Cognitive symptoms have largely been absent from narcolepsy clinical trials. New research defines these symptoms and illustrates their impact, with researchers hoping they will be included moving forward.
By Alyx Arnett
When researchers sat down with 46 adults living with narcolepsy type 1 (NT1) for 90-minute interviews, the results were striking but perhaps not surprising. All but one reported experiencing cognitive difficulties. Close to 75% said those difficulties occurred daily. And more than half described them as severe.1
These findings align with prior research showing cognitive symptoms are common and burdensome,2 says Brian Harel, PhD, senior scientific director of neuropsychology at Takeda Pharmaceuticals and corresponding author of the study. But key gaps remained. “We didn’t really have a good characterization of what those cognitive difficulties look like, and those weren’t being well linked to impacts on daily life,” Harel says.
The study, led by Kiran Maski, MD, MPH, of Boston Children’s Hospital and Harvard Medical School, coded transcripts from interviews and identified key categories of cognitive difficulty. Researchers then mapped those difficulties to their impacts across daily functioning, work and education, emotional well-being, and social relationships.
“What this information tells us, which I think is incredibly important, is how these cognitive symptoms affect their lives. It very much gives us some insight into the fact that these are incredibly impactful on their lives, and that it affects them in lots of different ways,” says Harel.
Harel says the findings support bringing cognitive symptoms into clinical trials and suggest they may not be solely driven by excessive daytime sleepiness. With 89% of participants reporting recent pharmacologic treatment, the findings suggest cognition may be a potential core feature of the disease.
More Than Sleepiness
NT1 is defined by symptoms that include excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, hypnagogic and hypnopompic hallucinations, and sleep paralysis—features that guide diagnosis and are typically measured in clinical trials. Cognitive difficulties are not part of that traditional framework. But the study adds to a growing body of evidence suggesting they should be.
“Cognition has been studied for a while,” says Maski. “However, many studies used neuropsychological testing, like IQ measurements, which are not different compared to non-narcolepsy populations.”
That measurement insensitivity, she suggests, may have contributed to cognitive symptoms being minimized. With this study, Maski says, “It’s really getting more granular in identifying the cognitive issues that people with narcolepsy are complaining about, which seems to be more specific to attention, focus, and memory.”
Participants described forgetting conversations moments after having them, losing their train of thought mid-sentence, struggling to process information at normal conversational speed, and being unable to sustain attention during routine activities like reading or watching television.
One participant, a 37-year-old woman, described having to re-read work materials repeatedly when brain fog was severe, affecting both her efficiency and accuracy. A 39-year-old man said that, even when he wasn’t sleepy, he didn’t want to do anything because he couldn’t focus or remember what he was supposed to do.
The Orexin Question
A common assumption has been that these cognitive problems are downstream effects of excessive daytime sleepiness—that if you treat the sleepiness, the thinking improves. Findings from this study indicate that this may not be the case. “Most of the participants in the study were treated for sleepiness and still were expressing a high degree of cognitive burden,” says Maski.
Harel points to additional supporting data from the CRESCENDO study, an observational study of 203 patients with NT1 on standard-of-care treatment, which he was not involved in.3 The study showed that over 70% of patients continue to report experiencing cognitive difficulties on standard of care treatment.
“I think it’s safe to say that standard of care does not ameliorate [cognitive symptoms] completely because patients are still reporting them, still describing them as burdensome and impactful, and in fact, describing them as something they’d really like addressed through treatment,” Harel says.
NT1 is caused by the loss of orexin-producing neurons in the hypothalamus.4 While orexin is best known for stimulating brain regions that maintain alertness, its loss has also been associated with changes in automatic behaviors, mood and emotional regulation, reward processing, and cognition.5
“We don’t know for sure, but certainly orexin deficiency, based on our understanding of the biology … could cause cognitive symptoms directly,” says Harel. “It is a reasonable hypothesis, certainly, so it would not be unreasonable to believe that the disorder is causing the cognitive symptoms.”
Harel says the study helps establish a clearer framework for identifying and measuring cognitive symptoms. With more consistent definitions, he says, those symptoms could be incorporated into clinical trials—an important step toward developing treatments that address them directly.
Orexin agonists—a newer class of drugs designed to replace the missing orexin signal—are one area of interest. Harel says early data are encouraging but preliminary. “What we’re seeing, at least with our early data, is that we can substantially improve these symptoms,” he says.
The Unexpected Social Cost
Regardless of the underlying biology, the study shows how these symptoms affect daily life. Cognitive difficulties extended beyond symptoms, affecting work and school for about two-thirds of participants, with impacts on productivity, grades, and workload management.
While those impacts weren’t surprising to Harel, the extent to which those difficulties affected social relationships was. Nearly two-thirds of participants said cognitive difficulties negatively impacted their social well-being. Some described avoiding parties and social gatherings because they couldn’t keep up with conversations or feared embarrassing themselves. Others spoke about straining relationships with friends and partners because they couldn’t remember important conversations or stay mentally present.
“You wouldn’t think that cognitive difficulties would impact social interactions, but in fact, what we were seeing is that patients would avoid social situations which were either highly demanding on their attentional resources—like a party where you have to attend to a lot of different pieces of information—or situations where they were expected to remember things,” Harel says.
One participant, a 43-year-old man, said he avoids socializing in larger groups because he might “slip into a fog and not know what I’m talking about” mid-conversation. A 40-year-old woman described avoiding sitting with other parents at her daughter’s gymnastics meets because the chatter became overwhelming when she was tired, and she worried others would think she was being antisocial.
“If you can’t focus on conversations in social functions, you may stop attending them and become more isolated, and if you’re more isolated, you might develop depressive symptoms,” says Maski. “I think that kind of network analysis that this study did is helpful for understanding that broad impact.”
More than half of the participants reported emotional consequences tied to their cognitive difficulties, including reduced self-confidence, embarrassment, frustration, and sadness. Several expressed worry about appearing incompetent at work. Others said they felt “stupid”—not because they lacked intelligence, but because their cognitive symptoms made them feel that way.
Compensating, Not Thriving
One detail that stands out is that 63% of participants had completed a college or graduate degree. Given the severity of cognitive difficulties described, this might seem contradictory. Harel says it’s an important nuance.
“The cognitive symptoms that these patients experience, while they are absolutely impactful and burdensome and should be addressed, it’s not dementia,” he says. “It doesn’t appear to be progressive. These are patients who have real cognitive symptoms that affect their daily lives, but they’re able to compensate. They’re able to manage it—not perfectly, and potentially not even really well because they still talk about it a lot as a problem.”
The study documented a range of coping strategies that participants used to get by: calendars and reminders, lists, scheduled naps, relying on family members, and seeking out stimulating activities to stay alert.
Patients reported that these strategies help, but cognitive difficulties remain burdensome.
More than a third of people with NT1, according to prior research cited in the paper, identify cognitive symptoms as the symptom they most want treated.5
Why Clinicians Aren’t Asking—and What They Can Do Now
If cognitive difficulties are this prevalent and disruptive, why aren’t they a bigger part of the clinical conversation? According to Harel, it’s because “standard-of-care treatments don’t well address cognition, and so I think physicians have felt like they don’t necessarily have good tools to deal with it.” He adds, “So why continue to bring something up that you don’t have good tools to deal with?”
He believes another barrier has been language. Patients often describe their symptoms as “brain fog,” but that can mean different things. “Because we don’t know what it means, it’s really hard to do anything,” Harel says.
The study aimed to clarify that language. When researchers asked participants to describe what “brain fog” meant, it consistently mapped to more specific issues, including attention, memory, processing, and word-finding. More broadly, researchers identified five core categories of cognitive difficulty: trouble remembering, difficulty with focus or sustained attention, trouble thinking clearly or processing information, difficulty forming thoughts or words, and difficulty learning new things.
These findings, Harel says, offer specific language that patients use to describe their problems “that can be used by healthcare providers to better understand their experience.”
For clinicians, that creates a starting point for more targeted conversations. Maski says providers can ask questions such as:
- “Do you have problems remembering?”
- “Do you have difficulties with focus and attention for long periods of time?”
- “How burdensome is that?” “What is it affecting?”
“Patients are experiencing cognitive symptoms, whether they’re addressed by clinicians or not … and I think there is a real risk that by not addressing these symptoms with these patients, they may either negatively internalize their cognitive difficulties, they may not appreciate that it’s a symptom of disease, and may think that they’re stupid or not intelligent or not capable,” Harel says.
Maski notes that the coping strategies documented in the study offer tools clinicians can discuss with patients today.
What Comes Next
Harel and Maski say a key next step is bringing cognitive symptoms into clinical trials. Without consistent measurement, they say, it’s difficult to determine whether treatments are addressing them—or to develop therapies that do.
“We hope to call out for research to start including cognitive outcomes in clinical trials, so that we’re better informed as clinicians to help patients,” Maski says.
Harel says that the shift could allow for treatments that more directly target cognitive symptoms. He also points to a need to better integrate objective, clinic-based assessments of cognition with patient-reported experiences to create a more complete picture of cognitive symptoms in NT1.
In the meantime, Maski says there is an opportunity to build on what patients are already doing. “It would be really helpful to have patient support groups come together and collate life hacks and management tips they find helpful and then disseminate that information for day-to-day management,” she says.
Maski hopes the findings push the field toward more comprehensive assessment and treatment approaches that better reflect patients’ day-to-day experience. “In terms of treating narcolepsy, there might be a broader number of outcomes that require treatment,” she says. “Cognitive difficulties being one of them.”
References
- Maski K, Pfeiffer KM, Brod M, et al. Patient-reported experiences of cognitive difficulties and their impact on daily life in narcolepsy type 1. Front Neurol. 2026 Mar 4;17:1760952.
- Maski K, Steinhart E, Williams D, et al. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy. J Clin Sleep Med. 2017 Mar 15;13(3):419-25.
- Thorpy MJ, Kant A, Harper K, et al. CRESCENDO: results from a survey of symptom burden and quality of life in patients with narcolepsy type 1 (P8-4.001). Neurology. 2025;104(7 suppl 1):2879.
- Mahoney CE, Cogswell A, Koralnik IJ, et al. The neurobiological basis of narcolepsy. Nat Rev Neurosci. 2019;20(2):83-93.
- Katzman MA, Katzman MP. Neurobiology of the orexin system and its potential role in the regulation of hedonic tone. Brain Sci. 2022 Jan 24;12(2):150.
- Ortiz LE, Morse AM, Krahn L, Lavender M, et al. A survey of people living with narcolepsy in the USA: path to diagnosis, quality of life, and treatment landscape from the patient’s perspective. CNS Drugs. 2025 Mar;39(Suppl 1):23-36.
