Table 2.

Resting State Scans and Non-Task Scans (Non-Depressed Populations)

Author(s)	Scanning Details and Study Design	Subjects and Ketamine Details	Significant Findings* (all p<0.05 unless otherwise noted)	Limitations
Deakin 200840	phMRI BOLD – starting 8 minutes and 8 minutes during the infusion Two experiments: DB, PBO controlled, randomized, crossover, counterbalanced orders. First experiment was ketamine vs. PBO; second experiment was ketamine following pre-treatment (2 hours before) with lamotrigine 300mg vs. PBO	Male right handed healthy volunteers in experiment 1 (n=20) and experiment 2 (n=19) Racemic ketamine; 0.26mg/kg for 1 minute bolus, then 0.25mg/kg/hr maintenance	Ketamine caused an immediate and focal reduction in sgACC and OFC blood flow; this strongly predicted dissociation (r=0.90 with CADSS scores). Furthermore, ketamine increased activity in the mid-posterior cingulate cortex, thalamus, and temporal cortical regions. Lamotrigine prevented many of the BOLD signal changes.
Stone 201541	3T phMRI—15-minute scan with ketamine starting at minute 5 OL within-subjects design	Male healthy volunteers (n=13), ages 18–50 years old Racemic ketamine; 0.26mg/kg for 20 seconds followed by 0.42mg/kg/hr	Ketamine led to decreases in BOLD response in sgACC and widespread cortical and subcortical increases in BOLD response in the cingulate gyrus, hippocampus, insula, thalamus, and midbrain. Perceptual distortions and delusion ratings correlated with increased BOLD response in the parietal cortex.	Small n
Doyle 201371 Shcherbinin 201572	rs-phMRI71 and ASL72 Randomized, PBO controlled, partial crossover design. Four scanning visits separated by at least 2 weeks apart. Sessions were as follows: PO risperidone/IV ketamine; PO lamotrigine/IV ketamine; PO PBO/ketamine; PO PBO/IV saline	Male healthy volunteers (n=16 completers) Racemic ketamine; Bolus ~0.12mg/kg for the first minute, then 0.31mg/kg/hr for about 20 min (BOLD resting state occurred for 15 min and ASL scanning occurred for 5 more min after start of infusion)	phMRI: Pre-treatment with lamotrigine and risperidone resulted in attenuation of ketamine-induced increases in BOLD signal (including medial prefrontal and cingulate regions and thalamic areas). ASL: Ketamine increased perfusions of the prefrontal and cingulate cortices, thalamus, and lateral parietal cortex. Pretreatment with risperidone, but not lamotrigine, significantly increased the ketamine induced perfusion changes.	Pharmacological dose – response curve for ketamine is only based on a few subjects.
Scheidegger 201243	3T rsfMRI—2 scans, at baseline and 24 hours post infusion. Randomized, DB, PBO controlled, crossover study. Ketamine and PBO infusions separated by 10 days.	Healthy volunteers (n=17) IV S-ketamine; 0.25mg/kg over 45	Ketamine decreases resting state functional network connectivity in healthy subjects; specifically, ketamine disrupted connectivity between the pgACC and the mPFC and the bilateral dmPFC) 24 hours after ketamine.	Healthy controls were used to make inferences about networks commonly disrupted in MDD. As such, inferences about antidepressant effect could not be made.
Bonhomme 201644	3T rsfMRI – 1 scan during ketamine infusion Ketamine dose gradually increased to reach deeper levels of sedation during the scanning session.	Healthy volunteers (n=8) analyzed Racemic ketamine; dose varied based on depth of sedation	Increased depth of sedation with increased ketamine doses correlated significantly with decreased connectivity in the mPFC with the DMN. Thalamo-cortical connectivity remains relatively preserved, but corticocortical connections were disrupted with ketamine.	Small n; heart rate and respiration not directly taken into account in analysis (though CO2 was). Multiple-seed ROI approach may bias results. Order of conditions was not randomized due to ketamine’s long recovery time.
Grimm 201545	3T rsfMRI – 1 scan post infusion DB, PBO-controlled, randomized; single IV infusion	Healthy volunteers (n=24); 12 males and 12 females Racemic ketamine; 0.5mg/kg over 40 min	Hyperconnectivity between the PFC and the left hippocampus occurred after acute ketamine challenge.	It is unclear what (if any) scrubbing methods were used for rsfMRI.
Hoflich 201648	3T rsfMRI – 1 scan during infusion DB, PBO-controlled, randomized, crossover trial of IV ketamine in the scanner. Infusion was administered 10 minutes after the start of the 50-minute scan; the first 5 minutes of the scan were infusion-free resting state scans, followed by 5 minutes of saline infusion).	Healthy volunteers (n=30); 15 males and 15 females (Because of scanner trouble, full data was available for only 5 patients) S-ketamine; 0.11mg/kg 1 min bolus followed by 0.12mg/kg over 19 minutes	Compared to PBO, ketamine increases neural activation in the bilateral MCC, ACC, and insula, as well as the right thalamus.	Pharmacological dose – response curve for ketamine is only based on a few subjects.
Wong 201664	3T rsfMRI—1 scan, 15 minute scan with IV ketamine started at the 5 minute point	Male healthy volunteers (n=13) Racemic ketamine; 0.26mg/kg rapid bolus over 20 seconds and then 0.42mg/kg/hr infusion	Following ketamine, there was a significant reduction in sgACC coupling with the hippocampus, RSC, and thalamus.	Healthy controls were used to make inferences about brain regions implicated in MDD. As such, inferences about antidepressant effect could not be made. Participants were studied 5min after infusion, and antidepressant effects are typically not seen for 1–2hrs post infusion.
Joules 201470	3T MRI – 2 scans, pre and post infusion DB, PBO controlled, crossover design of four sessions, each separated by 10 days. IV session was in the scanner. Sessions were as follows: PO PBO/IV ketamine, PO PBO/IV saline, PO Risperdal, IV ketamine, and PO lamotrigine/IV ketamine	Male healthy volunteers (n=16), all right handed Racemic ketamine; IV form given as 0.12mg/kg over 1 minute followed by 0.31mg/kg/hr	Ketamine significantly altered whole brain connectivity compared to PBO. Specifically, ketamine produced a shift from cortically-centered to subcortically-centered patterns of connections. This effect was modulated by pre-treatment with risperidone, but not lamotrigine, suggesting that the connectivity pattern shifts are due to NMDAR blockage (rather than downstream glutamatergic effects).	Measures of degree centrality (the metric used to determine whole brain connectivity) cannot be used to examine region-to-region coupling. As such, some important differences in connectivity may go undetected.
Niesters 201238 Khalili-Mahani 201473 (Biomarker study)	3T rsfMRI – 1 scan followed by PCASL measurement First study: Single blind, randomized, PBO controlled crossover study of IV S-ketamine vs. placebo during scanning. Scans separated by at least 1 week. Pain was also assessed with a noxious heat stimuli Second study was a biomarkers study: examine biomarkers on the extent to which ketamine infusion mimics a stress response	Male healthy volunteers (n=12) S-ketamine; 20mg/70kg/hr for 1 hour, then 40mg/70kg/hr for 1 hour	Ketamine increased connectivity in the cerebellum and visual cortex in relation to the medial visual network. Ketamine decreased connectivity in the auditory and somatosensory networks in relation to regions of pain sensing and affective processing of pain (amygdala, insula, and ACC). Ketamine caused a transient change in CBF; there was increased brain function in the prefrontal brain regions and decreased brain function in the hippocampal, visual, and parietal regions Ketamine induced hyperconnectivity in hippocampal networks vulnerable to mood and cognitive disorders Biomarkers: There were increased cortisol levels with the higher dose of ketamine within 30 minutes of starting the infusion; robust cortisol response was associated with perfusion of the hippocampus and hippocampal head connectivity	It is unclear what (if any) scrubbing methods were used for rsfMRI (Niesters 2012).
Lahti 199539	PET/MR – 2 scans, pre-and post-infusion DB, PBO controlled; Four administrations occurred over 2 weeks at the following doses: ketamine at three different doses vs. placebo	Patients with schizophrenia (n=9) maintained on stable haloperidol doses Racemic ketamine; 0.1 mg/kg, 0.3mg/kg, and 0.5mg/kg	Ketamine significantly increased rCBF in the ACC and reduced rCBF in the visual cortex and hippocampus.	Small n; Study was published in 1995.
Taylor 201213	3T proton MRS PBO-controlled, parallel group design; IV ketamine	Healthy volunteers (n=17); 11 male and 6 female Racemic ketamine; 0.5mg/kg over 40 minutes	No significant difference between ketamine and PBO in Glx or Glutamate concentrations in the ACC.	The study only tested one voxel in the sgACC, therefore changes in Glu/Glx in other parts of the brain may go undetected. n=11. H-MRS does not measure glutamate release directly and instead measures glutamine, which is an index of turnover of synaptic glutamate involved in neurotransmission.
Rowland 200574	4T proton MRS DB, PBO-controlled, crossover; 2 scanning sessions separated by 1–2 weeks	Male healthy volunteers (n=9 analyzed) Racemic ketamine; 0.27mg/kg loading dose over 10 minutes, then 0.00225mg/kg/min maintenance for the rest of the experiment (up to 2 hours)	Ketamine significantly increased ACC glutamine (a putative marker of glutamate release) compared to PBO.	Small n; H-MRS does not measure glutamate release directly and instead measures glutamine, which is an index of turnover of synaptic glutamate involved in neurotransmission.
Kraguljac 201646	3T MRS (to measure hippocampal Glx) and rsfMRI (to measure hippocampal connectivity) Ketamine IV was given in the scanner	Healthy volunteers (n=15) completed; 10 males and 5 females Racemic ketamine; 0.27mg/kg bolus over 10 min then 0.25mg/kg/hr for approximately 60 minutes	Ketamine induced an increase in hippocampal Glx, a decrease in frontotemporal and temporo-parietal functional connectivity, and a possible link between connectivity changes and elevated Glx.	Small n; placebo control group was not included. A one-sided t-test was used based on previous results from schizophrenia patients.
Muthukumaraswamy 201547	MEG – Two different experiments Exp. 1: Two MEG experiments on 2 days (ketamine vs. placebo); 5 min resting state MEG, then infusion Exp. 2: 10 minute resting state MEG	Male healthy volunteers (n=19 in Exp. 1 and n=6 in Exp. 2) Racemic ketamine Exp 1: 0.25mg/kg bolus over 1 min, then 0.375mg/kg/hr maintenance infusion for 10 minutes Exp 2: Same dose as Exp. 1 but with maintenance infusion for 20 minutes	Ketamine decreased NMDA- and AMPA-mediated frontal-to-parietal connectivity; specifically, ketamine caused a decrease in posterior alpha band power, an increase in prefrontal theta band power, and widespread increases in gamma band power.	The dynamic causal modeling (DCM) approach used here found significant frontoparietal connectivity changes. However, power correlations fail to replicate this result.