In a double-blind crossover MEG study using dynamic causal modelling during an emotional-face attentional task, a single ketamine infusion rapidly reduced symptoms in treatment-resistant depression and produced region-specific changes in glutamatergic and GABAergic transmission (faster GABA and NMDA in early visual cortex, faster NMDA in fusiform, slower NMDA in amygdala) with altered local inhibition in early visual and inferior frontal cortices. Symptom improvement correlated with faster AMPA transmission and increased gain of spiny stellate cells in early visual cortex, supporting GABA/NMDA inhibition–disinhibition models and emphasising AMPA throughput as a key mediator of ketamine's antidepressant effects.
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Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (TRD) and bipolar disorder. While its underlying mechanism of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with TRD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6–9 h after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across time points using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity via a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in TRD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in TRD participants post-ketamine were associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine's antidepressant effects.
Ketamine, a glutamatergic modulator and non-competitive NMDA receptor antagonist, produces rapid antidepressant effects in unipolar and bipolar depression, including treatment-resistant depression (TRD). While multiple lines of preclinical and clinical evidence implicate glutamatergic and GABAergic systems in ketamine's mechanism of action, it remains uncertain which receptor-level and circuit-level changes underlie clinical improvement. Prior work suggests that NMDA antagonism produces a transient disinhibition of pyramidal neurons via reduced interneuron firing, a glutamate surge and increased AMPA receptor throughput that engages plasticity pathways such as mTORC1 and BDNF signalling; gamma-band electrophysiology has also been proposed as an index of altered excitation–inhibition balance after ketamine. Gilbert and colleagues designed a mechanistic human study to probe how ketamine alters effective connectivity during emotional face processing. Using a double-blind, crossover, placebo-controlled design with magnetoencephalography (MEG) and dynamic causal modelling (DCM), the investigators modelled receptor-specific (AMPA, NMDA, GABA) time constants and intrinsic/extrinsic connectivity among the early visual cortex, fusiform cortex, amygdala and inferior frontal gyrus. The primary aim was to identify ketamine-induced changes in these parameters in TRD participants versus healthy volunteers and to test whether any modelled changes were associated with antidepressant response.
Participants comprised 19 drug-free individuals with DSM-IV-TR TRD (11 female; mean age 36.7 ± 10.9 years) and 15 healthy volunteers (11 female; mean age 34.7 ± 11.8 years) enrolled at the NIMH between 2011 and 2016. TRD participants were aged 18–65, experiencing a current major depressive episode of at least 4 weeks, had failed at least one adequate antidepressant during the current episode (lifetime mean 3.8 failed trials), and had MADRS ≥ 20 at screening and before each infusion. Healthy volunteers had no Axis I disorders and no first-degree family history of such disorders. All TRD participants were hospitalised for the study and were free from psychotropic medications for at least 2 weeks (longer washouts for specific agents). The subset reported here was chosen because they had usable MEG recordings at all three sessions. The study used a double-blind, crossover, placebo-controlled infusion protocol. Each participant received a single intravenous infusion of ketamine hydrochloride 0.5 mg/kg and a saline placebo infusion, 14 days apart with infusion order randomised. MEG recordings were acquired at three time points: baseline (pre-infusion) and 6–9 hours after both ketamine and placebo infusions; the delayed timing was chosen to avoid acute side effects and to assess therapeutic effects. Clinical outcome for TRD participants was measured with the Montgomery–Åsberg Depression Rating Scale (MADRS) administered 60 minutes pre-infusion and at multiple post-infusion times (230 minutes and Days 1–3). The primary clinical comparison reported here was the difference between ketamine and placebo at 230 minutes, the time point closest to the MEG scan. Clinical modelling controlled for period-specific and participant-average baselines and used an unstructured covariance to account for repeated observations within participants and infusions. During each MEG session participants completed a dot-probe attentional task with emotional face pairs (happy/neutral, angry/neutral, and neutral/neutral). Trials were categorised as congruent (probe behind emotional face) or incongruent (probe behind neutral face). The task used a mixed block/event-related design with 48 trials per emotional-congruency condition and a total of 96 neutral paired trials. Neuromagnetic data were recorded on a 275-channel CTF system at 600 Hz (0–300 Hz bandwidth), visually inspected for artefacts, bandpass filtered 1–58 Hz and epoched −100 to 1,000 ms. Source localisation targeted induced gamma-band activity (30–58 Hz) using the multiple sparse priors routine in SPM12, identifying task-activated regions which guided region-of-interest (ROI) selection. Dynamic causal modelling employed the conductance-based CMM_NMDA neural mass model in SPM12 to estimate receptor-specific (AMPA, NMDA, GABA) connectivity parameters and time constants, and intrinsic cell-population interactions. Four left-lateralised ROIs were modelled: early visual cortex, fusiform cortex, amygdala and inferior frontal gyrus, with thalamic input driving early visual cortex. Two plausible connectivity architectures were compared using Bayesian model selection: a hierarchical ventral-stream model (Model 1) and a model adding direct forward and reciprocal connections between early visual cortex and inferior frontal gyrus (Model 2). DCMs were fit to evoked responses over 1–500 ms and 1–50 Hz; posterior estimates from an iterative inversion procedure were extracted for the winning model. Group, drug and group-by-drug effects on all parameters were tested using a second-level parametric empirical Bayes approach, with parameters deemed meaningful at posterior probability Pp > 95%. Finally, exploratory post-hoc correlations examined whether baseline-to-ketamine parameter changes in TRD participants related to MADRS change from baseline to 230 minutes, using pairwise linear correlations and a liberal significance threshold (p < 0.05 uncorrected).
This study used MEG recordings collected while participants completed a dot probe task with emotional faces in tandem with DCM to probe ketamine's effects in individuals with TRD and healthy volunteers. The goal was to measure changes in effective (causal) connectivity within and between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus, in addition to changes in AMPA, GABA, and NMDA receptor time constants, following ketamine administration. We were particularly interested in ketamine's effects in the amygdala, a key region implicated in the pathophysiology of depressiondemonstrating upregulation to positive faces and downregulation to negative faces during an attentional dot probe task following ketamine administration. Clinically, we found significantly reduced depressive symptoms in our TRD sample post-ketamine, consistent with previous findings. Controlling for the period-specific baseline and the participant-average baseline, ketamine was found to result in a 5.37-point reduction in MADRS score in the TRD sample. Behaviorally, no differences in reaction time bias scores were observed on the task. However, accuracy differences were observed between the two groups, with TRD participants significantly more accurate than healthy volunteers during the task. In addition, session effects were noted with regard to accuracy rates, with the best performance occurring during the baseline session, followed by the ketamine and then placebo sessions. Importantly, post-hoc tests found significant differences in accuracy between the baseline and placebo sessions only. These findings suggest that healthy volunteers were less engaged in the task and therefore did not perform as well as the TRD participants. In addition, task repetition led to poorer performance, especially following placebo saline infusion, where participants were perhaps least motivated to perform well-during the scan procedures. We modeled induced gamma-band activity during the dot probe task, identifying a network of brain regions involved in the task. We also modeled regions showing an effect of infusion (ketamine vs. placebo) and found increased gamma Parametric empirical Bayes was used to identify the mixing of parameters that contributed to the effect of group. Note that the timing of data collection (6-9 h post-ketamine administration) occurred past the half-life of ketamine. Meaningful parameters were defined as those with a posterior probability (Pp) >95%. Ten parameters were found to significantly contribute to group effects. These included the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) time constant within the amygdala (Amy), gamma aminobutyric acid (GABA) time constants within the fusiform gyrus (Fusi) and inferior frontal gyrus (IFG), and N-methyl-D-aspartate (NMDA) time constants within the early visual cortex (EV) and IFG. In addition, the inhibitory self-connections on spiny stellate cells (ss) within the EV, Fusi, and IFG differed between groups, as did the inhibitory self-connection on superficial pyramidal cells (sp) within the Fusi, and the excitatory connections between sp and deep pyramidal cells (dp) in the Amy. Finally, the inhibitory self-connection on inhibitory interneurons (ii) in the EV showed a group effect, though not at our threshold. *Pp > 0.95. Parametric empirical Bayes was used to identify the mixing of parameters that contributed to the effect of drug. Meaningful parameters were defined as those with a probability (Pp) >95%. Nine parameters were found to significantly contribute to drug effects. These included the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) time constant within the early visual cortex (EV), gamma aminobutyric acid (GABA) time constants within the amygdala (Amy) and inferior frontal gyrus (IFG), and N-methyl-D-aspartate (NMDA) time constants within the EV, Amy, and IFG. In addition, the excitatory connections between superficial pyramidal cells (sp) and deep pyramidal cells (dp), and the inhibitory connections between inhibitory interneurons (ii) and sp differed following ketamine in the EV, as did excitatory connections between spiny stellate cells (ss) and ii in the IFG. Finally, the inhibitory self-connection on ss in the IFG showed a drug effect, though not at our threshold. *Pp > 0.95. power in the amygdala post-ketamine vs. placebo for both TRD participants and healthy volunteers. These findings are in keeping with preclinical studies suggesting increased cortical excitation following ketamine administration, due to NMDA inhibition reducing the activity of putative GABA interneurons. At a delayed rate, this increases the firing rate of pyramidal neurons due to enhanced AMPA throughput (15) that, in turn, leads to increased cortical excitation. Given that gamma power in the amygdala showed a drug-specific effect, with increased cortical excitation post-ketamine, this suggests that increased cortical excitation in this key emotional face processing region may be related to previous reports of normalization of emotional processing following drug administration. Notably, normalization of amygdalar activity post-ketamine was previously described in an fMRI study that included an attentional dot probe task with emotional faces in TRD participants, though this was not specifically examined in the present study. Two plausible models of message passing between the early visual cortex and the inferior frontal gyrus were subsequently Parametric empirical Bayes was used to identify the mixing of parameters that contributed to group by drug interactions. Meaningful parameters were defined as those with a probability (Pp) >95%. Nine parameters were found to significantly contribute to group by drug effects. These included gamma aminobutyric acid (GABA) time constants within the early visual cortex (EV) and N-methyl-D-aspartate (NMDA) time constants within the EV, fusiform cortex (Fusi), and amygdala (Amy). In addition, the inhibitory self-connections on spiny stellate cells (ss) and inhibitory interneurons (ii), as well as inhibitory connections between ii and ss in the EV showed group by drug interactions. Excitatory connections between deep pyramidal cells (dp) and ii in the Amy, in addition to inhibitory self-connections on superficial pyramidal cells (sp) in the inferior frontal gyrus (IFG) also showed group by drug interactions. * Pp > 0.95. fit. A model that included traditional feedforward processing along the ventral stream to the amygdala in tandem with feedforward connections from the early visual cortex to the inferior frontal gyrus provided the best model fits, in line with ideas that top-down predictions serve to constrain bottom-up signal propagation. All fitted parameters were subsequently extracted, and a Bayesian modeling extension of DCM was used to test for meaningful parameters contributing to the group effect, drug effect, and group by drug interactions. Here, we focus on discussing group by drug interactions, as these are identified parameters where ketamine had differential effects between TRD participants and healthy volunteers. Four modeled receptor time constants showed group by drug interactions, including the GABA and NMDA time constants in the early visual cortex and the NMDA time constants in the fusiform cortex and amygdala. In the early visual cortex, ketamine administration led to faster GABA and NMDA transmission estimates for TRD participants, while GABA transmission slowed for healthy volunteers postketamine. In the fusiform cortex, faster NMDA transmission followed ketamine administration for TRD participants, though the rate of transmission slowed for healthy volunteers postketamine. Interestingly, a slowing of NMDA transmission was observed in the amygdala post-ketamine for both TRD and healthy volunteers, though healthy volunteers had significantly faster NMDA transmission at baseline/placebo than TRD participants. As the amygdala ROI was identified based on the effect of infusion (ketamine vs. placebo), slowing of NMDA transmission within this region is clearly related to drug effects. Although no association was noted between NMDA transmission in the amygdala and antidepressant response within our sample, future studies should examine whether these changes in NMDA time constants are related to other clinical measures of mood changes following drug administration. In addition to changes in receptor time constants, group by drug interactions were found for modeled intrinsic connectivity within the early visual cortex, amygdala, and inferior frontal gyrus. In the early visual cortex, three intrinsic connection parameters showed group by drug changes in inhibitory drive. First, decreased GABAergic inhibitory drive on self-connections were found for both inhibitory interneurons and spiny stellate cells following ketamine in the TRD participants, while healthy volunteers demonstrated increased GABAergic inhibitory drive post-ketamine. These self-connections reflect gain or precision of different cell types, suggesting reductions in self-gain on inhibitory interneurons and spiny stellate cells following ketamine administration in the TRD group. Second, reduced inhibitory drive was observed on the intrinsic connection from inhibitory interneurons to spiny stellate cells in the early visual cortex in our TRD and healthy volunteers. Third, ketamine increased the excitatory drive from deep pyramidal cells to inhibitory interneurons in the amygdala in TRD participants, while healthy volunteers showed reduced excitatory drive for this connection post-ketamine. Finally, ketamine also reduced the inhibitory self-gain on superficial pyramidal cells in the inferior frontal gyrus in our healthy volunteers only. Interestingly, these findings all reflect changes in intrinsic connectivity that regulate or modulate inhibition locally. Within the amygdala in particular, increased excitatory drive onto inhibitory interneurons for TRD participants seems at odds with an increased state of excitability within this region; however, similar accounts of increased pyramidal-to-inhibitory interneuron drive have previously been reportedand are thought to reflect a link between increased pyramidal cell excitability locally and downstream effects of increased gamma power. Separately, we tested whether any meaningful parameters identified in our analysis of group effects, drug effects, or group by drug interactions were associated with antidepressant response in our TRD participants. We specifically examined changes in parameter estimates from the baseline to ketamine sessions (baseline minus ketamine) and correlated them with change in MADRS score from baseline to 230 min post-ketamine (the time point closest to the MEG recording session). Two parameters were found to be associated with antidepressant response, both in the early visual cortex. The first was the AMPA time constant in the early visual cortex, where faster AMPA transmission post-ketamine was associated with better antidepressant response. The second was inhibitory selfgain on spiny stellate cells in the early visual cortex, where larger self-inhibition on spiny stellate cells post-ketamine was associated with better antidepressant response. The findings of an association between AMPA transmission and antidepressant response are particularly striking because AMPA receptor throughput following NMDA receptor blockade) is thought to result in delayed increases in synaptic potentiation and synaptogenesis, key mechanisms associated with ketamine's antidepressant effects. Similar associations between AMPA receptor connectivity and antidepressant response were also previously reported in a time window overlapping with our MEG recordings. One important limitation of this study is that MEG recordings were not collected during or immediately following infusions, but rather 6-9 h following ketamine administration in order to avoid side effects while measuring therapeutic drug effects. Thus, we cannot comment on acute changes in modeled parameter estimates. However, studies of ketamine's acute effects in healthy volunteers suggest robust changes in both gamma powerand AMPA and NMDA receptor drive (30) during ketamine infusion. Future studies should explore ketamine's acute effects in TRD participants to better understand the mechanisms via which ketamine reduces depressive symptoms. Another limitation is that we set a liberal criteria of p < 0.05 uncorrected for determining whether modeled parameters were associated with antidepressant response. Though this increases the likelihood of false positives, previous findings have demonstrated associations between AMPA parameters and antidepressant response in TRD. In addition, our study included secondary analyses of data collected during a clinical trial of ketamine's mechanisms of actions, and we limited our sample to participants having baseline, post-ketamine, and postplacebo scan data. Additional work should include a larger sample of study participants to model effective connectivity during a task probing attentional bias toward emotional faces, in order to better characterize effective connectivity changes in regons of the emotion processing network following ketamine administration.
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Papers in Blossom that reference this study
Nakajima, W., Hatano, M., Ohtani, Y. et al. · Molecular Psychiatry (2026)
Sample and clinical effects: Nineteen TRD participants and 15 healthy volunteers completed the analyses with MEG data at all three sessions. Clinically, ketamine produced a significant antidepressant effect in the TRD group at 230 minutes post-infusion compared with placebo: t(18) = 2.07, p < 0.05, with an estimated MADRS reduction of 5.37 points (SE = 2.28; 95% CI: −0.05 to +9.48). Reported mean MADRS values were ketamine pre-infusion 33.37 ± 4.39 and 230 min 26.95 ± 11.06; placebo pre-infusion 32.26 ± 4.79 and 230 min 31.21 ± 5.03. Behavioural task performance: No significant effects emerged on reaction time bias scores. Accuracy rates showed main effects of group (F = 14.43, p < 0.01) and session (F = 3.58, p < 0.05). TRD participants were more accurate (mean 94.2%) than healthy volunteers (mean 88.8%). Across sessions accuracy was highest at baseline (94.2%), intermediate after ketamine (91.6%) and lowest after placebo (89.8%); post-hoc tests (Bonferroni-corrected) found a significant difference between baseline and placebo (t = 3.45, p < 0.05). Source-level gamma activity: Group-level source localisation of induced gamma-band (30–58 Hz) responses revealed a network including bilateral early visual cortices, fusiform gyrus and regions of parietal and frontal cortex including inferior frontal gyrus. At a liberal threshold (p < 0.05 uncorrected) a left-lateralised amygdala response distinguished ketamine from placebo; subsequent DCM analyses therefore focused on a left-lateralised network comprising early visual cortex, fusiform cortex, amygdala and inferior frontal gyrus. Increased gamma power in the amygdala post-ketamine relative to placebo was reported for both TRD participants and healthy volunteers. DCM model selection and parameter-level findings: Bayesian model selection favoured Model 2, which added direct forward and reciprocal connections between early visual cortex and inferior frontal gyrus. Parametric empirical Bayes identified parameters with posterior probability Pp > 95% contributing to group, drug, and group-by-drug effects. Group-by-drug receptor time-constant effects: Four receptor time constants showed meaningful group-by-drug interactions: the GABA time constant in early visual cortex, and NMDA time constants in early visual cortex, fusiform cortex and amygdala. Interpreting time constants as inverse rate parameters, TRD participants showed faster GABA and NMDA transmission in early visual cortex post-ketamine, whereas healthy volunteers showed slower GABA transmission coupled with faster NMDA transmission after ketamine. In the fusiform cortex, NMDA transmission accelerated for TRD participants post-ketamine but slowed for healthy volunteers. The amygdala exhibited slower NMDA transmission post-ketamine in both groups; healthy volunteers had faster baseline/placebo NMDA transmission in the amygdala than TRD participants. Intrinsic connectivity group-by-drug effects: Five within-region (intrinsic) connections showed meaningful group-by-drug interactions: three in early visual cortex, one in amygdala and one in inferior frontal gyrus. In early visual cortex, TRD participants showed decreased self-inhibitory drive on spiny stellate cells and inhibitory interneurons after ketamine, while healthy volunteers exhibited increased self-inhibition on these cell types post-ketamine. Both groups showed reduced inhibitory drive from inhibitory interneurons to spiny stellate cells in early visual cortex following ketamine. In the amygdala, TRD participants demonstrated increased excitatory drive from deep pyramidal cells to inhibitory interneurons after ketamine, whereas healthy volunteers showed decreased excitatory drive on this connection. In inferior frontal gyrus, ketamine reduced the inhibitory self-connection of superficial pyramidal cells in healthy volunteers only. Parameters associated with antidepressant response: In exploratory analyses restricted to TRD participants, two baseline-to-ketamine changes correlated with clinical improvement (change in MADRS from baseline to 230 minutes). Faster AMPA transmission (shorter AMPA time constant) in early visual cortex post-ketamine correlated with better antidepressant response (r = 0.4917, p < 0.05). Greater increase in self-inhibitory drive of spiny stellate cells in early visual cortex post-ketamine was associated with better response (r = −0.6545, p < 0.01). The investigators note these correlations used an uncorrected liberal threshold and are exploratory.
Gilbert and colleagues interpreted their findings as evidence that ketamine produces measurable changes in receptor-related time constants and intrinsic inhibitory/excitatory connectivity in a visual–emotion processing network, and that some of these changes relate to clinical improvement in TRD. The investigators highlight four receptor time-constant effects showing group-by-drug interactions: faster GABA and NMDA transmission in early visual cortex for TRD participants post-ketamine, faster NMDA transmission in fusiform cortex for TRD, and slowed NMDA transmission in amygdala for both groups after ketamine. Increased gamma power in the amygdala post-ketamine was taken as congruent with preclinical models linking NMDA antagonism of interneurons to net cortical disinhibition and enhanced AMPA-mediated excitation, which could underlie normalization of emotional processing. At the level of intrinsic connectivity, the reported pattern emphasises ketamine-related modulation of local inhibitory gain. In early visual cortex, decreased self-inhibition on spiny stellate cells and interneurons in TRD participants contrasted with increased self-inhibition in healthy volunteers, while both groups showed reduced interneuron-to-stellate inhibition after ketamine. The amygdala effect—greater deep pyramidal to interneuron excitatory drive in TRD post-ketamine—was discussed as potentially reflecting increased local pyramidal excitability linked to downstream increases in gamma power. The investigators saw the association between faster AMPA transmission and better antidepressant response as supportive of theories that AMPA throughput after NMDA blockade promotes synaptic potentiation and synaptogenesis, mechanisms implicated in ketamine's antidepressant action. The authors acknowledge limitations that temper interpretation. MEG recordings were obtained 6–9 hours post-infusion to avoid acute side effects, so acute pharmacodynamic effects during infusion were not captured. The exploratory correlations used a liberal uncorrected threshold (p < 0.05), increasing the risk of false positives. The sample was a subset selected for complete data at all three sessions, limiting sample size and generalisability. The authors recommend future studies with larger samples and designs that probe both acute and delayed effects to better characterise ketamine's temporal dynamics on receptor- and circuit-level parameters. They also emphasise the utility of DCM combined with MEG for modelling receptor-specific and cell-population level changes associated with ketamine administration.
Ketamine administration led to changes in modelled GABA and NMDA time constants and altered estimates of intrinsic excitatory and inhibitory connectivity within regions involved in visual processing of emotional faces. Associations between faster AMPA transmission and clinical improvement in TRD participants align with hypotheses that AMPA throughput contributes to ketamine's antidepressant effects. The investigators conclude that DCM applied to MEG data is a useful approach for modelling connectivity changes linked to ketamine administration.