This Week in The Journal

Balancing Speed and Accuracy in Decision-Making

Shinichiro Kira, Ariel Zylberberg, and Michael N. Shadlen

(see article e2426242025)

How do people balance speed and accuracy during decision-making? To make decisions, the brain gathers evidence and commits to a choice when enough information has accumulated. In this issue, Kira et al. explored how flexible the threshold of sufficient evidence accumulation is in response to costs associated with the time it takes to deliberate. In their study, participants judged the direction of motion in random-dot displays of varying difficulty. Participant choices and reaction times followed the patterns expected from an evidence accumulation process: the amount of evidence to inform a choice gradually decreased as time passed within a trial. Partway through trials, and without the participants’ awareness, the authors introduced random deadlines that caused some trials to end prematurely. Kira and colleagues used a computational method they developed to estimate decision-making changes over time. This approach confirmed that the amount of information required for a decision decreases as a function of time and that this reduction in evidence criteria occurs even faster under time pressure. According to the authors, these findings highlight the brain's flexibility in determining when to stop deliberating and commit to a choice.

Representative images of hiPSC-derived motoneurons with colors representing MAP2 and Islet1 indicated. ALS-related KIF5A mutations did not alter co-expression. See Zanella et al. for more information.

Characterizing ALS-Related Kinesin Mutations

Pietro Zanella, Isabel Loss, Rosanna Parlato, Jochen H. Weishaupt, Carlo Sala et al.

(see article e1658242025)

Selective motoneuron death underlies amyotrophic lateral sclerosis (ALS). While the mechanisms underlying this selective vulnerability remain unclear, studies have implicated several genes. A gene called kinesin family member 5A (KIF5A) undergoes specific mutations in ALS patients that have yet to be characterized. Zanella et al. caused ALS-related KIF5A mutations in human-induced pluripotent stem cell (hiPSC)-derived motoneurons, which led to a buildup of mutant KIF5A protein. This protein aggregation caused cytosolic mislocalization of the RNA-binding protein TDP-43. Notably, the authors also observed similar phenotype when overexpressing mutant KIF5A in healthy control hiPSCs and primary neurons. Probing differences in the wild-type isoform compared with the ALS version of the protein, the researchers discovered that the terminal domain of wildtype KIF5A has an acidic isoelectric point (pI), while the ALS version has a basic pI. The authors overexpressed a KIF5A ALS isoform with a lower—or more acidic—pI and this manipulation reduced protein aggregation and TDP-43 mislocalization. According to the authors, this work advances understanding of how KIF5A mutations lead to ALS-related TDP-43 pathology.