlight how subcellular processes can contribute to our understanding of both biological and artificial neural computation.

Neural basis of anticipation and premature impulsive action in the frontal cortex.

Planning motor actions can improve behavioral performance; however, it can also lead to premature actions. Although the anterior lateral motor cortex (ALM) is known to be important for correct motor planning, it is currently unknown how it contributes to premature impulsive motor output. This was addressed using whole-cell voltage recordings from layer 2/3 pyramidal neurons within the ALM while mice performed a cued sensory association task. Here, a robust voltage response was evoked during the auditory cue, which was greater during incorrect premature behavior than during correct performance in the task. Optogenetically suppressing ALM during the cued sensory association task led to enhanced behavior, with fewer, and more delayed, premature responses and faster correct responses. Taken together, our findings extend the current known roles of the ALM, illustrating that ALM plays an important role in impulsive behavior by encoding and influencing premature motor output.

Effectiveness of universal school-based mindfulness training compared with normal school provision on teacher mental health and school climate: results of the MYRIAD cluster randomised controlled trial.

BACKGROUND: Education is broader than academic teaching. It includes teaching students social-emotional skills both directly and indirectly through a positive school climate. OBJECTIVE: To evaluate if a universal school-based mindfulness training (SBMT) enhances teacher mental health and school climate. METHODS: The My Resilience in Adolescence parallel group, cluster randomised controlled trial (registration: ISRCTN86619085; funding: Wellcome Trust (WT104908/Z/14/Z, WT107496/Z/15/Z)) recruited 85 schools (679 teachers) delivering social and emotional teaching across the UK. Schools (clusters) were randomised 1:1 to either continue this provision (teaching as usual (TAU)) or include universal SBMT. Data on teacher mental health and school climate were collected at prerandomisation, postpersonal mindfulness and SBMT teacher training, after delivering SBMT to students, and at 1-year follow-up. FINDING: Schools were recruited in academic years 2016/2017 and 2017/2018. Primary analysis (SBMT: 43 schools/362 teachers; TAU: 41 schools/310 teachers) showed that after delivering SBMT to students, SBMT versus TAU enhanced teachers' mental health (burnout) and school climate. Adjusted standardised mean differences (SBMT minus TAU) were: exhaustion (-0.22; 95% CI -0.38 to -0.05); personal accomplishment (-0.21; -0.41, -0.02); school leadership (0.24; 0.04, 0.44); and respectful climate (0.26; 0.06, 0.47). Effects on burnout were not significant at 1-year follow-up. Effects on school climate were maintained only for respectful climate. No SBMT-related serious adverse events were reported. CONCLUSIONS: SBMT supports short-term changes in teacher burnout and school climate. Further work is required to explore how best to sustain improvements. CLINICAL IMPLICATIONS: SBMT has limited effects on teachers' mental and school climate. Innovative approaches to support and preserve teachers' mental health and school climate are needed.

Effectiveness and cost-effectiveness of universal school-based mindfulness training compared with normal school provision in reducing risk of mental health problems and promoting well-being in adolescence: the MYRIAD cluster randomised controlled trial.

BACKGROUND: Systematic reviews suggest school-based mindfulness training (SBMT) shows promise in promoting student mental health. OBJECTIVE: The My Resilience in Adolescence (MYRIAD) Trial evaluated the effectiveness and cost-effectiveness of SBMT compared with teaching-as-usual (TAU). METHODS: MYRIAD was a parallel group, cluster-randomised controlled trial. Eighty-five eligible schools consented and were randomised 1:1 to TAU (43 schools, 4232 students) or SBMT (42 schools, 4144 students), stratified by school size, quality, type, deprivation and region. Schools and students (mean (SD); age range=12.2 (0.6); 11-14 years) were broadly UK population-representative. Forty-three schools (n=3678 pupils; 86.9%) delivering SBMT, and 41 schools (n=3572; 86.2%) delivering TAU, provided primary end-point data. SBMT comprised 10 lessons of psychoeducation and mindfulness practices. TAU comprised standard social-emotional teaching. Participant-level risk for depression, social-emotional-behavioural functioning and well-being at 1 year follow-up were the co-primary outcomes. Secondary and economic outcomes were included. FINDINGS: Analysis of 84 schools (n=8376 participants) found no evidence that SBMT was superior to TAU at 1 year. Standardised mean differences (intervention minus control) were: 0.005 (95% CI -0.05 to 0.06) for risk for depression; 0.02 (-0.02 to 0.07) for social-emotional-behavioural functioning; and 0.02 (-0.03 to 0.07) for well-being. SBMT had a high probability of cost-effectiveness (83%) at a willingness-to-pay threshold of £20 000 per quality-adjusted life year. No intervention-related adverse events were observed. CONCLUSIONS: Findings do not support the superiority of SBMT over TAU in promoting mental health in adolescence. CLINICAL IMPLICATIONS: There is need to ask what works, for whom and how, as well as considering key contextual and implementation factors. TRIAL REGISTRATION: Current controlled trials ISRCTN86619085. This research was funded by the Wellcome Trust (WT104908/Z/14/Z and WT107496/Z/15/Z).

Dendritic Compartmentalization of Learning-Related Plasticity.

The dendrites of cortical pyramidal neurons receive synaptic inputs from different pathways that are organized according to their laminar target. This architectural scheme provides cortical neurons with a spatial mechanism to separate information, which may support neural flexibility required during learning. Here, we investigated layer-specific plasticity of sensory encoding following learning by recording from two different dendritic compartments, tuft and basal dendrites, of layer 2/3 (L2/3) pyramidal neurons in the auditory cortex of mice. Following auditory fear conditioning, auditory-evoked Ca2+ responses were enhanced in tuft, but not basal, dendrites leading to increased somatic action potential output. This is in direct contrast to the long held (and debated) hypothesis that, despite extensive dendritic arbors, neurons function as a simple one-compartment model. Two computational models of varying complexity based on the experimental data illustrated that this learning-related increase of auditory responses in tuft dendrites can account for the changes in somatic output. Taken together, we illustrate that neurons do not function as a single compartment, and dendritic compartmentalization of learning-related plasticity may act to increase the computational power of pyramidal neurons.

Intracellular calcium release: A conductor of compartmentalized dendritic plasticity.

Dendrites endow neurons with multiple compartments within their elaborate morphologies. In a recent study published in the journal Science, O'Hare et al. (2022) used elegant techniques to show that augmenting the intracellular calcium released by the endoplasmic reticulum caused behaviorally relevant plasticity to occur in spatially distinct dendritic compartments.

The role of higher-order thalamus during learning and correct performance in goal-directed behavior.

The thalamus is a gateway to the cortex. Cortical encoding of complex behavior can therefore only be understood by considering the thalamic processing of sensory and internally generated information. Here, we use two-photon Ca2+ imaging and optogenetics to investigate the role of axonal projections from the posteromedial nucleus of the thalamus (POm) to the forepaw area of the mouse primary somatosensory cortex (forepaw S1). By recording the activity of POm axonal projections within forepaw S1 during expert and chance performance in two tactile goal-directed tasks, we demonstrate that POm axons increase activity in the response and, to a lesser extent, reward epochs specifically during correct HIT performance. When performing at chance level during learning of a new behavior, POm axonal activity was decreased to naive rates and did not correlate with task performance. However, once evoked, the Ca2+ transients were larger than during expert performance, suggesting POm input to S1 differentially encodes chance and expert performance. Furthermore, the POm influences goal-directed behavior, as photoinactivation of archaerhodopsin-expressing neurons in the POm decreased the learning rate and overall success in the behavioral task. Taken together, these findings expand the known roles of the higher-thalamic nuclei, illustrating the POm encodes and influences correct action during learning and performance in a sensory-based goal-directed behavior.

The Unfulfilled Promise of Inhaled Therapy in Ventilator-Associated Infections: Where Do We Go from Here?

Respiratory infection is common in intubated/tracheotomized patients and systemic antibiotic therapy is often unrewarding. In 1967, the difficulty in treating Gram-negative respiratory infections led to the use of inhaled gentamicin, targeting therapy directly to the lungs. Fifty-three years later, the effects of topical therapy in the intubated patient remain undefined. Clinical failures with intravenous antibiotics persist and instrumented patients are now infected by many more multidrug-resistant Gram-negative species as well as methicillin-resistant Staphylococcus aureus. Multiple systematic reviews and meta-analyses suggest that there may be a role for inhaled delivery but "more research is needed." Yet there is still no Food and Drug Administration (FDA) approved inhaled antibiotic for the treatment of ventilator-associated infection, the hallmark of which is the foreign body in the upper airway. Current pulmonary and infectious disease guidelines suggest using aerosols only in the setting of Gram-negative infections that are resistant to all systemic antibiotics or not to use them at all. Recently two seemingly well-designed large randomized placebo-controlled Phase 2 and Phase 3 clinical trials of adjunctive inhaled therapy for the treatment of ventilator-associated pneumonia failed to show more rapid resolution of pneumonia symptoms or effect on mortality. Despite evolving technology of delivery devices and more detailed understanding of the factors affecting delivery, treatment effects were no better than placebo. What is wrong with our approach to ventilator- associated infection? Is there a message from the large meta-analyses and these two large recent multisite trials? This review will suggest why current therapies are unpredictable and have not fulfilled the promise of better outcomes. Data suggest that future studies of inhaled therapy, in the milieu of worsening bacterial resistance, require new approaches with completely different indications and endpoints to determine whether inhaled therapy indeed has an important role in the treatment of ventilated patients.

Local and Global Dynamics of Dendritic Activity in the Pyramidal Neuron.

There has been increasing interest in the measurement and comparison of activity across compartments of the pyramidal neuron. Dendritic activity can occur both locally, on a single dendritic segment, or globally, involving multiple compartments of the single neuron. Little is known about how these dendritic dynamics shape and contribute to information processing and behavior. Although it has been difficult to characterize local and global activity in vivo due to the technical challenge of simultaneously recording from the entire dendritic arbor and soma, the rise of calcium imaging has driven the increased feasibility and interest of these experiments. However, the distinction between local and global activity made by calcium imaging requires careful consideration. In this review we describe local and global activity, discuss the difficulties and caveats of this distinction, and present the evidence of local and global activity in information processing and behavior.

Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST): protocol for identification of novel biomarkers via neurophysiology.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood. METHODS/DESIGN: This neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity. DISCUSSION: ECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT03191058 . Registered on June 19, 2017.

Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST): study protocol for a randomized non-inferiority trial of magnetic seizure therapy versus electroconvulsive therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is well-established and effective for treatment-resistant depression (TRD), but in Canada and the USA, less than 1% of patients with TRD receive ECT mainly due to its cognitive adverse effects (i.e. amnesia). Thus, new treatment alternatives for TRD are urgently needed. One such treatment is magnetic seizure therapy (MST). ECT involves applying a train of high-frequency electrical stimuli to induce a seizure, whereas MST involves applying a train of high-frequency magnetic stimuli to induce a seizure. METHODS: In this manuscript, we introduce our international, two-site, double-blinded, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. This trial will compare the efficacy of MST to right unilateral ultra-brief pulse width electroconvulsive therapy (RUL-UB-ECT) with a combined primary endpoint of remission of depression and superior cognitive adverse effects in 260 patients with TRD. Amelioration of suicidal ideation will be assessed as a secondary endpoint. Inpatients or outpatients, over 18 years of age with a MINI International Neuropsychiatric Interview (MINI) diagnosis of non-psychotic major depressive disorder (MDD) can be enrolled in the study provided that they meet illness severity and full eligibility criteria. Participants are randomized to receive MST or RUL-UB ECT, 2-3 days per week over seven weeks, or a maximum of 21 treatments. The study will involve before-, during-, and after-treatment assessments of depression severity, suicidal ideation, subjective side-effects, and cognitive performance consistent with an intent-to-treat study design approach. DISCUSSION: Positive results from this trial could have an immediate and tremendous impact for patients with TRD. If MST demonstrates comparable antidepressant treatment efficacy to ECT, but with greater cognitive safety, it could rapidly be adopted into clinical practice. Indeed, given that the administration of MST is nearly identical to ECT, the majority of ECT facilities in North America could readily adopt MST. Furthermore, the potential for cognitive safety could lead to improved treatment acceptability. Healthcare providers, patients and care partners, and policymakers would therefore demand this form of convulsive therapy. TRIAL STATUS: Enrollment for this study began on June 26, 2018, and is estimated to complete recruitment by July 2024. At the time of submission, we have enrolled and randomized 117 participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT03191058 , Registered on June 19, 2017. Primary sponsor: Daniel Blumberger (DMB), Principal Investigator Daniel.Blumberger@camh.ca , 416-535-8501 x 33662 Contact for public queries: DMB, Daniel.Blumberger@camh.ca Contact for scientific queries: ZJD, Zdaskalakis@health.ucsd.edu.

Setting Measurement-Based Care in Motion: Practical Lessons in the Implementation and Integration of Measurement-Based Care in Psychiatry Clinical Practice.

Measurement-based care (MBC) involves the systematic use of standardized measurements to inform treatment decisions. MBC can enhance clinical decision-making and quality of care by prompting personalized changes in treatment based on measured patient outcomes. MBC can also promote more precise communications between patients and clinicians around individual patient care. While commonly employed in psychiatric clinical research, the use of MBC in everyday practice can be complicated by clinic operations and variability across patients. We implemented MBC in the UT Southwestern Psychiatry Multispecialty Outpatient Clinic during the expansion of our general psychiatry clinic and subspecialty targeted programs. This article describes the top 10 lessons we learned as we confronted practical obstacles around implementing the ideals of MBC into a pre-existing, busy psychiatric clinical practice and how doing so impacts care, provider engagement, patient engagement, and research opportunity.

The Role of Schools in Early Adolescents' Mental Health: Findings From the MYRIAD Study.

OBJECTIVE: Recent studies suggest mental health in youths is deteriorating. The current policy in the United Kingdom emphasizes the role of schools for mental health promotion and prevention, but little data exist on what aspects of schools influence mental health in pupils. This study explored school-level influences on the mental health of young people in a large school-based sample from the United Kingdom. METHOD: Baseline data from a large cluster randomized controlled trial collected between 2016 and 2018 from mainstream secondary schools selected to be representative in relation to their quality rating, size, deprivation, mixed or single-sex pupil population, and country were analyzed. Participants were pupils in their first or second year of secondary school. The study assessed whether school-level factors were associated with pupil mental health. RESULTS: The study included 26,885 pupils (response rate = 90%; age range, 11‒14 years; 55% female) attending 85 schools in the United Kingdom. Schools accounted for 2.4% (95% CI: 2.0%‒2.8%; p < .0001) of the variation in psychopathology, 1.6% (95% CI: 1.2%‒2.1%; p < .0001) of depression, and 1.4% (95% CI: 1.0%‒1.7%; p < .0001) of well-being. Schools in urban locations, with a higher percentage of free school meals and of White British, were associated with poorer pupil mental health. A more positive school climate was associated with better mental health. CONCLUSION: School-level variables, primarily related to contextual factors, characteristics of pupil population, and school climate, explain a small but significant amount of variability in mental health of young people. This information might be used to identify schools that are in need of more resources to support mental health of young people. CLINICAL TRIAL REGISTRATION INFORMATION: MYRIAD: My Resilience in Adolescence, a Study Examining the Effectiveness and Cost-Effectiveness of a Mindfulness Training Programme in Schools Compared With Normal School Provision; https://www.isrctn.com/; 86619085.

Costs and outcomes of active and passive case detection for visceral leishmaniasis (Kala-Azar) to inform elimination strategies in Bihar, India.

BACKGROUND: Effective case identification strategies are fundamental to capturing the remaining visceral leishmaniasis (VL) cases in India. To inform government strategies to reach and sustain elimination benchmarks, this study presents costs of active- and passive- case detection (ACD and PCD) strategies used in India's most VL-endemic state, Bihar, with a focus on programme outcomes stratified by district-level incidence. METHODS: Expenditure analysis was complemented by onsite micro-costing to compare the cost of PCD in hospitals alongside index case-based ACD and a combination of blanket (house-to-house) and camp ACD from January to December 2018. From the provider's perspective, a cost analysis evaluated the overall programme cost of each activity, the cost per case detected, and the cost of scaling up ACD. RESULTS: During 2018, index case-based ACD, blanket and camp ACD, and PCD reported 1,497, 131, and 1,983 VL-positive cases at a unit cost of $522.81, $4,186.81, and $246.79, respectively. In high endemic districts, more VL cases were identified through PCD while in meso- and low-endemic districts more cases were identified through ACD. The cost of scaling up ACD to identify 3,000 additional cases ranged from $1.6-4 million, depending on the extent to which blanket and camp ACD was relied upon. CONCLUSION: Cost per VL test conducted (rather than VL-positive case identified) may be a better metric estimating unit costs to scale up ACD in Bihar. As more VL cases were identified in meso-and low-endemic districts through ACD than PCD, health authorities in India should consider bolstering ACD in these areas. Blanket and camp ACD identified fewer cases at a higher unit cost than index case-based ACD. However, the value of detecting additional VL cases early outweighs long-term costs for reaching and sustaining VL elimination benchmarks in India.

Meta-analysis of survival and functional outcomes after total mesorectal excision with or without lateral pelvic lymph node dissection in rectal cancer surgery.

BACKGROUND: To compare outcomes of total mesorectal excision with or without lateral pelvic lymph node dissection for the treatment of rectal cancer. METHODS: The electronic data sources were explored to capture all studies comparing total mesorectal excision with and without lateral pelvic lymph node dissection in patients undergoing operation for rectal cancer. Random effects modelling was utilized for the analyses. The uncertainties associated with varying follow-up periods among the included studies were resolved by analysis of time-to-event outcomes. RESULTS: Eighteen comparative studies enrolling 6,133 patients were eligible. No difference was found between the 2 groups in terms of overall survival (hazard ratio: 0.92, 95% confidence interval 0.77-1.10, P = .36, I2 = 67%), overall survival at maximum follow-up (odds ratio: 1.02, 95% confidence interval 0.83-1.25, P = .86, I2 = 22%), 5-year overall survival (odds ratio: 1.01, 95% confidence interval 0.78-1.30, P = .94, I2 = 50%), disease-free survival (hazard ratio: 1.25, 95% confidence interval 0.87-1.82, P = .23, I2 = 74%), disease-free survival at maximum follow-up (odds ratio 1.07, 95% confidence interval 0.88-1.31, P = .50, I2 = 0%), 5-year disease-free survival (odds ratio: 1.07, 95% confidence interval 0.86-1.32, P = .54, I2 = 0%), local recurrence (odds ratio: 1.01, 95% confidence interval 0.72-1.42, P = .97, I2 = 34%), distant recurrence (odds ratio: 0.96, 95% confidence interval 0.62-1.46, P = .84, I2 = 18%), and total recurrence (odds ratio: 0.97, 95% confidence interval 0.72-1.29, P = .82, I2 = 0%). Total mesorectal excision with lateral pelvic lymph node dissection resulted in longer operative time (mean difference: 116.02, 95% confidence interval 89.20-142.83, P < .00001, I2 = 68%) and higher risks of postoperative complications (odds ratio: 1.59, 95% confidence interval 1.14-2.24, P = .007, I2 = 0%), urinary dysfunction (odds ratio: 6.66, 95% confidence interval 3.31-13.39, P < .00001, I2 = 23%), and sexual dysfunction (odds ratio: 9.67, 95% confidence interval 2.38-39.26, P = .002; I2 = 51%). The results remained consistent through separate analyses for randomized trials, observational studies, and patients with or without neoadjuvant chemoradiotherapy. CONCLUSION: The available evidence suggests that lateral pelvic lymph node dissection results in greater postoperative morbidity, urinary dysfunction, and sexual dysfunction without improving recurrence and survival. Further evidence is needed from randomized controlled trials to enable experts in the nerve-sparing surgical experiences and neoadjuvant therapy experience to advise on the best treatment strategies for the management of rectal cancer patients including those with possible positive nodes on pretreatment imaging.