Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans

Abstract

Substantial evidence implicates the nucleus accumbens in motivated performance, but very little is known about the neurochemical underpinnings of individual differences in motivation. Here, we applied 1H magnetic resonance spectroscopy (1H-MRS) at ultra-high-field in the nucleus accumbens and inquired whether levels of glutamate (Glu), glutamine (Gln), GABA or their ratios predict interindividual differences in effort-based motivated task performance. Given the incentive value of social competition, we also examined differences in performance under self-motivated or competition settings. Our results indicate that higher accumbal Gln-to-Glu ratio predicts better overall performance and reduced effort perception. As performance is the outcome of multiple cognitive, motor and physiological processes, we applied computational modeling to estimate best-fitting individual parameters related to specific processes modeled with utility, effort and performance functions. This model-based analysis revealed that accumbal Gln-to-Glu ratio specifically relates to stamina; i.e., the capacity to maintain performance over long periods. It also indicated that competition boosts performance from task onset, particularly for low Gln-to-Glu individuals. In conclusion, our findings provide novel insights implicating accumbal Gln and Glu balance on the prediction of specific computational components of motivated performance. This approach and findings can help developing therapeutic strategies based on targeting metabolism to ameliorate deficits in effort engagement.

A Randomized Clinical Trial to Evaluate the Effects of Safinamide on Apathetic Non-demented Patients With Parkinson's Disease

“…Substantial evidence implicates the nucleus accumbens glutamine-to-glutamate ratio on the prediction of specific components of motivated behavior ( 34 ), and glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans ( 34 ). These arguments added to preliminary evidence from post-hoc and open-label studies showing some improvement in apathy in patients treated with safinamide ( 27 , 28 , 35 ) moved us to formally explore whether a therapeutic strategy using a drug targeting both, dopaminergic and glutamatergic systems, could help to ameliorate apathetic symptoms in PD.…”

Brain mitochondrial diversity and network organization predict anxiety-like behavior in mice

“…Targeted mitochondrial defects even cause mood disorder-like phenotypes in animals 38 and are likely implicated in the etiology of psychiatric, neurological and degenerative disorders in humans 39 . Moreover, in vivo human brain metabolic imaging studies show that energy metabolism in specific brain areas (e.g., nucleus accumbens, NAc) predict performance and anxiety [40][41][42] . Thus, current evidence positions mitochondria as an upstream modulator of brain function and behavior.…”

“…Targeted mitochondrial defects even cause mood disorder-like phenotypes in animals 41 , positioning mitochondria as upstream modulators of brain function and behavior. Moreover, mitochondrial RC defects are likely implicated in the etiology of psychiatric, neurological and degenerative disorders in humans 42 , and in vivo brain metabolic imaging studies show that energy metabolism in specific brain areas (e.g., nucleus accumbens, NAc) predict cognitive performance and anxiety [43][44][45] , making these biological questions also potentially relevant to human mental health.…”

Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort

“…To assess whether the concentration of GSH in the NuAc in humans is related to motivated performance, and to do so in an unbiased manner, we computed levels of a number of metabolites [creatine (Cr), glycerylphosphorylcholine (GPC), GSH, inositol (Ins), lactate (Lac), N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), phosphocreatine (PCr), phosphatidylethanolamine (PE) and taurine (Tau)] extracted from the 1 H-MRS spectra acquired - but not previously analyzed- in the Strasser et al 28 study (Supplementary Figure 1a). Following 1 H-MRS acquisition at 7T, participants performed an effortbased motivated task in which they could earn different monetary rewards (0.2, 0.5 or 1 CHF, depending on the trials) by squeezing a handgrip at 50% of their maximal voluntary contraction and maintaining that force for 3 sec (Figure 1a).…”