Local activity alterations in autism spectrum disorder correlate with neurotransmitter properties and ketamine induced brain changes.
Pascal Grumbach, Jan Kasper, Joerg F. Hipp, Anna Forsyth, Sofie L. Valk, Suresh Muthukumaraswamy, Simon B. Eickhoff, Leonhard Schilbach, Juergen Dukart
medRxiv October 21, 2024 preprint DOI: 10.1101/2024.10.20.24315801 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort |
|---|---|
| Sample size | 878 |
| Population | Individuals with autism spectrum disorder and neurotypical controls from ABIDE1 and ABIDE2 cohorts |
| Interventions | midazolam ketamine |
| Topics | Esketamine Ketamine |
| Keywords | Autism spectrum disorders Brain chemistry Neurotransmitters Ketamine research |
| Citations | 1 |
| Key findings | Reduced local brain activity in default mode network nodes and increased activity in temporal regions, cerebellum, and brainstem in autism co-localized with multiple neurotransmitter systems, and ketamine-induced changes resembled these alterations. |
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with altered resting-state brain function. An increased excitation-inhibition (E/I) ratio is discussed as a potential pathomechanism but in-vivo evidence of disturbed neurotransmission underlying these functional alterations remains scarce. We compared rs-fMRI local activity (LCOR) between ASD (N=405, N=395) and neurotypical controls (N=473, N=474) in two independent cohorts (ABIDE1 and ABIDE2). We then tested how these LCOR alterations co-localize with specific neurotransmitter systems derived from nuclear imaging and compared them with E/I changes induced by GABAergic (midazolam) and glutamatergic medication (ketamine). Across both cohorts, ASD subjects consistently exhibited reduced LCOR, particularly in higher-order default mode network nodes, alongside increases in bilateral temporal regions, the cerebellum, and brainstem. These LCOR alterations negatively co-localized with dopaminergic (D1, D2, DAT), glutamatergic (NMDA, mGluR5), GABAergic (GABAa) and cholinergic neurotransmission (VAChT). The NMDA-antagonist ketamine, but not GABAa-potentiator midazolam, induced LCOR changes which co-localize with D1, NMDA and GABAa receptors, thereby resembling alterations observed in ASD. We find consistent local activity alterations in ASD to be spatially associated with several major neurotransmitter systems. NMDA-antagonist ketamine induced neurochemical changes similar to ASD-related alterations, supporting the notion that pharmacological modulation of the E/I balance in healthy individuals can induce ASD-like functional brain changes. These findings provide novel insights into neurophysiological mechanisms underlying ASD.
Comparable studies
Other observational and cohort studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Taming the Ketamine Tiger Volunteers from a prison population | 2010 | Observational study | n = 20 |
| Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin Humans | 2017 | Observational study | |
| Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane Surgical patients undergoing induction of anesthesia with intravenous ketamine | 2013 | Observational cohort | n = 30 |
| Do the dissociative side effects of ketamine mediate its antidepressant effects? Treatment-resistant inpatients with major depressive disorder or bipolar disorder | 2014 | Observational cohort | n = 108 |
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
Citations in the library
Cites 6
- 20 years of the default mode network: A review and synthesis Neuron May 10, 2023
- Modulation of simultaneously collected hemodynamic and electrophysiological functional connectivity by ketamine and midazolam Human Brain Mapping December 6, 2019
- Mapping Pharmacologically-induced Functional Reorganisation onto the Brain’s Neurotransmitter Landscape bioRxiv (Cold Spring Harbor Laboratory) July 13, 2022
- Resting-state abnormalities in functional connectivity of the default mode network in migraine: A meta-analysis Frontiers in Neuroscience March 1, 2023
- Ketamine administration in early postnatal life as a tool for mimicking Autism Spectrum Disorders core symptoms. Progress in Neuro-Psychopharmacology and Biological Psychiatry April 1, 2022
and 1 more in the library