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Efforts to achieve an energy transition often neglect to account for the levelling of benefits realizable with higher levels of energy use, despite knowledge of a saturation effect and recognition of increasing harms of use. This research examines energy sufficiency as a maximum quantity of energy associated with improvements in human well-being to inform a recalibration of energy targets among high-energy societies. A systematic review of recent research was performed to identify the point at which increasing levels of energy use no longer correlate with meaningful increases in well-being. For selected studies (n = 18), energy sufficiency values range from 60–221 gigajoules per capita per year with a mean of 132 gigajoules per capita per year for associated measures of well-being. The review finds agreement in a pattern of saturation and provides a range of values for energy sufficiency maximums, suggesting that a relatively modest amount and a diverse quality of energy is needed to support high levels of human well-being. Beyond the conventional emphasis on energy efficiency and renewable energy, energy sufficiency therefore offers a necessary and complementary approach for supporting just and ecological energy transitions.

Our perception of free will is composed of a desire to act (volition) and a sense of responsibility for our actions (agency). Brain damage can disrupt these processes, but which regions are most important for free will perception remains unclear. Here, we study focal brain lesions that disrupt volition, causing akinetic mutism (n = 28), or disrupt agency, causing alien limb syndrome (n = 50), to better localize these processes in the human brain. Lesion locations causing either syndrome were highly heterogeneous, occurring in a variety of different brain locations. We next used a recently validated technique termed lesion network mapping to determine whether these heterogeneous lesion locations localized to specific brain networks. Lesion locations causing akinetic mutism all fell within one network, defined by connectivity to the anterior cingulate cortex. Lesion locations causing alien limb fell within a separate network, defined by connectivity to the precuneus. Both findings were specific for these syndromes compared with brain lesions causing similar physical impairments but without disordered free will. Finally, our lesion-based localization matched network localization for brain stimulation locations that disrupt free will and neuroimaging abnormalities in patients with psychiatric disorders of free will without overt brain lesions. Collectively, our results demonstrate that lesions in different locations causing disordered volition and agency localize to unique brain networks, lending insight into the neuroanatomical substrate of free will perception.

Functional neurological disorder and somatic symptom disorder are complex neuropsychiatric conditions that have been linked to circuit-based dysfunction of brain networks. Neuromodulation is a novel therapeutic strategy capable of modulating relevant brain networks, making it a promising potential candidate for the treatment of these patient populations. We conducted a systematic review of Medline, Embase and PsycINFO up to 4 March 2021. Trials investigating neuromodulation devices for the treatment of functional neurological disorder or somatic symptom disorder were selected. Extracted variables included study design, demographic and clinical characteristics, psychiatric comorbidity, neurostimulation protocols, clinical outcome measures and results. 404 studies were identified with 12 meeting inclusion criteria. 221 patients were treated in the included studies with mean study sample size of 18 (4–70). Five studies were randomised clinical trials. Functional motor symptoms (six weakness, four movement disorders) were the most studied subpopulations. Transcranial magnetic stimulation (TMS) was the most frequently used device (10 studies), followed by electroconvulsive therapy (one study) and direct-current stimulation (one study). Treatment protocols varied in intended therapeutic mechanism(s): eight studies aimed to modulate underlying network dysfunction, five aimed to demonstrate movement (one also leveraged the former) and three boosted their primary mechanism with enhanced suggestion/expectation. All but one study reported positive results; however, methodological/outcome heterogeneity, mixed study quality and small sample sizes precluded quantitative meta-analysis. Neuromodulation, particularly TMS for the treatment of functional motor symptoms, shows preliminary promise in a growing line of research. Larger, sham-controlled studies are needed to further establish efficacy and better understand therapeutic mechanisms.

Zhu and Burke discuss the case study of a 50-year-old woman who developed involuntary movements of her legs about 4 days after her first dose of vaccine against SARS CoV-2. These involuntary jerks progressed to involve the rest of her body. The movements occurred intermittently during the day, lasting for seconds, but they affected her gait so that she required a cane to walk. In addition, she described fatigue, headache and intermittent paresthesia and pain in different parts of her body. She reported being stressed because of the pandemic and was initially hesitant to receive the SARS-CoV-2 vaccine, but had decided to get her first dose because she was employed in the education sector. She had no history of smoking, recreational drug use or substantial alcohol intake. She had no relevant medical history and no psychiatric history. She reported no family history of any neurologic disorders.

Background Adeno‐associated virus (AAV) 8 and 9 are in clinical trials for treating neuromuscular diseases such as Duchenne muscular dystrophy (DMD). Muscle consists of myofibres of different types and sizes. However, little is known about the fibre type and fibre size tropism of AAV in large mammals. Methods We evaluated fibre type‐ and size‐specific transduction properties of AAV8 and AAV9 in 17 dogs that received systemic gene transfer (dose 1.94 ± 0.52 × 1014 vg/kg; injected at 2.86 ± 0.30 months; harvested at 20.79 ± 3.30 months). For AAV8, two DMD dogs and three carrier dogs received an alkaline phosphatase (AP) reporter vector, and five DMD dogs received a four‐repeat microdystrophin (uDys) vector. For AAV9, one normal and one DMD dog received the AP vector, and five DMD dogs received a five‐repeat uDys vector. Association between AAV transduction and the fibre type/size was studied in three muscles that showed mosaic transgene expression, including the biceps femoris, teres major and latissimus dorsi. Results Transgene expression was detected in 30%–45% of myofibres. In the AP reporter vector–injected dogs, neither AAV8 nor AAV9 showed a statistically significant fibre type preference. Interestingly, AP expression was enriched in smaller fibres. In uDys‐treated DMD dogs, slow and fast myofibres were equally transduced. Notably, uDys‐expressing myofibres were significantly larger than uDys‐negative myofibres irrespective of the AAV serotype (p < 0.0001). In AAV8 uDys vector–injected dogs, the mini‐Feret diameter was 15%, 16% and 23% larger in uDys‐positive slow, fast and hybrid fibres, respectively; the cross‐sectional area was 30%, 34% and 46% larger in uDys‐positive slow, fast and hybrid fibres, respectively. In AAV9 uDys vector–injected dogs, the mini‐Feret diameter was 12%, 13% and 25% larger in uDys‐positive slow, fast and hybrid fibres, respectively; the cross‐sectional area was 25%, 28% and 59% larger in uDys‐positive slow, fast and hybrid fibres, respectively. Conclusions Our studies suggest that AAV8 and AAV9 transduce fast and slow myofibres at equivalent efficiency. Importantly, uDys therapy effectively prevented dystrophic myofibre atrophy. Our study provides important insight into systemic muscle AAV delivery in large mammals and supports further development of uDys gene therapy for DMD.

Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

Background We sought to explore outcomes at 1 year in functional neurological disorder (FND) following a neuroscience‐informed education and counseling assessment. Methods Patients with FND were assessed at a quaternary neuropsychiatry clinic in Toronto, Canada, and provided education and counseling to build insight into their FND diagnosis. Patient‐determined diagnostic agreement at follow‐up was categorized as a binary variable: (i) symptoms attributable primarily to FND or (ii) attributable to another cause (neurological disease or unknown). One‐year symptom status was patient‐reported on a 7‐point scale (−3 to +3), with scores ≥2 defined as meaningful improvement. Return to work/school was assessed as an indicator of global improvement of functional status. Univariate tests screened variables for inclusion in multivariate logistic regression models, which evaluated associations between diagnostic agreement and other outcomes. Results A total of 282 patients with FND were assessed (mean age 38.9 ± 12.0 years; 80.3% female), and of these, 127 had 1‐year follow‐up data. FND subtypes included functional movement disorder (functional weakness [26.8%], hyperkinetic movement [15.7%]), seizure (15.0%), sensory (16.5%), functional cognitive disorder (7.9%), persistent postural perceptual dizziness (14.2%), and speech/swallowing (3.9%). Diagnostic agreement was significantly associated with symptom improvement (odds ratio [OR] = 3.81, 95% CI: 1.33–11.71, p = 0.015) and global improvement (OR = 5.74, 95% CI: 1.11–37.54, p = 0.047). Psychiatric comorbidity (p = 0.026), childhood trauma (p = 0.015), and psychological triggers (p = 0.013) were associated with diagnostic agreement, while ongoing medical/neurological workup was linked to disagreement (p < 0.001). Conclusion Diagnostic agreement was associated with symptom improvement and return‐to‐work/school status in FND patients who received a neuroscience‐informed education and counseling assessment. However, given the observational design and lack of baseline measurement of diagnostic agreement, the directionality of this relationship cannot be determined. This retrospective cohort study examined one‐year outcomes in 282 patients with Functional Neurological Disorder (FND) following a neuroscience‐informed neuropsychiatry assessment with education and counseling. At one‐year follow‐up (N = 127), 40% showed moderate‐to‐strong symptom improvement and 44% showed global functional improvement. Two‐thirds of patients (66%) agreed with their FND diagnosis, and diagnostic agreement was independently associated with improved symptom status and return to work or school, suggesting that neuroscience‐informed education may support diagnostic acceptance and better outcomes in FND.

Background Cytosolic calcium overload contributes to muscle degradation in Duchenne muscular dystrophy (DMD). The sarcoplasmic reticulum (SR) is the primary calcium storage organelle in muscle. The sarco-endoplasmic reticulum ATPase (SERCA) pumps cytosolic calcium to the SR during muscle relaxation. Calcium is kept in the SR by calcium-binding proteins. Methods Given the importance of the canine DMD model in translational studies, we examined transcriptional changes of SERCA (SERCA1 and SERCA2a), SERCA regulators (phospholamban, sarcolipin, myoregulin, and dwarf open reading frame), and SR calcium-binding proteins (calreticulin, calsequestrin 1, calsequestrin 2, and sarcalumenin) in skeletal muscle (diaphragm and extensor carpi ulnaris) and heart (left ventricle) in normal and affected male dogs by droplet digital PCR before the onset (≤ 2-m-old), at the active stage (8 to 16-m-old), and at the terminal stage (30 to 50-m-old) of the disease. Since many of these proteins are expressed in a fiber type-specific manner, we also evaluated fiber type composition in skeletal muscle. Results In affected dog skeletal muscle, SERCA and its regulators were down-regulated at the active stage, but calcium-binding proteins (except for calsequestrin 1) were upregulated at the terminal stage. Surprisingly, nominal differences were detected in the heart. We also examined whether there exists sex-biased expression in 8 to 16-m-old dogs. Multiple transcripts were significantly downregulated in the heart and extensor carpi ulnaris muscle of female dogs. In fiber type analysis, we found significantly more type I fiber in the diaphragm of 8 to 16-m-old affected dogs, and significantly more type II fibers in the extensor carpi ulnaris of 30 to 50-m-old affected dogs. However, no difference was detected between male and female dogs. Conclusions Our study adds new knowledge to the understanding of muscle calcium regulation in normal and dystrophic canines.

Potent antibody-mediated neutralization is critical for an organism to combat the vast array of pathogens it will face during its lifetime. Due to the potential genetic diversity of some viruses, such as HIV-1 and influenza, standard neutralizing antibodies are often ineffective or easily evaded as their targets are masked or rapidly mutated. This has thwarted efforts to both prevent and treat HIV-1 infections and means that entirely new formulations are required to vaccinate against influenza each year. However, some rare antibodies isolated from infected individuals confer broad and potent neutralization. A subset of these broadly neutralizing antibodies possesses a long complementarity-determining 3 region of the immunoglobulin heavy chain (CDR H3). This feature generates unique antigen binding site configurations that can engage conserved but otherwise inaccessible epitope targets thus neutralizing many viral variants. Remarkably, ultralong CDR H3s are a common feature of the cow antibody repertoire and are encoded by a single variable, diversity, joining (VDJ) recombination that is extensively diversified prior to antigen exposure. Recently, it was shown that cows rapidly generate a broadly neutralizing response upon exposure to HIV-1 and this is primarily mediated by these novel ultralong antibody types. This review summarises the current knowledge of these unusual CDR H3 structures and discusses their known and potential future uses.