Observing brain lactate dynamics during a working memory task in first episode and chronic schizophrenia

Project Summary
Schizophrenia (SZ) is a severe mental disorder characterized by hallucinations, delusions, disorganized
thought, impaired emotional and motivational processes, and cognitive dysfunction. Antipsychotic medications
help diminish positive symptoms but do not alleviate negative symptoms or cognitive impairments.
Abnormalities in energy metabolism in SZ have attracted growing interest. Mitochondrial and bioenergetic
alterations may have a role in the pathophysiology of this illness, either directly or through impacting the
neurotransmitter systems. Significantly altered glutamate, creatine kinase reaction flux, pH and redox ratio in
the frontal cortex and breakdown of their associations with blood oxygen level dependent (BOLD) signal has
been documented in psychosis using 1H/31P MRS and resting-state fMRI. The overall picture is consistent
with impairment in high-efficiency oxidative phosphorylation and a compensatory shift towards glycolysis.
Lactate is an important intermediate of metabolic activity under glycolysis. A few pioneering studies using 7 T
1H MRS observed substantial lactate increase in chronic SZ compared to first episode (FE) SZ and healthy
controls (HC). However, the resting-state lactate level cannot fully address the cognitive impairments observed
in SZ, especially in the early stages of the disease. Functional magnetic resonance spectroscopy (fMRS),
which acquires multiple spectra over time during stimulation, provides a more direct measure of behaviorally
relevant neural activity. It may help us better understand the underlying bioenergetic and neurotransmission
abnormalities present in SZ under cognitive stress.
Lactate quantification has been subject to overlapping with macromolecule signals and reduced quantification
reliability. We recently developed a sequence we term HOPE (Half-intensity with macrOmolecule-suPprEssion)
to suppress macromolecule signal while preserving short TE and signal-to-noise ratio. Using HOPE, lactate
can be reliably measured with significantly reduced quantification variations on 3 T.
In the current study, we propose to measure brain lactate dynamics in FE and chronic SZ in response to the
Sternberg working memory task. This will be the first fMRS study to monitor lactate dynamically in the brains of
SZ patients during a cognitive task. The HOPE sequence will be used to acquire fMRS on a clinical 3 T
scanner. We hypothesize that a hyperactivation of lactate would be observed in FE SZ because the switch to
glycolysis happens more than in healthy brain during activation, while the dynamic change from the elevated
lactate baseline in chronic SZ may be limited by a potential ceiling of bioenergetic compensation with
glycolysis. We will also quantify glutamate dynamics with the same scan and measure BOLD changes using
fMRI. We will assess how they are linked to lactate dynamics, and this may reveal a change in the interplay of
biological processes from earlier to later phases of illness. We will also evaluate how the fMRS/fMRI measures
may potentially contribute to the impaired cognitive functions and negative symptoms.

Grant Number: 5R21MH138861-02
NIH Institute/Center: NIH
Principal Investigator: Xi Chen