Behavioral activities that require control over automatic routines typically feel effortful and result in cognitive fatigue. Beyond subjective report, cognitive fatigue has been conceived as an ...inflated cost of cognitive control, objectified by more impulsive decisions. However, the origins of such control cost inflation with cognitive work are heavily debated. Here, we suggest a neuro-metabolic account: the cost would relate to the necessity of recycling potentially toxic substances accumulated during cognitive control exertion. We validated this account using magnetic resonance spectroscopy (MRS) to monitor brain metabolites throughout an approximate workday, during which two groups of participants performed either high-demand or low-demand cognitive control tasks, interleaved with economic decisions. Choice-related fatigue markers were only present in the high-demand group, with a reduction of pupil dilation during decision-making and a preference shift toward short-delay and little-effort options (a low-cost bias captured using computational modeling). At the end of the day, high-demand cognitive work resulted in higher glutamate concentration and glutamate/glutamine diffusion in a cognitive control brain region (lateral prefrontal cortex lPFC), relative to low-demand cognitive work and to a reference brain region (primary visual cortex V1). Taken together with previous fMRI data, these results support a neuro-metabolic model in which glutamate accumulation triggers a regulation mechanism that makes lPFC activation more costly, explaining why cognitive control is harder to mobilize after a strenuous workday.
•Cognitive fatigue is explored with magnetic resonance spectroscopy during a workday•Hard cognitive work leads to glutamate accumulation in the lateral prefrontal cortex•The need for glutamate regulation reduces the control exerted over decision-making•Reduced control favors the choice of low-effort actions with short-term rewards
Despite more than a century of research, the origins of cognitive fatigue have remained elusive. Here, Wiehler et al. suggest a neuro-metabolic account: daylong cognitive work leads to glutamate accumulation in the lateral prefrontal cortex, which reduces control over decisions and thereby favors effortless behaviors with immediate gratifications.
Adult metabolic medicine (AMM) is an expanding medical subspecialty, due to the increasing number of adult patients with inherited metabolic diseases (IMD). However, a formal training and ...postgraduate education in this field is not available in the majority of countries. Existing adult metabolic specialists (AMS) come from many different backgrounds. The aim of this survey was to assess the state of play as regards education and training in AMM worldwide. Members of the Society for the Study of Inborn Error of Metabolism adult metabolic group (n = 89) were asked to take part in this survey. Forty‐two AMS (47.2%) from 18 different countries completed the questionnaire. The most common specialties were internal medicine (38.1%), endocrinology (26.2%), genetics (21.4%), and neurology (21.4%). Ninety‐five percent of respondents considered that practical clinical experience had contributed importantly for their professional development, while only 27% felt the same for formal academic education. The current state of available education and training was judged as generally poor or fair (73% of the respondents). The most suggested ways of improving education and training in AMM were: to facilitate international internships; to implement courses on adult‐IMD; and to create a formal academic education. The skills considered most important for AMS were: recognition of signs and symptoms of diseases, knowledge of the available treatments, and ability to perform a correct follow up. In conclusion, worldwide, current available education and training in AMM is considered inadequate. This survey emphasizes the need for development of new, formal training opportunities to improve knowledge, and competence in this rapidly expanding field.
Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 ...mutations.
We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.
In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.
Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.
The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.
Background: KIF1C (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia. Case report: We report fraternal twins presenting with cerebellar ...ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous KIF1C variant in both patients. Discussion: KIF1C variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. KIF1C variants may also cause a hypomyelinating leukoencephalopathy.
Parkinson’s disease (PD) is the second most common neurodegenerative disease clinically characterized by classical motor symptoms and a range of associated non-motor symptoms. Due to the ...heterogeneity of symptoms and variability in patient prognosis, the discovery of blood biomarkers is of utmost importance to identify the biological mechanisms underlying the different clinical manifestations of PD, monitor its progression and develop personalized treatment strategies. Whereas studies often rely on motor symptoms alone or composite scores, our study focused on finding relevant molecular markers associated with three clinical models describing either motor, cognitive or emotional symptoms. An integrative multiblock approach was performed using regularized generalized canonical correlation analysis to determine specific associations between lipidomics, transcriptomics and clinical data in 48 PD patients. We identified omics signatures confirming that clinical manifestations of PD in our cohort could be classified according to motor, cognition or emotion models. We found that immune-related genes and triglycerides were well-correlated with motor variables, while cognitive variables were linked to triglycerides as well as genes involved in neuronal growth, synaptic plasticity and mitochondrial fatty acid oxidation. Furthermore, emotion variables were associated with phosphatidylcholines, cholesteryl esters and genes related to endoplasmic reticulum stress and cell regulation.
Objective
To study if treatment with triheptanoin, a 7‐carbon triglyceride, improves exercise tolerance in patients with McArdle disease. McArdle patients have a complete block in glycogenolysis and ...glycogen‐dependent expansion of tricarboxylic acid cycle (TCA), which may restrict fat oxidation. We hypothesized that triheptanoin metabolism generates substrates for the TCA, which potentially boosts fat oxidation and improves exercise tolerance in McArdle disease.
Methods
Double‐blind, placebo‐controlled, crossover study in patients with McArdle disease completing two treatment periods of 14 days each with a triheptanoin or placebo diet (1 g/kg/day). Primary outcome was change in mean heart rate during 20 min submaximal exercise on a cycle ergometer. Secondary outcomes were change in peak workload and oxygen uptake along with changes in blood metabolites and respiratory quotients.
Results
Nineteen of 22 patients completed the trial. Malate levels rose on triheptanoin treatment versus placebo (8.0 ± SD2.3 vs. 5.5 ± SD1.8 µmol/L, P < 0.001), but dropped from rest to exercise (P < 0.001). There was no difference in exercise heart rates between triheptanoin (120 ± SD16 bpm) and placebo (121 ± SD16 bpm) treatments. Compared with placebo, triheptanoin did not change the submaximal respiratory quotient (0.82 ± SD0.05 vs. 0.84 ± SD0.03), peak workload (105 ± SD38 vs. 102 ± SD31 Watts), or peak oxygen uptake (1938 ± SD499 vs. 1977 ± SD380 mL/min).
Interpretation
Despite increased resting plasma malate with triheptanoin, the increase was insufficient to generate a normal TCA turnover during exercise and the treatment has no effect on exercise capacity or oxidative metabolism in patients with McArdle disease.
Autosomal-recessive cerebellar ataxias (ARCAs) comprise a heterogeneous group of rare degenerative and metabolic genetic diseases that share the hallmark of progressive damage of the cerebellum and ...its associated tracts. This Review focuses on recent translational research in ARCAs and illustrates the steps from genetic characterization to preclinical and clinical trials. The emerging common pathways underlying ARCAs include three main clusters: mitochondrial dysfunction, impaired DNA repair, and complex lipid homeostasis. Novel ARCA treatments might target common hubs in pathogenesis by modulation of gene expression, stem cell transplantation, viral gene transfer, or interventions in faulty pathways. All these translational steps are addressed in current ARCA research, leading to the expectation that novel treatments for ARCAs will be reached in the next decade.
This Review highlights mitochondrial dysfunction, impaired DNA repair, and complex lipid homeostasis as major molecular themes relevant in autosomal-recessive cerebellar ataxias. Improved understanding of pathogenesis and recent progress in trial readiness are likely to translate into new causative therapies.
BackgroundMEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome) is a severe neurometabolic disease with infantile onset. Phenomenology ShownProgressive and ...marked dystonia over a 6-year period in an adult male with MEGDEL syndrome. Educational ValueGeneralized dystonia may be the main manifestation of a milder form of MEGDEL syndrome, which begins during adulthood.
Huntington disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and ...account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in humans and animal models. Here we review the clinical, biochemical, and molecular evidence of an energy deficit in HD and discuss the mechanisms underlying mitochondrial and related alterations.
PDF
