We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

In Vivo Evidence for Cerebral Bioenergetic Abnormalities in Schizophrenia Measured Using 31P Magnetization Transfer Spectroscopy

Fei Du, PhD1,2; Alissa J. Cooper, BA1; Thida Thida, BA1; Selma Sehovic, BA1; Scott E. Lukas, PhD2,3; Bruce M. Cohen, MD, PhD2,4; Xiaoliang Zhang, PhD5; Dost Öngür, MD, PhD1,2
[+] Author Affiliations
1Psychotic Disorders Division, McLean Hospital, Belmont, Massachusetts
2Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
3McLean Imaging Center, McLean Hospital, Belmont, Massachusetts
4Shervert Frazier Research Institute, McLean Hospital, Belmont, Massachusetts
5Department of Radiology, University of California, San Francisco
JAMA Psychiatry. 2014;71(1):19-27. doi:10.1001/jamapsychiatry.2013.2287.
Text Size: A A A
Published online

Importance  Abnormalities in neural activity and cerebral bioenergetics have been observed in schizophrenia (SZ). Further defining energy metabolism anomalies would provide crucial information about molecular mechanisms underlying SZ and may be valuable for developing novel treatment strategies.

Objective  To investigate cerebral bioenergetics in SZ via measurement of creatine kinase activity using in vivo 31P magnetization transfer spectroscopy.

Design, Setting, and Participants  Cross-sectional case-control study in the setting of clinical services and a brain imaging center of an academic psychiatric hospital. Twenty-six participants with chronic SZ (including a subgroup diagnosed as having schizoaffective disorder) and 26 age-matched and sex-matched healthy control subjects (25 usable magnetic resonance spectroscopy data sets from the latter).

Intervention  31P magnetization transfer spectroscopy.

Main Outcomes and Measures  The primary outcome measure was the forward rate constant (kf) of the creatine kinase enzyme in the frontal lobe. We also collected independent measures of brain intracellular pH and steady-state metabolite ratios of high-energy phosphate-containing compounds (phosphocreatine and adenosine triphosphate [ATP]), inorganic phosphate, and the 2 membrane phospholipids phosphodiester and phosphomonoester.

Results  A substantial (22%) and statistically significant (P = .003) reduction in creatine kinase kf was observed in SZ. In addition, intracellular pH was significantly reduced (7.00 in the SZ group vs 7.03 in the control group, P = .007) in this condition. The phosphocreatine to ATP ratio, inorganic phosphate to ATP ratio, and phosphomonoester to ATP ratio were not substantially altered in SZ, but a significant (P = .02) reduction was found in the phosphodiester to ATP ratio. The abnormalities were similar between SZ and schizoaffective disorder.

Conclusions and Relevance  Using a novel 31P magnetization transfer magnetic resonance spectroscopy approach, we provide direct and compelling evidence for a specific bioenergetic abnormality in SZ. Reduced kf of the creatine kinase enzyme is consistent with an abnormality in storage and use of brain energy. The intracellular pH reduction suggests a relative increase in the contribution of glycolysis to ATP synthesis, providing convergent evidence for bioenergetic abnormalities in SZ. The similar phosphocreatine to ATP ratios in SZ and healthy controls suggest that the underlying bioenergetics abnormality is not associated with change in this metabolite ratio.

Figures in this Article


Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

First Page Preview

View Large
First page PDF preview


Place holder to copy figure label and caption
Figure 1.
T2-Weighted Brain Anatomic Imaging (in the Sagittal Orientation) and the Sensitivity Profile (6 × 6 × 4 cm3) of the 7-cm 31P Surface Coil Placed Over the Forehead

To delineate the 31P sensitivity region of the surface coil with outer-volume saturation in this experiment (dotted rectangle), 1-dimensional profiles of inorganic phosphate signal along 3 orthogonal dimensions (white profiles) were acquired from a phantom (14-cm-diameter cylindrical bottle) with inorganic phosphate solution (inorganic phosphate concentration, 0.6M; pH, 7.1).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
In Vivo 31P Spectra With 10-Hz Line Broadening in the Absence and Presence of Saturating γ–Adenosine Triphosphate (γ-ATP) Resonance (Arrowheads) in the Left and Right Columns, Respectively

The spectra on the top and bottom rows were acquired from a representative patient in the schizophrenia (SZ) group and a participant in the healthy control (HC) group, respectively. The saturation time was 12.28 seconds. All resonance peaks are labeled in the lowest spectrum. The magnetization of phosphocreatine (PCr) was reduced by 43% and 56% for the SZ and HC participants, respectively. The pH was calculated via equation 6, where δ is the distance between the chemical shifts of PCr and inorganic phosphate (Pi). This distance is different in the SZ and HC participants (aligned by vertical lines across the 2 spectra), indicating intracellular pH reduction in SZ. GPC indicates glycerophosphocholine; GPE, glycerophosphoethanolamine; and PME, phosphomonoester.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Dependence of the Phosphocreatine Signal on γ–Adenosine Triphosphate Saturation Time for the Schizophrenia (SZ) Group (n = 26) and the Healthy Control (HC) Group (n = 25).

The peak integrals for phosphocreatine represent the normalized ratios of Ms to M0, which in equation 4 are the magnetization of phosphocreatine at saturation time (t) and Boltzmann thermal equilibrium condition, respectively. The intrinsic spin-lattice relaxation times of phosphocreatine (intrinsic longitudinal T1 relaxation times) and the forward rate constants (kf) were determined from these data by regression analyses using equation 4.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Relationship Between pH and the PCr:γ-ATP Ratio in the Schizophrenia (SZ) Group and the Healthy Control (HC) Group

PCr:γ-ATP ratio indicates the ratio of phosphocreatine to γ–adenosine triphosphate.

Graphic Jump Location




Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment


Some tools below are only available to our subscribers or users with an online account.

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.