Use of Ketosis in Modulating Metabolic Pathways in Bipolar Disorder

The goal of this clinical trial is to test how specific components of diet affect brain function and behavior for individuals with bipolar. The main question it aims to answer is how glucose and ketones each affect the brain's response to risk and reward. Participants will be asked to provide blood (to assess baseline measures of how the body uses energy), and then to receive two MRI scan sessions, on separate days. During each MRI scan session, participants will play three games, from which they can win money, before and after drinking glucose (on one day) or ketones (on the other day). Investigators will compare individuals with and without bipolar to test whether the two groups differ in how their brains use energy, and to test how the brain's use of energy affects behavior.

The purpose of the study is to understand the impact of glucose vs. ketones on brain metabolism and function, in individuals with bipolar. The specific aims are to examine:

1. Stability of the brain's signaling over time.
2. Regulation of the neural circuits that process risk
3. Regulation of the neural circuits that process reward

Study Procedures:

Baseline Blood Samples: Blood will be taken at Massachusetts General Hospital (Translational and Clinical Research Center) to measure baseline levels of several key variables associated with metabolic function. These variables include insulin resistance (HbA1c), thyroid function (T3, T4, TSH), the efficiency of the tricarboxylic acid (TCA) cycle (lactate/pyruvate), energy sensing (AMPK), mitochondrial regulation, and inflammation (IL-6, tumor necrosis factor (TNF)-alpha).

Scanning Procedure: The scanning procedure for magnetic resonance (MR) imaging, on each day, will include 1) functional MR (fMRI) during cognitive task (three games), 2) MR spectroscopy (MRS), and 3) resting state. Following the scan, the participant will drink either glucose or ketones and repeat 1-3 above.

Blood glucose and ketone monitoring: Using a finger-prick test, investigators will measure blood glucose and ketones three times during each scan session. This will be done immediately before starting the scan session, 10 minutes after consuming either glucose or ketones, and immediately after ending the scan session. Mild temporary pain/discomfort may occur at the site of finger-prick for blood glucose and ketone concentration measurements (pre-scan, post-drink, and post-scan), but no other side effects are expected from this test. Precision Xtra is a standard over-the-counter blood glucose and ketone monitoring system routinely self-administered by diabetic patients. Participants' fingers will be sanitized with alcohol wipes and a fresh lancet will be used to perform each finger prick test.

Eligibility Criteria:
Inclusion/Exclusion Criteria:

* Bipolar disorder diagnosis: Patients must have a Diagnostic Statistical Manual (DSM)-V diagnosis of bipolar disorder on the Structured Clinical Interview for DSM (SCID)
* Bipolar disorder symptoms: Patients must be stable and euthymic at time of consent and testing, documented by no hospitalizations in the prior 4 weeks
* Age: between 18-45 yrs for patients with bipolar disorder and age-matched controls
* Weight does not exceed 350lbs.
* Diameter does not exceed 60 cm when supine
* HbA1C \< 7%
* No non-MRI-compatible metal in the body (e.g., pacemaker, shrapnel, joint pins)
* No claustrophobia
* No history of significant head injury
* No history of electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) within the last 3 months
* No history of previous treatment with following procedures: vagus nerve stimulation, or deep brain stimulation
* Are not deemed a serious suicide or homicide risk
* No unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease
* No seizure disorders
* Have the capacity to sign informed consent
* No current diagnosis or history of an alcohol or substance use disorder in the last 6 months or positive test for an illicit drug on the screening urine analysis (positive cannabis screen is not exclusionary): confirmed using urine toxicology test during the initial screening visit and before each MRI scan visit.
* For Healthy Volunteers Only: No psychotropic medication and no history of neurological disease
* Must have vision that is 20/20 or correctable to 20/20 with contact lenses
* No Type 1 diabetes mellitus
* No regular consumption of insulin and other antidiabetics, like Metformin®, GLP1-RA's and others.
* No kidney disease, as determined by medical history and/or blood work
* No history of heart attack or stroke
* No difficulty swallowing
* No myxedema
* No Pregnancy (pre-menopausal females): confirmed during medical screening and each MRI scan visit using a urine test
* No breastfeeding