# Stable and dynamic neurobehavioral phenotypes of social isolation and loneliness in serious mental illness

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $265,310

## Abstract

Summary
Some of the most debilitating and harmful aspects of serious mental illnesses (SMI) are the 1) social isolation
(low numbers of social contacts) and 2) the subjective experiences of social disconnection (loneliness) that
frequently accompany these conditions. Social isolation and loneliness greatly impact day-to-day functioning and
are associated with poor cardiometabolic health and early mortality in SMI, and currently there are no available
treatments that can prevent or reverse these devastating consequences of having these illnesses. This may be
in part because the neural and psychological mechanisms underlying social isolation and loneliness in SMI, and
how they impact health outcomes, are poorly understood. However, recent clues from studies employing
advanced neuroimaging and digital assessments have formed the basis of a novel approach to investigating
such mechanisms, outlined in this proposal. Prior work has indicated that objective isolation and loneliness are
correlated but also somewhat independent. Recent neuroimaging findings support this model, revealing that
social isolation and loneliness have both shared and distinct neural correlates. However, it is also clear that these
are not static phenomena; smartphone-based assessments have revealed transient, dynamic changes in social
isolation and loneliness. Individual differences in the anticipation of rejection are associated with momentary
experiences of loneliness, greater avoidance and subsequent increases in social isolation. Thus, in the current
application, we propose to comprehensively measure both the relatively stable neural and behavioral predictors
of social isolation and loneliness, as well as the moment-to-moment changes in these experiences, in 60
individuals with SMI and 60 control subjects. In Aim 1 of the proposed project, we will show that the higher levels
of social isolation and loneliness in SMI are linked to shared and distinct neural responses to social stimuli, with
deficient responses of social perception-related circuitry (medial temporal lobe regions) linked to social isolation,
and deficient responses of reward-related circuitry (basal ganglia regions) linked to loneliness. In Aim 2, we will
measure transient changes in social isolation and loneliness with smartphone assessments using a longitudinal
“burst” design. Lastly, in Aim 3, we will determine how the quantitative markers of social isolation and loneliness
identified in Aims 1 and 2 predict indices of cardiometabolic health, measuring the stability of these associations
over time. Thus, in this project, we will show that fundamental neural and behavioral processes drive momentary
variation in the experience of social isolation and loneliness, and directly impact cardiometabolic health in SMI.
In follow-up work, these findings can be used as objective targets in studies of novel interventions which aim to
address these major causes of early mortality.

## Key facts

- **NIH application ID:** 10815863
- **Project number:** 5R01MH125426-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** DANIEL C FULFORD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $265,310
- **Award type:** 5
- **Project period:** 2022-03-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815863

## Citation

> US National Institutes of Health, RePORTER application 10815863, Stable and dynamic neurobehavioral phenotypes of social isolation and loneliness in serious mental illness (5R01MH125426-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10815863. Licensed CC0.

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