GABAergic modulation of beta power enhances motor adaptation in frontotemporal lobar degeneration

Alzheimers Dement. 2025 May;21(5):e14531. doi: 10.1002/alz.14531. Epub 2025 Feb 19.

Abstract

Introduction: We examined how abnormal prefrontal neurophysiology and changes in gamma-aminobutyric acid-ergic (GABAergic) neurotransmission contribute to behavioral impairments in disorders associated with frontotemporal lobar degeneration (FTLD).

Methods: We recorded magnetoencephalography during an adaptive visuomotor task from 11 people with behavioral-variant frontotemporal dementia, 11 with progressive supranuclear palsy, and 20 age-matched controls. We used tiagabine, a gamma-aminobutyric acid (GABA) re-uptake inhibitor, as a pharmacological probe to assess the role of GABA during motor-related beta power changes.

Results: Task impairments were associated with diminished movement-related beta power. Tiagabine facilitated partial recovery of behavioral impairments and neurophysiology, moderated by executive function, such that the greatest improvements were seen in those with higher cognitive scores. The right prefrontal cortex was revealed as a key site of drug interaction.

Discussion: Behavioral and neurophysiological deficits can be mitigated by enhancement of GABAergic neurotransmission. Clinical trials are warranted to test for enduring clinical benefits from this restorative-psychopharmacology strategy.

Highlights: Event-related beta power changes during movement can be altered by the GABA reuptake inhibitor, tiagabine. In people with behavioral-variant frontotemporal dementia and progressive supranuclear palsy, tiagabine enhanced beta modulation and concurrently improved task performance, dependent on baseline cognition, and diagnosis. The effects of the drug suggest a GABA-dependent beta-related mechanism that underlies adaptive motor control. Restoring selective deficits in neurotransmission is a potential means to improve behavioral symptoms in patients with dementia.

Keywords: FTLD; GABA; beta power; magnetoencephalography; motor adaptation; tiagabine.

MeSH terms

  • Aged
  • Beta Rhythm* / drug effects
  • Beta Rhythm* / physiology
  • Executive Function / drug effects
  • Female
  • Frontotemporal Lobar Degeneration* / drug therapy
  • Frontotemporal Lobar Degeneration* / physiopathology
  • Humans
  • Magnetoencephalography
  • Male
  • Middle Aged
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiopathology
  • Supranuclear Palsy, Progressive / drug therapy
  • Supranuclear Palsy, Progressive / physiopathology
  • Tiagabine / pharmacology
  • gamma-Aminobutyric Acid* / metabolism

Substances

  • Tiagabine
  • gamma-Aminobutyric Acid