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Resting-state connectivity studies as a marker of the acute and delayed effects of subanaesthetic ketamine administration in healthy and depressed individuals: A systematic review:

Resting-state connectivity studies as a marker of the acute and delayed effects of subanaesthetic... Acute ketamine administration has been widely used in neuroimaging research to mimic psychosis-like symptoms. Within the last two decades, ketamine has also emerged as a potent, fast-acting antidepressant. The delayed effects of the drug, observed 2–48 h after a single infusion, are associated with marked improvements in depressive symptoms. At the systems’ level, several studies have investigated the acute ketamine effects on brain activity and connectivity; however, several questions remain unanswered around the brain changes that accompany the drug’s antidepressant effects and how these changes relate to the brain areas that appear with altered function and connectivity in depression. This review aims to address some of these questions by focusing on resting-state brain connectivity. We summarise the studies that have examined connectivity changes in treatment-naïve, depressed individuals and those studies that have looked at the acute and delayed effects of ketamine in healthy and depressed volunteers. We conclude that brain areas that are important for emotional regulation and reward processing appear with altered connectivity in depression whereas the default mode network presents with increased connectivity in depressed individuals compared to healthy controls. This finding, however, is not as prominent as the literature often assumes. Acute ketamine administration causes an increase in brain connectivity in healthy volunteers. The delayed effects of ketamine on brain connectivity vary in direction and appear to be consistent with the drug normalising the changes observed in depression. The limited number of studies however, as well as the different approaches for resting-state connectivity analysis make it very difficult to draw firm conclusions and highlight the importance of data sharing and larger future studies. Keywords Ketamine, resting state, acute ketamine changes, delayed ketamine effects, major depressive disorder Received: 30 December 2020; accepted: 24 September 2021 by commonly prescribed antidepressant medication (Berman Introduction et al., 2000). While current antidepressant medications typically Ketamine is a N-methyl-d -aspartate receptor (NMDA) receptor take several weeks to produce a detectable clinical effect, antagonist which is commonly prescribed as an anaesthetic and is also used recreationally. In research, ketamine has been widely Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology used as a model of psychosis in both animal as well as human and Neuroscience, King’s College London, London, UK studies (Frohlich and Van Horn, 2014). Within minutes of admin- GKT School of Medical Education, London, UK istration, subanaesthetic doses of ketamine produce strong dis- University of Sussex, Brighton, UK sociative effects that have been described as psychosis-like symptoms (Krystal et al., 2005). Several studies have investi- Corresponding authors: gated these acute effects of ketamine in the brain which include Vasileia Kotoula, Centre for Neuroimaging Sciences, Institute of widespread increases in metabolism, blood flow and blood oxy- Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK. gen level–dependent (BOLD) signal (Bryant et al., 2019; Lally Email: vasileia.kotoula@kcl.ac.uk et al., 2015; Mueller et al., 2018). During the last two decades, ketamine has emerged as a potent, fast-acting antidepressant, Mitul Mehta, Centre for Neuroimaging Sciences, Institute of Psychiatry, currently licenced for Treatment-Resistant Depression (Schwartz Psychology and Neuroscience, King’s College London, London SE5 8AF, et al., 2016; Zarate et al., 2006). The antidepressant effects of UK. ketamine appear to be different compared to the effects produced Email: mitul.mehta@kcl.ac.uk Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Brain and Neuroscience Advances ketamine’s antidepressant action has been detected within hours 2 h post its administration (delayed effects). A total of 15 studies of drug administration and can last on average, up to 1 week after looking at the acute effects of ketamine in healthy participants a single infusion (Zarate et al., 2006). were identified whereas only three studies that reported the Several studies have focused on the molecular mechanisms delayed effects of ketamine in healthy participants were found. that may underlie the antidepressant effects of ketamine in the Finally, we searched for studies that have administered ketamine brain (for review, see Zanos and Gould, 2018). At the systems’ as an antidepressant treatment and have used resting-state MRI to level, the delayed effects that accompany the antidepressant examine the brain changes during the antidepressant effects time action (2–24 h after infusion) are only now beginning to be window. The terms we have used for this search were ‘antide- understood. Several key outstanding questions need to be pressant’ and ‘ketamine’, ‘depression’ and ‘resting state’. A total addressed in order to comprehend ketamine’s antidepressant of five studies fulfilled our research criteria and are included in effects in the brain. Are the brain areas sensitive to acute drug this review. In addition to our online search, we also used refer- administration different from those areas that are sensitive to the ence lists from the identified articles, reviews and meta-analyses delayed effects? Are the brain changes produced by ketamine to find additional articles not indexed by PubMed. The number of directly targeting areas affected in depression or is ketamine’s studies which fulfilled the inclusion criteria of this review was antidepressant action demonstrated in a more indirect manner? relatively low, and therefore, we decided not to use a sample size At the systems’ level, neuroimaging studies are beginning to criterion in decisions to exclude studies. This allowed a more chart these effects. While important insights may be gained from complete overview of the published literature, but this limitation other modalities, such as positron emission tomography (PET) or should be taken into account when the results of those studies are task-based magnetic resonance imaging (MRI), this review will presented, and conclusions are drawn. However, this mainly focus on the resting-state studies since this methodology has affected the healthy volunteer studies. We also did not exclude been more widely employed to examine not only the connectivity any studies based on the connectivity methodology that they changes observed in major depressive disorder (MDD) but also have followed as long as sufficient details about the data process- the acute and delayed effects of ketamine’s administration in ing and analysis were provided in the appropriate section. All the healthy and depressed volunteers. articles in this article were judged by all the authors to meet rigor- In this systematic literature review, we aim to (1) summarise ous scientific standards. Figure 1 provides a summary of all the reported changes in connectivity in unmedicated patients with studies that were identified, screened and selected to be part of depression, (2) present reported effects of ketamine on brain con- this review. nectivity in healthy participants and (3) report the effects of keta- mine on brain activity in patients with depression. For the purpose Results of this review, we use the term ‘delayed effects’ to describe any post-acute changes in brain connectivity that occur 2 h to 2 weeks Connectivity changes in treatment-naïve MDD after the drug’s administration. When those ‘delayed effects’ con- patients cern MDD patients, they also reflect the antidepressant actions of the drug. By describing the patterns of brain connectivity in Subcortical regions of interests depression and ketamine’s effects on the healthy and depressed Subcortical brain areas – namely, the ventral caudate (Yang and brain, we hope to identify potential systems-level mechanisms Wang, 2017), the nucleus accumbens (ΝA) (Gong et al., 2017) for ketamine’s delayed effects which can serve as candidates for and the amygdala (Wei et al., 2016) – were used as seed regions understanding rapid-acting antidepressant mechanisms. to investigate connectivity changes in depressed patients com- pared to healthy controls (HCs). The ventral caudate, bilaterally, showed increased Methods Functional Connectivity (FC) with the right cuneus in the We followed the PRISMA guidelines for a systematic review and MDD group (n = 40) compared to healthy participants (n = 36). performed a Medline and Web of Science search for articles up to However, the FC of the right ventral caudate with the right 1 September 2020. Overall, we conducted three main searches. middle temporal gyrus and the left ventral caudate with the Our first search focused on the identification of studies that have right superior parietal lobule and right superior frontal gyrus used resting-state MRI to investigate connectivity in treatment- was significantly reduced in MDD patients (Yang and Wang, naïve depressed patients. For that purpose, we have used the 2017). When the functional coupling of the reward circuits in search terms ‘depression’, ‘drug-naïve’, ‘treatment-free’ ‘resting patients with MDD (80 patients and 43 HCs) was examined, state’ and ‘imaging’. Studies with participants who were in their the right NA presented with decreased positive FC with the left in the first-episode depressed and drug-naïve or chronically superior temporal gyrus, insular lobe, bilateral middle orbital depressed but with no history of antidepressant treatment were frontal cortex (OFC), left medial OFC and rostral anterior cin- included in our review. A total of 12 studies that fulfilled our gulate cortex (ACC) (Gong et al., 2017). Negative FC between research criteria were identified and included in this review. In the NA, the bilateral dorsal medial prefrontal cortex (DMPFC) order to identify studies that examined the acute and delayed and the left dorsal ACC was also identified in the HC group effects of ketamine with the use of resting-state MRI, we entered and was significantly reduced in depression (Gong et al., the search terms ‘ketamine’, ‘healthy’, ‘resting state’ and ‘imag- 2017). The connectivity of the bilateral amygdala with the ven- ing’. We then separated those studies into those that have scanned tral prefrontal cortex (VPFC) as well as the dorsal lateral pre- participants right after the administration of the drug (acute frontal cortex (DLPFC) was also reduced in the MDD group effects) and those that have studied the effects of the drug at least (49 patients and 50 HCs) (Wei et al., 2016). Kotoula et al. 3 Figure 1. The PRISMA flow diagram shows the process that was followed in order to identify relevant publications for our literature review. From the 166 studies initially identified, 35 fulfil our inclusion criteria and are described in our review. areas including the superior and inferior frontal gyrus, the pre- Cortical region of interests. When the between connectivity of central gyrus and OFC presented with decreased connectivity 90 region of interests (ROIs) was examined and compared with frontal and parietal cortical areas as well as the fusiform between depressed and healthy volunteers, several cortical gyrus and the precuneus (for more details see Table 1). regions presented with increased connectivity in MDD (n = 15) The insula bilaterally presented with decreased connectivity in compared to HCs (n = 37). These areas included, the left hippo- the depressed (n = 44) compared to healthy individuals (n = 44) campus which presented with increased connectivity with the with the left middle frontal gyrus, left superior temporal gyrus and right parahippocampal gyrus, the right inferior frontal gyrus left superior temporal pole as well as the middle occipital gyrus which presented with increased connectivity with the right infe- (Guo et al., 2015). Negative FC was found between the left hip- rior OFC, as well as the right cuneus that was hyperconnected to pocampus and the bilateral middle frontal gyrus, the right hip- the left superior occipital gyrus (Tao et al., 2013). Brain areas that pocampus and the right inferior parietal lobule as well as the right presented with decreased connectivity between the MDD and HC cerebellum. The magnitude of negative FC was smaller in MDD group included the bilateral insula which presented with (n = 42) compared to the control subjects (n = 32) (Cao et al., 2012). decreased connectivity with the bilateral putamen. Several brain 4 Brain and Neuroscience Advances Table 1. Connectivity studies with MDD, drug-naïve volunteers are summarised in this table based on the connectivity methodology that each study has used. The methodology, aims and hypotheses as well as a brief description of the main findings are included for each study. Connectivity analysis in treatment-naïve, MDD patients Seed-based functional connectivity Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Yan et al. First-episode, drug- 33 ROIs were selected to examine DMN within-network FC using To identify abnormal FC patterns DMN connectivity (2019) naïve MDD patients, LMM (Linear Mixed Models) associated with the DMN across First-episode, drug-naïve patients > HC – no significant difference. n = 318. Reproducibility of the analysis assessed by: cohorts and investigate whether First-episode, drug-naïve patients > first-episode, on-meds patients – con- HC, n = 394. Using different atlases episode type, medication status, nectivity within the DMN. These patients form Finer parcellations illness severity and illness dura- First-episode, drug-naïve patients > recurrent, on-meds patients – con- part of a larger cohort Performing meta-analysis instead of LMM tion contributed to abnormali- nectivity within the DMN. of 1300 MDD patients Use of global signal regression ties. Exploratory analysis (826 female). Use of scrubbing in addition to 24 motion parameters First-episode, drug-naïve patients < HC – connectivity within the VN. Exploratory network analysis of within and between connectivity First-episode, drug-naïve patients < recurrent, on-meds patients – connec- included: tivity between the VN and the SMN and between the SMN and DAN. Visual Network (VN) Sensory Motor Network (SMN) Dorsal Attention Network (DAN) Ventral Attention Network (VAN) Subcortical Network (SN) Frontoparietal Network (FN) Yang and First-episode MDD The seeds selected for the FC analysis included: MDD patients would express MDD > HC Wang patients, n = 40 (21 Bilateral Ventral Caudate (VC) greater abnormalities in the Right VC with the right Occipital Lobe, Cuneus (2017) males). Superior Temporal Gyrus (STG) VC and increased connectivity Left VC with the right Occipital Lobe, Cuneus Three participants were The time course of these seed regions was correlated with the between the STG and the cuneus Left STG with the left Parietal Lobe, the Precuneus, the right Angular Gyrus, excluded. entire brain. and precuneus. the left Occipital Lobe and the Cuneus HC, n = 36 (17 males). MDD < HC Four participants were Right VC with the right Middle Temporal Gyrus excluded. Left VC with the right Superior Parietal Lobule and the right Superior Frontal Gyrus Gong et al. First-episode MDD The left and right Nucleus Accumbens (NA) were used as seeds and Dysfunctional reward circuits in MDD < HC (2017) patients, n = 80 (33 examine separately. the NA would contribute to cog- Left NA with the left Bilateral Caudate, the left Medial and Middle Orbital males). The time course of the seed regions was correlated with the rest nitive deficits in depression. Frontal Cortex, the left Rostral ACC, the left Superior Temporal Gyrus and the Five participants were of the brain. Insular Lobe. excluded. Right NA with the left Superior Temporal Gyrus, the Insular Lobe, the Bilateral HC, n = 43 (23 males). Middle Orbital Frontal Cortex, the right ACC and the left Medial Orbital Cortex. One participant was MDD > HC excluded. Right NA with the right Bilateral Dorsal Medial Prefrontal Cortex and the left Dorsal ACC. Guo et al. MDD patients, n = 44 The time course of the bilateral insular cortex seeds was correlated Altered rsFC of the insula with MDD < HC (2015) (22 males). with the rest of the brain. the rest of the brain between Right Insula with the left Middle Frontal Gyrus, the left Superior Temporal HC, n = 44 (20 males). MDD patients and controls. Gyrus and the right Putamen. Left Insula with the right Middle Occipital Gyrus, the left Superior Temporal Pole and the right Middle Occipital Gyrus. (Continued) Kotoula et al. 5 Table 1. (Continued) Connectivity analysis in treatment-naïve, MDD patients Seed-based functional connectivity Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Guo et al. MDD patients, n = 44 The time course of the Bilateral Crus I was correlated with the rest Increased Crus I-DMN connectiv- MDD > HC (2015) (22 males). of the brain. ity. Right Crus I with the right Inferior Frontal Cortex, the right Superior Tempo- HC, n = 44 (20 males). ral Pole, the bilateral MPFC and the left Middle Temporal Gyrus. Cao et al. MDD patients, n = 42 The time course of the Bilateral hippocampal seeds was corrected Abnormal FC pattern of the hip- MDD > HC (2012) (18 males). with the rest of the brain. pocampus with the cortical-limbic Left Hippocampus with the Bilateral Middle Frontal Gyrus. HC, n = 32 (17 males). circuits in MDD. Right Hippocampus with the right Inferior Parietal Lobule and the right Cerebellar Tonsil. ICA (independent component analysis) Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Zhu et al. MDD patients, n = 37 ICA was conducted and a template of the DMN was used to exam- Dissociated connectivity pattern Within the DMN (2012) (17 males). ine connectivity changes between the two groups. between anterior and posterior MDD > HC Five participants were parts of the DMN. Dorsal MPFC/Ventral ACC, Ventral MPFC and the Medial Orbital PFC. excluded. MDD < HC HC, n = 37. PCC/Precuneus, Right AG and the left AG/Precuneus. Four participants were excluded. Veer et al. MDD patients, n = 23 The following ICA networks were identified and compared between Altered connectivity in the Within the Medial Visual Network* (RSN3) MDD < HC (2010) (8 males). the two groups: resting-state network (RSN) that Four participants were Primary Visual Network. includes brain areas associated Lingual Gyrus with the rest of the network. Within the Auditory Network** (RSN12) excluded. Lateral Visual Network. with affective (ventral PFC, limbic HC, n = 19 (8 males). Medial Visual Network. areas) and cognitive (lateral PFC, MDD < HC parietal areas) as well as net- Amygdala and Left Insula with the rest of the network and the right Sensory–Motor Network. Right Lateral Network. works that show corticostriatal Superior Temporal Gyrus. connectivity. MDD > HC (within the network) Left Lateral Network. Precuneus. Right Inferior Frontal Gyrus. Between the Task Positive (attention and working memory) Ventral Stream Network. Medial Temporal Network. Network***(RSN11) and the rest of the brain MDD < HC Salience Network. Task Positive Network. The left Frontal Pole with the rest of the network. Auditory Network. Default Mode Network. (Continued) 6 Brain and Neuroscience Advances Table 1. (Continued) ROI-to-ROI Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Zhu et al. First-episode MDD The following ROIs of the DMN were defined and included: MDD patients would exhibit Between the DMN ROIs (2017) patients, n = 33 (14 Anterior medial Prefrontal Cortex (MPFC). altered connectivity in the DMN Within system connectivity in the DMPFC subsystem males). Posterior Cingulate Cortex (PCC). subsystems. MDD > HC – DMPFC-Temp and TPJ-LTC. Two participants Dorsal Medial Prefrontal Cortex (DMPFC) Inter system connectivity between the DMPFC and Medial Temporal Lobe (MTL) excluded due to head Temporo-parietal junction (TPJ). subsystems motion. Lateral Temporal Cortex (LTC). MDD > HC – TPJ-PHC (inter-system connectivity between the DMPFC and HC, n = 33 (15 males). Temporal Pole (TempP). MTL subsystems), LTC-PHC (inter-system connectivity between the DMPFC One participant Ventral MPFC. and MTL subsystems), TempP-vMPFC (inter-system connectivity between excluded due to head Retrosplenial cortex (Rsp). the DMPFC and MTL subsystems), TempP-pIPL (inter-system connectivity motion. posterior Inferior Parietal Lobule (pIPL). between the dMPFC and MTL subsystems), TempP-Rsp (inter-system connec- Parahippocampal Cortex (PHC). tivity between the DMPFC and MTL subsystems), TempP-PHC (inter-system Hippocampal Formation (HF). connectivity between the DMPFC and MTL subsystems). The three DMN subsystems were defined as Within the DMN subsystems Midline core: anterior MPFC and PCC. MDD > HC – DMPFC subsystem. DMPFC subsystem: DMPFC, TPJ, LTC and TempP. Between the DMN subsystems MTL subsystem: vMPFC, pIPL, Rsp, PHC, HF. MDD > HC – DMPFC subsystem – MTL subsystem. Wei et al. First-episode MDD Correlation analysis between the bilateral amygdala ROI and Altered connectivity between the MDD < HC (2016) patients, n = 49 (17 bilateral PFC mask including Brodmann area 9–12, 24, 25, 32 and amygdala – PFC and amygdala Amygdala – VPFC and DLPFC. males). 44–47. – DLPFC in MDD. HC, n = 50 (17 males). Tao et al. First-episode MDD Connectivity analysis To unambiguously identify key MDD > HC (2013) patients, n = 15 (8 The whole brain was parcellated in 90 ROIs based on the anatomi- connections which are modified Left Hippocampus – Right Parahippocampal Gyrus, Right Inferior Frontal males). cal labelling atlas and the time series of these ROIs were compared in depressed patients. Gyrus – Right Inferior Orbitofrontal Cortex, Right Medial Frontal Gyrus HC, n = 37 (8 males). between the two groups. – Right Inferior Frontal Gyrus, Right Cuneus – Left Superior Occipital Gyrus and the Right Superior Orbitofrontal Cortex – Right Inferior Orbitofrontal Cortex. MDD < HC Bilateral Insula – Bilateral Putamen, Left Superior Frontal Gyrus – Right Insula, Left Precentral Gyrus – Left Inferior Frontal Gyrus, Right Inferior Frontal Gyrus – Right Supramarginal Gyrus, Left Precentral Gyrus – Left Inferior Parietal Lobule. Right Lingual Gyrus – Right Fusiform Gyrus, Right Angular Gyrus – Right Precuneus and the Left Superior Orbitofrontal Cortex – Left Inferior Orbitofrontal Cortex. (Continued) Kotoula et al. 7 Table 1. (Continued) Other connectivity techniques Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Wang et al. First-episode MDD ALFF (Amplitude of Low-Frequency Fluctuations) and fALFF (frac- Altered low frequency amplitude ALFF results (2012) patients, n = 18 (9 tional ALFF) analysis was performed and differences between the found widely across brain regions MDD > HC males). two groups were explored. linked with PFC, temporal, pari- Right Fusiform Gyrus, Right Anterior Lobe of the Cerebellum and the Right HC, n = 18 (9 males). etal, occipital and limbic regions. Posterior Lobe of the Cerebellum. MDD < HC Left Inferior Temporal Gyrus, Bilateral Inferior Parietal Lobule and the Right Lingual Gyrus. fALFF results MDD > HC Right Precentral Gyrus, Bilateral Fusiform Gyrus, Bilateral Anterior Lobes of the Cerebellum and the Bilateral Posterior Lobes of the Cerebellum. MDD < HC Left Dorsolateral Prefrontal Cortex, Bilateral Medial Orbitofrontal Cortex, Bilateral Middle Temporal Gyrus, Left Inferior Temporal Gyrus and the Right Inferior Parietal Lobule. Zhang et al. First-episode MDD Graph connectivity theory trying to examine the topological Disrupted topological organisa- MDD > HC (2011) patients, n = 31 (8 organisation of functional brain networks in MDD and compare tion of intrinsic functional brain Decreased path length and increased global efficiency imply a disturbance males). them to HC. networks. of the normal global integration of whole-brain networks. One participant was Increased nodal centralities were observed in the Caudate Nucleus and the excluded. DMN. HC, n = 64(30 males). Decreased nodal centralities were observed in the Temporal Lobes and the One participant was Occipital Lobes. excluded. *The Medial Visual Network comprised of areas of the medial occipital cortex. **The Auditory Network comprised of a functional assembly of regions of the auditory cortex extending into pre- and post-central gyri and more ventral areas such as the insula and temporal poles bilaterally, the media PFC as well as the amygdala. ***The Task Positive network included the lateral parietal cortex, temporal-occipital junction and the precentral gyrus. DMN: default mode network; DLPFC: dorsal lateral prefrontal cortex; ACC: anterior cingulate cortex. 8 Brain and Neuroscience Advances sample of 24 healthy participants. When cortico-limbic connec- Brain networks. Using Independent Component Analysis tivity was examined (n = 23) between the subgenual Anterior (ICA), Veer et al. (2010) identified three networks with whose Cingulate Cortex (sgACC) and the hippocampus and the amyg- significantly altered connectivity between treatment-naïve dala, no significant changes were identified between the ket- depressed individuals (n = 23) and HCs (n = 19). Specifically, amine and placebo sessions (Scheidegger et al., 2016). Moreover, within the auditory network, the functional connectivity of the in a study by Anticevic and colleagues (n = 19), Global Brain amygdala with the left insula was significantly decreased in the Connectivity (GBC) was used to study connectivity of the PFC depressed group. For the attention/working memory network, and voxels within that region and increased connectivity was referred to as the task positive network, the connectivity of the found between the superior frontal gyrus and the middle frontal frontal poles with this network was also reduced in the MDD gyrus (Anticevic et al., 2015) in ketamine compared to placebo. group compared to healthy volunteers. Finally, within the visual The acute effects of ketamine’s administration on corticohip- network, the lingual gyrus was less strongly connected with the pocampal connectivity were examined by Khalili-Mahani et al. rest of the network, in the MDD patients compared to the HCs. (2015). In this study of 12 participants, the hippocampus was The changes in connectivity between and within these networks segmented into three anatomical regions: body, head and tail and in depression could relate to some of the emotional as well as the connectivity of those regions was correlated with the rest of cognitive deficits often observed in depressed patients (Veer the brain. Acute ketamine administration increased the connec- et al., 2010). tivity between the hippocampal body (bilateral) and the superior The default mode network (DMN) was the main focus of part of the precuneus, the premotor cortex and the lateral visual three resting-state studies since increased connectivity within cortices, compared to placebo (Khalili-Mahani et al., 2015). that network has been linked to depression. A study looking at the Hippocampal connectivity under ketamine was also examined overall connectivity within the DMN revealed that compared to (n = 19) focusing on the left hippocampus and decreased connec- HC subjects (n = 37), depressed patients (n = 32) showed increased tivity between that seed region and several brain areas including resting-state functional connectivity within this network. Some the ACC, the PCC and the insula (Kraguljac et al., 2017) was decreases, however, were also identified within this network identified. Finally, Zacharias et al., have used the PCC/precuneus between the posterior cingulate cortex (PCC) and the precuneus/ as a seed region to examine the connectivity of the DMN with the right Angular Gyrus(AG) as well as the left AG and the precu- rest of the brain in a sample of 24 healthy volunteers. Ketamine neus (Zhu et al., 2012). compared to placebo increased the connectivity between the seed In another study of the same sample by Zhu et al., 11 pre- region and the medial Prefrontal Cortex (mPFC). Decrease con- defined ROIs were used in order to assess in more detail the con- nectivity was observed between the PCC/precuneus and the nectivity within the DMN and revealed increased FC within the interparietal lobe, bilaterally (Zacharias et al., 2019). DMN (Zhu et al., 2017). Finally, in a very large study (Yan et al., 2019), DMN connectivity in cohort of 318 first-episode drug- naïve patients no significant changes were found in DMN con- Networks. The majority of studies – seven out of fifteen – that nectivity when that group was compared to HCs (n = 266). examined the effects of acute ketamine administration on connec- Interestingly, when the treatment-naïve patients were compared tivity focused on brain networks. Bonhomme and colleagues to medicated first-episode MDD patients, decreased DMN con- assessed FC changes (n = 14) induced by different doses of ket- nectivity was found in the treatment group. A summary of those amine in brain networks related to consciousness including the studies based on the connectivity methodology that they have DMN, the right and left executive control network, the salience net- used is also available in Table 1. work, the auditory network, the sensorimotor network and visual network. Ketamine, when administered in doses that were relevant for this review, reversed the significant anticorrelations that were Acute effects of ketamine administration on identified between the DMN and three brain clusters (see Table 2). brain connectivity – healthy volunteers Moreover, within the DMN, ketamine produced a breakdown of connectivity and there was a significant correlation between the Subcortical ROIs. The acute effects of ketamine on fronto- depth of sedation and decreased connectivity of the mPFC with the striato-thalamic connectivity with the rest of the brain, revealed DMN (Bonhomme et al., 2016). that ketamine, compared to placebo, increased the connectivity When the connectivity of the thalamus hub network (n = 35) (n = 21) between the dorsal caudate and the thalamus bilaterally, and the cortico-thalamic network were examined, significant as well as the ventral striatum and the superior and inferior ven- increases were identified when acute ketamine was compared to tromedial prefrontal cortex and the frontopolar cortex (Dandash placebo. Specifically, ketamine increased connectivity between et al., 2015). Ketamine-induced increases in the connectivity the thalamus hub network and a cluster extending from the supe- correlated with the changes in positive psychosis symptoms as rior parietal lobule towards the temporal cortex. In the cortico- well as the dissociative effects that accompany acute ketamine thalamic network, ketamine increased the connectivity of the administration. post-central gyrus with the ventromedial region of the thalamus as well as the temporal lobe with medial dorsal nucleus (Höflich Cortical ROIs. Four studies have used cortical seeds to investi- et al., 2015). gate the acute effects of ketamine’s administration in brain con- Niesters et al. (2012) showed that acute ketamine adminis- nectivity. Specifically, when the connectivity between the dorsal tration (n = 12) increased the connectivity between the medial lateral PFC and the hippocampus was examined, ketamine visual network and the thalamus, the occipital cortex, the pri- increased the connectivity between the dorsal lateral PFC (left mary and secondary somatosensory cortex. In the same study, and right) and the left hippocampus (Grimm et al., 2015) in a increase connectivity was also identified between the auditory Kotoula et al. 9 Table 2. Studies investigating changes in brain connectivity after acute ketamine administration in healthy volunteers are summarised in this table. The methodology, aims and hypotheses as well as a brief description of the main findings are included for each study. Acute effects of ketamine’s administration on resting-state fMRI in healthy volunteers GBC (Global Brain Connectivity) Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Anticevic Pharmacological Intravenous administration GBC focusing only on the PFC and voxels Acute ketamine administra- Pharmacological imaging et al. (2015) imaging of racemic ketamine via bolus within that region. tion would be associated Ketamine > Placebo HC, n = 19 males. (0.23 mg/kg over 1 min) fol- with PFC functional hyper- L/R Superior Frontal Gyrus and R Middle Frontal Gyrus. Early Course and lowed by continuous infusion connectivity. No regions showed connectivity decrease following ketamine administration. Chronic Schizophrenia, (0.58 mg/kg over 1 h). Explore the differences in Comparison of early course (EC-SCZ) and chronic schizophrenia (C-SHZ), high High Risk and Healthy PFC connectivity across risk (HR) and healthy control (HC). Control Comparison schizophrenia stages. Right Superior Lateral Prefrontal Cortex EC-SCZ, n = 28. Ketamine’s effects would HC > C-SCZ and EC-SCZ > C-SCZ C-SCZ, n = 20. resemble early course but Superior Medial Prefrontal Cortex HR, n = 21. not chronic schizophrenia. EC-SCZ > HC, HR > HC, EC-SCZ > C-SCZ HC, n = 96 Ketamine’s effects on PFC connectivity appear to be more relevant to earlier than later stages of schizophrenia. Driesen et al. HC, n = 22 (14 males). Intravenous administration GBC analysis of the whole brain – cor- Acute ketamine administra- GBC analysis (2013) of racemic ketamine via bolus relation with positive, negative and tion would alter cortical Ketamine > Placebo (0.23 mg/kg over 1 min) fol- cognitive symptoms as captured by the functional connectiv- Increase in connectivity occurred across all voxels in the brain and no lowed by continuous infusion PANSS. ity during rest and that discrete clusters of increased GBC were identified within this pattern. (0.58 mg/kg over 1 h). would relate to psychosis Increased GBC under ketamine in the: L/R Paracentral Lobule, L/R Posterior symptoms. Areas, L Middle Occipital Gyrus, L Parietal Operculum, L Insula, L Precentral Gyrus, L Medial Frontal Gyrus, R Middle Frontal Gyrus predicts positive symptoms. Increased GBC under ketamine in the: Dorsal Anterior Striatum, Medial Anterior Striatum and Thalamus predicts negative symptoms. No correlations were found between changes in GBC and cognitive symptoms. (Continued) 10 Brain and Neuroscience Advances Table 2. (Continued) ROI-to-ROI analysis Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Grimm et al. HC, n = 24 (12 males). Humans Humans Acute ketamine administra- Humans (2015) Rats, n = 9. Steady-State intravenous keta- ROI-to-ROI connectivity analysis tion would increase the Ketamine > Placebo mine infusion of 0.5 mg/kg. between the dorsal lateral PFC and PFC-HC connectivity in the Right dorsal lateral PFC and left Hippocampus and Left dorsal lateral PFC Resting-State scanning 20- the hippocampus bilaterally. human and rat brain. and left Hippocampus. min post-infusion. Animals Animals Animals ROI-to-ROI connectivity analysis Ketamine > Placebo Subcutaneous injection of between the left and right prelimbic Left Prelimbic Cortex and left Hippocampus, Left Prelimbic Cortex and S-ketamine. cortex and the hippocampus bilaterally. right Hippocampus and Right Prelimbic Cortex and left Hippocampus. Scheidegger HC, n = 23 (12 males). Intravenous administration of S- ROI-to-ROI cortico-limbic connectivity Ketamine infusion would Cortico-limbic Connectivity analysis et al. (2016) ketamine via bolus (0.12 mg/kg) Seed regions include the bilateral decrease reactivity in the No significant changes in cortico-limbic functional connectivity between followed by continuous infusion pregenual ACC (Anterior Cingulate amygdalo-hippocampal ketamine and placebo. (0.25 mg/kg/h). Cortex), the bilateral hippocampus complex, during processing BOLD change signal correlations and the bilateral amygdala. of negative stimuli. During Ketamine administration: Percentage changes in the BOLD signal This reduction would be % BOLD signal changes to negative pictures positively correlated with during an emotional faces task were cor- reflected in changes in functional connectivity to the pregenual ACC and bilateral Amygdala. related with cortico-limbic connectivity functional connectivity to No significant correlation between % BOLD change for positive or neutral changes. the pregenual ACC. stimuli and connectivity changes. ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Zacharias HC, n = 24 males. Intravenous administration of S- Functional connectivity of the Default Frontal decrease of DMN Default Mode Network Connectivity et al. (2019) ketamine (0.1 mg/kg) for 5 min. Mode network with the rest of the brain functional connectivity to Ketamine < Placebo Infusion stopped for 1 min and was assessed using the PCC/precuneus parietal brain regions. PCC/precuneus – Medial Prefrontal Cortex. continued at 0.015625 mg/kg/ as a core region. Ketamine > Placebo min for a maximum of 1 h with a PCC/precuneus – Left and Right Interparietal Lobe. 10% reduction in the dose every 10 min. Bonhomme HC, n = 14 (9 males). Intravenous administration of Functional Connectivity was assessed in To explore the effects Default Mode Network Connectivity et al. (2016) Six excluded from the racemic ketamine following the specific networks which included: of ketamine at different Ketamine > Placebo analysis. Domino protocol. Default Mode Network (DMN). anaesthetic doses on brain Cluster 1: Right Supramarginal gyrus, Bilateral Somatosensory cortex and Ketamine target concentrations Right and Left Executive Control Network. connectivity. Insula Cortex. progressively increased by steps Salience Network. Cluster 2: Bilateral Premotor Cortes, Ventral ACC and Dorsal ACC. of 0.5 μγ/mL until deep sedation Auditory Network. Cluster 3: Left Supramarginal Gyrus, Somatosensory Association Cortex, was achieved. Sensorimotor Network. Insular Cortex, Primary Auditory Cortex and Subcentral Area. Visual Network. Networks were identified using specific ROIs and the activation in these regions was correlated to the rest of the brain. Resting-State data were acquired in the absence of ketamine, during light keta- mine sedation and ketamine-induced unresponsiveness. (Continued) Kotoula et al. 11 Table 2. (Continued) ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Intravenous ketamine administra- Corticostriatal functional connectivity was Ketamine would reduce the Corticostriatal Functional Connectivity Dandash HC, n = 21 (10 males). et al. (2015) Two excluded from the tion using a three-compartment characterised in relation to the following functional connectivity in the Ketamine > Placebo pharmacokinetic model to achieve bilateral seed regions: dorsal fronto-striato-thalaminc Dorsal Caudate – L/R Thalamus and Ventral Striatum – L Superior Ventro- analysis. a standard plasma concentration Dorsal Caudate. circuit. medial Prefrontal Cortex, Ventral Striatum – L Frontopolar Cortex, Ventral of 100 ng/mL using a computerised Ventral Striatum/Nucleus Accumbens. Striatum – L Inferior Ventromedial Prefrontal Cortex. pump. Dorsal-Caudal Putamen. Correlation with psychosis symptom scales Ventral-Rostral Putamen. Higher ketamine-induced functional connectivity between: the L Ventral Striatum Changes in connectivity were also corre- – L Superior Ventromedial Prefrontal Cortex and R Dorsal Caudate – R Midbrain. lated with in positive psychotic symptoms Correlated with higher ΔBPRS scores (RSPS) and the brief rating scale (BPRS) as Higher ketamine-induced functional connectivity between: the L Ventral well as dissociative symptoms (CADSS) Striatum – L Inferior Ventromedial Prefrontal Cortex and L Dorsal Caudate – L Ventromedial Thalamus and Subthalamic Nuclei. Correlated with higher ΔCADSS scores Higher ketamine-induced functional connectivity between: the L Dorsal Cau- date – L Ventrolateral Prefrontal Cortex and R Dorsal Caudate – R Midbrain. Höflich et al. HC, n = 35 (18 males). Intravenous administration of S- Analysis 1 To explore the involvement of Analysis 1 (2015) Five excluded from ketamine (5 mg/mL) using a 1-min Seed-based analysis of the thalamus specific functional connec- Ketamine > Placebo analysis. bolus of 11 mg/kg followed by a hub network including: tions of the thalamus in the Increased connectivity between the thalamus hub network and a bilateral maintenance infusion of 0.12 mg/ L/R Thalamus. schizophrenia-like state. cluster extending from the superior parietal lobule towards the temporal kg for 19 min. Cingulate Cortex. cortex, including post and precentral gyri. Lingual Gyrus. These changes start at 2.5-min post-infusion and remain for 17.5 min after The time course of these seed regions the end of the infusion. was correlated with the entire brain. Analysis 2 Analysis 2 Ketamine > Placebo Seed-based analysis of the cortico- Increased connectivity of the post-central gyrus with the ventromedial thalamic network including: region of the thalamus as well as the temporal seed region with the medial Motor cortex/Supplementary Motor Area. dorsal nucleus. Somatosensory cortex. Temporal lobe. Posterior Parietal Cortex. Occipital Lobule. Khalili- HC, n = 12 male. Intravenous administration The hippocampus was segmented into To investigate ketamine’s Emergence of connectivity between the hippocampal head and the insula, Mahani et al. of S-ketamine, 20 mg/70 kg/h three anatomical regions: body, head, effects on the biomarkers of medial visual and posterior parietal cortices (2015) for the first 60 min followed tail and the time series of these regions stress, including corticohip- Ketamine > Placebo by 40 mg/70 kg/h for another were correlated with the rest of the pocampal connectivity. L/R hippocampal body – superior part of the precuneus, L/R hippocam- 60 min. brain. pal body – premotor cortex and L/R hippocampal body – lateral visual cortices. Niesters et al. HC, n = 12 male. Intravenous administration Networks of Interest Resting-state fMRI would be Medial Visual Network Connectivity (2012) of S-ketamine, 20 mg/70 kg/h Medial Visual Network (NOI1). able to detect ketamine- Ketamine > Placebo for the first 60 min followed Lateral Visual Network (NOI2). induced alterations in large- NOI1: R Frontal Lobe, L Thalamus, R Primary Somatosensory cortex, L by 40 mg/70 kg/h for another Auditory-Somatosensory Network scale network patterns that Secondary Somatosensory cortex, L Occipital cortex, L Optic radiation, R 60 min. (NOI3). would involve brain areas Supramarginal Gyrus, R Cerebellum. Acquisition of data occurred Sensorimotor Network (NOI4). associated with analgesia, Auditory and Somatosensory Network Connectivity during the last 10 min of the Default Mode Network (NOI5). ketamine’s side effects and Ketamine > Placebo low-dose administration and Executive Saline Network (NOI6). pain processing. NOI3: R Hippocampus, L Precuneus, R Primary Visual Cortex, L Orbito- the last 10 min of the high-dose Visual-Spatial Network (NOI7). frontal Cortex, L Premotor Cortex, R Middle Temporal Gyrus, R Thalamus, administration. Working Memory Network (NOI8). L Primary Auditory Cortex, L/R Caudate Nucleus, L Anterior/Posterior Cingulate Cortex, L Lateral Occipital Cortex, L Amygdala, L Superior Lon- gitudinal Fasciculus, R Insula, R Occipital Cortex and L Cerebellum. (Continued) 12 Brain and Neuroscience Advances Table 2. (Continued) ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Kraguljac HC, n = 19 male. Intravenous bolus (0.27 mg/ The left hippocampus was used as seed Ketamine’s administration Left hippocampal connectivity et al. (2017) kg over 10 min) infusion, fol- and time series from that regions were would result in fronto-tem- Ketamine < Placebo lowed by a continuous infusion correlated with the rest of the brain. poral and temporo-parietal Left Hippocampus: Anterior Cingulate Cortex, Medial Prefrontal Cortex, (0.25 mg/kg/h flow rate of functional dysconnectivity. Middle Cingulate, Bilateral Hippocampus, Right Insula, Posterior Cingu- 0.02 mL/s). late Cortex, Lingual Gyrus and Calcarine Sulcus. Resting-state scans started 45 min after the start of the challenge and lasted for 7.5 min. Mueller et al. HC, n = 17. Intravenous bolus infusion Seeds were selected to represent five brain To examine ketamine’s Executive Control Network Connectivity Analysis (2018) (0.1 mg/kg) of S-ketamine, fol- networks and their mean BOLD time series effects on the Default Mode Ketamine < Placebo lowed by a continuous infusion was correlated with the rest of the brain Network, the Dorsal Atten- DLPFC and Bilateral Calcarine Fissure of 0.015625 mg/kg/min for Seeds include: tion Network, the Executive Ketamine > Placebo maximum 1 h with a 10% dosage Posterior Cingulate Cortex for the Control Network and the DLPFC and Left Anterior Cingulum and Left Superior Frontal Gyrus. reduction every 10 min. Default Mode Network. Salience Network. Salience Network Connectivity Analysis Bilateral Intraparietal sulcus for the Ketamine < Placebo Dorsal Attention Network. Insular Cortex and Right Calcarine Fissure. Bilateral DLPFC for Executive Control Correlation with clinical symptoms Network. Connectivity between the fronto-insular cortex (Salience Network) and the Bilateral fronto-insular cortex for the right calcarine fissure correlates with negative symptoms as captured by Salience Network. the PANSS. The PANSS and 5D-ASC were administered before and after ketamine and the delta score was correlated with changes in ketamine-induced changes in connectivity. Within network connectivity Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis To assess the influence of Converging results between the different approaches show that Spies et al. HC, n = 35 (18 males). Intravenous administration of Functional connectivity of within and (2019) Five excluded from S-ketamine (5 mg/mL) using between all main brain networks was ketamine on functional con- Esketamine < Placebo assessed using different methodological nectivity using multiple FC Within the left Visual Network and between the left Visual Network and analysis. a 1-min bolus of 11 mg/kg followed by a maintenance infu- approaches to evaluate the effect of estimation methods. the right Visual Network. esketamine on rsFC. sion of 0.12 mg/kg for 19 min. Kleinloog HC, n = 5. Intravenous administration Within connectivity was examined in The connectivity within the Within Network Connectivity Analysis et al. (2015) of S-ketamine, 20 mg/70 kg/h those networks: DMN and specifically that Connectivity between the sensory motor network and a cluster containing for the first 60 min followed Medial Visual Network. of the posterior cingulate the PCC and the Precentral Gyrus significantly correlated with subjective by 40 mg/70 kg/h for another Occipital Visual Network. cortex would be associated effects of perception under ketamine. 60 min. Lateral Visual Network. with the psychotomimetic Acquisition of data occurred Default Mode Network. effects. during the last 10 min of the Cerebellum Network. low-dose administration and Sensorimotor Network. the last 10 min of the high-dose Auditory Network. administration. Executive Control Network. Right Frontoparietal Network. Left Frontoparietal Network. Changes in connectivity were also correlated with subjective effects. (Continued) Kotoula et al. 13 Table 2. (Continued) Pattern recognition connectivity networks Joules et al. HC, n = 18. Intravenous administration Node connectivity and pattern recogni- To identify spatial patterns Node Connectivity Analysis (2015) of racemic ketamine, 1 min tion techniques of whole-brain connectivity Ketamine > Placebo bolus infusion of 0.12 mg/ underlying the effects of Basal Ganglia and Cerebellum kg/h followed by a steady state ketamine. Ketamine < Placebo 0.31 mg/kg/h. Occipital Cortex, Temporal Cortex, Medial Temporal Cortex and Frontal Cortex Delayed effects of ketamine administration on resting-state fMRI in healthy volunteers ROI-to-ROI Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Lehmann HC, n = 17. Steady-state infusion of Connectivity between the posterior The psychotomimetic experi- Ketamine < Placebo et al. (2016) 0.25 mg/kg of S-ketamine. ACC (pACC) and dorsal PCC (dPCC) was ences of ketamine might Reduced connectivity between the pACC and dPCC. assessed. be related to changes in Correlation with psychotomimetic changes The activation of these regions was also functional connectivity 24 h The stronger the psychotomimetic effects, the more reduced the resting- correlated with psychotomimetic effects after its administration. state connectivity between the pACC and dPCC. as captured by the ‘5D-ASC’ scale. Participants were scanned 24 h after the ketamine/placebo administration. ROI to whole brain Scheidegger HC, n = 17. Steady-state infusion of 0.25 ROI to whole-brain connectivity analysis To investigate pharmaco- Seed-Based Analysis et al. (2012) mg/kg of S-ketamine. was conducted using the following key logical changes in functional Ketamine < Placebo network regions as seeds: connectivity in the healthy Default Mode Network Connectivity of the Bilateral PCC with the Bilateral Bilateral DLPFC – Cognitive Control brain as a model for DMPFC, posterior ACC and mPFC. Network. ketamine’s antidepressant Affective Network Connectivity of the sgACC with the right DMPFC. Bilateral PCC – Default Mode Network. actions. Connectivity of the Dorsal Nexus with the PCC sgACC – Affective Network. Connectivity between the dorsal nexus* and the whole brain was assessed. Participants were scanned 24 h after the ketamine/placebo administration. (Continued) 14 Brain and Neuroscience Advances Table 2. (Continued) ROI to whole brain Li et al. HC, n = 61. Steady-state infusion of 0.5 mg/ Seed-based FC at the dPCC. A data-driven investigation FC Results (2020) kg of S-ketamine or saline. fALFF to assess whole-brain activity of ketamine – induced ef- 1 h post-ketamine compared to placebo – no significant changes. changes from baseline to 1 and 24 h. fects at 1 and 24 h. 24 h post-ketamine compared to placebo Participants underwent two MRI ses- Decreased FC between the dPCC and the DMPFC (strongest finding), sions: the inferior frontal gyrus and the vMPFC and pgACC and increased FC Day 1: baseline scan (20 min prior to between the dPCC and the precuneus. infusion) and 1 h after infusion. fALFF Results Day 2: 24 h post-infusion 1 h post-ketamine compared to placebo Increased fALFF in the ventral PCC and decreased fALFF in the bilateral inferior occipital gyri. 24 h post-ketamine compared to placebo – no significant changes. Post-hoc seed based analysis in the vPCC 1 h post-ketamine compared to placebo Decreased FC between the vPCC and the midcingulate cortex. 24 h post-ketamine compared to placebo – no significant changes. *The dorsal nexus seed was created by overlapping voxels that showed significant changes in both the posterior and subgenual cingulate cortices. fMRI: functional magnetic resonance imaging; PFC: prefrontal cortex; BOLD: blood oxygen level–dependent; PCC: posterior cingulate cortex; DMN: default mode network; fALFF: Fractional amplitude of low-frequency fluctuation. Kotoula et al. 15 Table 3. Acute and delayed (2 h to 2 weeks post-drug administration) changes in brain connectivity after ketamine administration in MDD patients are summarised in this table. The studies are classified based on their connectivity methodology and a brief description of the aims, hypotheses and main findings are included for each study. Delayed effects of ketamine’s administration on resting-state fMRI in depressed volunteers Single dose GBC (Global Brain Connectivity) Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Kraus MDD, n = 33. Intravenous admin- GBC analysis of the whole To independently replicate Whole-brain GBC at baseline et al. HCs, n = 22. istration of racemic brain as well as intra-PFC the finding of disrupted MDD < HC (2020) Patients were treatment- ketamine (0.5 mg/ GBC. GBCr in individuals with Bilateral MCC and ACC spreading to the superior medial frontal cortices. resistant and in a current kg over 40 min) via a Participants were scanned at MDD. Intra-PFC GBC at baseline depressive episode at the steady-state, continu- baseline and on day 2 and to examine the specific MDD < HC time of the scan. ous infusion. day 10 after the ketamine effects of pre-processing Right superior frontal cortex and Right middle frontal cortex. All patients were medica- and placebo infusion. strategies on GBCr. No effects of ketamine vs placebo were observed in GBCr, 24-h post-ketamine administration. tion free for 2 weeks before randomisation and for the duration of the study. Abdal- MDD, n = 18. Intravenous admin- GBC analysis of the whole Patients with MDD in a cur- MDD group-pre ketamine lah et al. HC, n = 25. istration of racemic brain. rent depressive episode will Widespread dysconnectivity in MDD compared to HC in the PFC. (2017) Patients had a chronic and ketamine (0.5 mg/ Participants received a show reduced PFC GBCr. MDD group post-ketamine treatment-refractory illness. kg over 40 min) via a baseline rs-fMRI scan. Mood normalisation, fol- Ketamine increased GBCr in the lateral PFC and reduced GBC in the left cerebellum. Following ketamine, 56% steady-state, continu- MDD patients underwent a lowing ketamine treatment, MDD group post-ketamine of MDD patients achieved ous infusion. repeated rs-fMRI scan 24-h would parallel a normalisa- Responders > non-responders response. post-ketamine infusion. tion in the functional con- Bilateral Caudate, Right lateral PFC and Left middle Temporal Gyrus. nectivity. ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Mkrtch- See Evans et al., 2018. See Evans et al., ROI analysis of bilateral stri- Ketamine would increase HCs vs MDD ian et al. 2018. atal subregions including: functional connectivity Baseline compared to Day 2, increased connectivity after ketamine (2020) Ventral Striatum (VS). within the fronto-striatal VS – left dorsolateral Prefrontal Cortex, DC – right ventrolateral Prefrontal Cortex, DCP – Dorsal Caudate (DC). circuitry of Treatment pregenual Anterior Cingulate Cortex and VRP – Orbital Frontal Cortex. Dorsal Caudate Putamen Resistant Depressed (TRD) Baseline compared to Day 2, ketamine decreased connectivity in the same brain areas as in the (DCP). participants but decrease MDD group, described above. Ventral-Rostral Putamen in HVs. Relationship between connectivity changes and CRP: (VRP). These effects would be Increased CRP levels correlated with decreased connectivity between the VRP–Orbital Frontal Inflammatory biomarkers associated with ketamine- Cortex, in HCs. (CRP), anhedonia (SHAPS) induced changes in inflam- Relationship between connectivity changes and SHAPS scores on Day 2: and depression scores matory response. Reduction in SHAPS scores correlated with increased connectivity between the DC – right (MADRS) were examined ventrolateral Prefrontal Cortex, post-ketamine in the MDD group. in relation to connectivity Relationship between connectivity changes and SHAPS scores on Day 10: changes. Reduction in SHAPS scores correlated with post-ketamine increases in the connectivity between the DC – right ventrolateral Prefrontal Cortex in the MDD group. (Continued) 16 Brain and Neuroscience Advances Table 3. (Continued) ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Intravenous admin- ROI analysis of the DMN differences between HCs vs MDD Evans MDD, n = 33. et al. HC, n = 25. istration of racemic Salience Network (SAL). the MDD and HC subjects Baseline ketamine (0.5 mg/ Central Executive Network would be reduced after Right dorsolateral PFC (BA6 and BA9) and Left postcentral gyrus (insula to BA43). (2018) Patients were treatment- resistant and experiencing kg over 40 min) via (CEN). ketamine administration, Baseline, Day 2 and Day 10, both for increased DMN connectivity with: a depressive episode at a steady-state, con- Default Mode Network particularly in regions Right precentral gyrus and Bilateral post-central gyrus for both the ketamine and placebo the time of the scan. tinuous infusion. (DMN). associated with SAL and sessions. All patients were medica- The study was a Participants were scanned at CEN. Day 2 of the ketamine session tion free for 2 weeks placebo-controlled, baseline and on Day 2 and Smaller difference between the HCs and MDD in connectivity between the DMN and the before randomisation and cross over design. Day 10 after the ketamine insula which normalised at Day 10. for the duration of the and placebo infusion. The ACC showed increased connectivity in the HCs compared to MDDs that was still apparent study. at Day 10 but not present during the Baseline scan or the placebo Day 2 scan. Following ketamine admin- Day 10 of the ketamine session istration depression scores Increased connectivity of the right supramarginal gyrus (BAs 22 and 39) in subjects with were reduced for MDD MDD compared to HCs. patients and remained Ketamine Day 2 > Placebo Day 2 significantly improved for MDD group 2 days post-infusion. Right and left insula, the Middle frontal gyrus (BA31), Post-central gyrus (BA5) and the Occipital gyrus (BAs 18 and19). HC group Left thalamus, the Cingulate cortex (BA24), the Cuneus (BA18) and the Right middle frontal gyrus (BAs 6, 8 and 9). Ketamine day 10 < Placebo Day 10 MDD group Occipital gyrus and Left dorsolateral prefrontal cortex (BA 9). Ketamine Day 10 < Placebo Day 10 MDD group Right post-central gyrus (BA 40). (Continued) Kotoula et al. 17 Table 3. (Continued) Repeat dose ROI to network Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Vasavada MDD, n = 44. Intravenous admin- Two bilateral ROIs were Functional connectivity MDD vs HCS et al. HC, n = 50. istration of racemic selected: between the amygdala and/ Baseline (2021) Patients were treatment- ketamine (0.5 mg/ Amygdala. or hippocampus and cortical Increased connectivity between the right amygdala and right CEN in HCs compared to MDD patients. resistant and experiencing kg over 40 min) via a Hippocampus. RSNs would be deficient No changes in hippocampal connectivity between HCs and MDD patients. a depressive episode at the steady-state, continu- And the connectivity of the in depression and restored MDD group time of the scan. ous infusion. ROI with the: by ketamine in patients Ketamine T2 compared T1 All patients were allowed The study was a Default Mode Network. with TRD. Decreased connectivity of amygdala to left CEN. to remain on stable placebo-controlled, Central Executive Network. Post-hoc analyses investi- Increased negative connectivity of right hippocampus to left CEN. antidepressant medication cross-over design. Salience Network was gated cross-sectional dif- Ketamine T3 compared to T1 (unchanged for 6 weeks MDD patients received examined. ferences between patients Increased connectivity of right amygdala to right CEN. prior to scanning). four ketamine infusion MDD patients we scanned at: and control subjects and Decreased connectivity of left amygdala with SN. Depressive scores signifi- in 2–2.5 weeks. Baseline (T1-44 patients). correlations with longitudi- Increased negative connectivity of right hippocampus to left CEN. cantly decreased after the This study employed 24 h post the first infusion nal change in FC in order to Correlation of connectivity changes with symptoms’ improvement four ketamine infusions. an open label experi- (T2-43 patients) 24–72 h post understand the antide- Acute change in functional connectivity between the left amygdala and the Salience Network mental design. the fourth infusion (T3-39 pressant response under after the first infusion correlated with post-treatment improvement in the BIS (Behavioural patients). ketamine. Inhibition System) scale. HCs were scanned at: The same effect was observed at the end of the treatment. Baseline (T1-30 participants). Acute change in functional connectivity between the hippocampus and the right Central Execu- 2 weeks after the first scan tive Network correlated with changes in the SHAPS (Snaith–Hamilton Pleasure Scale) scale after – 17 participants. the first infusion. 18 Brain and Neuroscience Advances and somatosensory network and brain regions including the (sgACC). The connectivity of the dorsal nexus with the rest of hippocampus, the precuneus, the thalamus, the caudate nucleus, the brain was also examined. Ketamine decreased connectivity the anterior and PCC as well as the insula and cerebellum (for between the bilateral PCC (DMN seed) and the bilateral DMPFC, details, see Table 2) (Niesters et al., 2012). In a study by Spies posterior ACC and mPFC, compared to placebo. Decreased con- et al., various methodological approaches were used to examine nectivity was also identified between the sgACC (affective net- the acute effects of ketamine on brain connectivity (n = 35) work seed) and the right DMPFC whereas the dorsal nexus compared to placebo. Decreased connectivity within the left presented with decreased connectivity with the PCC (Scheidegger visual network and between the left and right visual network et al., 2012). A summary of those studies can be found in Table 2. was the common finding between the different methodologies (Spies et al., 2019). Antidepressant effects of ketamine Increases as well as decreases following acute ketamine administration (n = 17) were also identified when the FC between administration on brain connectivity – MDD the executive control network and the salience network (SN) with patients the rest of the brain was examined and compared to placebo. The Most studies investigating the effects of ketamine in MDD DLPFC was used as a seed region to examine connectivity patients focus on 24 h past the drug administration, when keta- between the executive control network and the rest of the brain, mine’s antidepressant effects peak. Abdallah and colleagues and it was shown that ketamine decreased the connectivity found that before the ketamine administration, patients with between the DLPFC and the bilateral calcarine fissure. MDD present with decreased GBC in the PFC compared to HCs. Connectivity was increased, following ketamine administration, When connectivity was assessed 24-h post-ketamine administra- between the DLPFC and the left anterior cingulum and the left tion, MDD patients presented with increased connectivity in the superior frontal gyrus. Decreased connectivity was identified lateral PFC and reduced GBC in the left cerebellum. Moreover, between the insular cortex – a seed region for the SN – and the when the MDD patients were classified as ketamine responders right calcarine fissure. This decrease in connectivity correlated and non-responders, it was shown that responders had increased with negative symptoms as captured by the PANSS (Mueller GBC in the bilateral caudate, the right lateral PFC and the left et al., 2018). A positive correlation between the sensory motor middle temporal gyrus (Abdallah et al., 2017). network and a cluster containing the PCC and subjective effects Another study looked at the delayed effects of ketamine, com- of perception under ketamine was also identified in another study pared to placebo, 2 days and 10 days after the ketamine adminis- examining the psychotomimetic effects of several pharmacologi- tration on MDD patients and HCs. An ROI approach was used in cal compounds including ketamine, this study however, had a order to assess connectivity changes in the SN, the central execu- very small sample size (n = 5) (Kleinloog et al., 2015). tive control network and the DMN. At baseline, MDD patients exhibited decreased connectivity between the DMN and the right Global connectivity and pattern recognition tech- dorsolateral PFC (BA6 and BA9) and the left postcentral gyrus niques. When GBC was assessed at a whole-brain level, ket- (insula to BA43). When the effects of ketamine were compared amine (n = 22) produced a significant increase across all voxels in to placebo, 48 h (day 2) after the drug administration, between the brain (Driesen et al., 2013), compared to placebo. Moreover, MDD and HCs, smaller differences in the connectivity between increases in GBC in several cortical and subcortical brain areas the DMN and the insula were identified for the two groups which predicted the presence of positive symptoms or the absence of normalised at day 10. In contrast, the ACC showed increased negative symptoms as measured by the PANSS. Pattern recogni- connectivity in the HCs compared to MDDs at day 2 that was still tion techniques were also used to compare ketamine and placebo apparent at day 10 and was not present at baseline scans or the (n = 18) and it was shown that ketamine produced a pattern of placebo session (Evans et al., 2018). brain activations that could be discriminated from placebo with Using the same data set, Kraus and colleagues used GBC in high accuracy (Joules et al., 2015). The nodes that appeared to order to assess connectivity changes in MDD patients com- have a strong presence in the pattern were subcortical nodes pared to HCs and examine the effects of ketamine. At baseline, including the caudate, thalamus and cerebellum. These showed MDD patients had decreased GBC at the middle Cingulate increased connectivity on ketamine, whereas the cortical nodes Cortex (MCC) and the ACC. When the GBC was examined on average showed decreased connectivity on ketamine. specifically at the PFC, it was shown that at baseline MDD patients had decreased connectivity in the right superior frontal cortex and the right middle frontal cortex. However, no signifi- Delayed effects of ketamine administration cant changes were observed between the ketamine and placebo on brain connectivity – healthy volunteers sessions in MDD patients (Kraus et al., 2020). The same data set was also used to assess the effects of ketamine on striatal Two studies have investigated the delayed (24-h post-administra- connectivity. It was shown that 2 days after the ketamine tion) effects of ketamine in healthy volunteers (n = 24) using administration, MDD patients presented with increased con- resting-state fMRI. The first study examined the connectivity nectivity between the different striatal seeds and areas of the between the pACC and dPCC, and it was shown that 24-h post- prefrontal cortex, ACC and OFC. Decreased connectivity was ketamine connectivity reduced between those two brain areas. identified, after ketamine in healthy volunteers. Increased con- Moreover, the reduction in connectivity between these two areas nectivity between the dorsal caudate and the ventromedial pre- correlated with increased acute psychotomimetic symptoms frontal cortex, 2 days and 10 days after ketamine, also correlated (Lehmann et al., 2016). The second study (n = 17) used as seeds with a reduction in anhedonia in the MDD group (Mkrtchian key brain areas of the cognitive control network (bilateral et al., 2020). DLPFC), the DMN (bilateral PCC) and the Affective Network Kotoula et al. 19 Finally, in a study by Vasavada et al., the effects of four keta- recall and a bias towards negative affect and is not currently tar- mine infusions on the connectivity of the amygdala and the hip- geted successfully by commonly prescribed antidepressants pocampus with the Central Executive Network (CEN), the DMN (Jones et al., 2008). It is striking, however, that only two of the and the SN were examined and compared to placebo. Decreased thirteen studies identified in treatment-naïve depressed individu- connectivity between the amygdala and the left CEN as well as als have reported significant changes in DMN connectivity. In the increased negative connectivity between the right hippocampus study by Yan et al., when a very large sample of first-episode, and the left CEN was identified when connectivity was assessed treatment-naïve individuals were compared to HC, connectivity 24 h after the first infusion and was compared to baseline. This within the DMN did not differ between the two groups. Most increase in hippocampal connectivity predicted decreases in interestingly, when DMN connectivity was compared between the anhedonia. When the effects of ketamine on connectivity were first-episode, treatment-naïve patients and first-episode patients assessed 24–72 h after the fourth infusion and were compared to receiving treatment at the time of the scan, it was shown that the baseline, ketamine increased the connectivity between the amyg- medicated patients exhibited significantly reduced connectivity. dala and the right CEN as well as the negative connectivity This result could indicate that some of the previous research find- between the right hippocampus and the left CEN and decreased ings about the DMN showing significantly altered connectivity the connectivity between the left amygdala and the SN and this between depressed patients and HCs could partly be attributed to change predicted improvements in anxiety (Vasavada et al., antidepressant treatment (Yan et al., 2019). The long-term and 2021). A summary of those studies can be found in Table 3. short-term effects of antidepressant treatment on brain connectiv- ity are not very well-understood and could, along with methodol- ogy inconsistencies, explain why in this review there in no great overlap between the brain areas that present with altered connec- Discussion tivity in treatment-naïve depressed individuals and the treatment- Drug-naïve MDD connectivity research resistant depressed patients who are recruited in the ketamine studies when they are compared to control individuals. It is thus The studies that investigate connectivity changes in MDD drug- crucial for research studies to properly report the medication sta- naïve patients (Table 1) can be divided into two groups. The first tus of their participants. group includes studies that examine brain regions which are important for emotional regulation and cognition such as the hip- pocampus, fronto-limbic areas, the caudate and the NA (Cao Ketamine’s effects in healthy volunteers et al., 2012; Gong et al., 2017; Yang and Wang, 2017). The sec- ond group comprises of only two studies that look at the DMN Acute ketamine effects in healthy volunteers. In general, connectivity by examining this network as a whole (Zhu et al., acute ketamine administration in healthy volunteers caused an 2012) and by selecting DMN seeds for connectivity analyses overall increase in brain connectivity (Anticevic et al., 2015; Dri- (Zhu et al., 2017). esen et al., 2013). This was a consistent finding despite the differ- In order to examine the brain regions that are important for ent methodologies used by different studies. An overall increase emotional regulation, which appears to be problematic in depres- in brain connectivity during the ketamine infusion (acute ket- sion and investigate how their connectivity might differ between amine administration) was associated the positive and negative patients and HCs, most studies have used seed-to-whole-brain symptoms psychosis-like symptoms produced by the drug. connectivity approaches. The findings of these studies demon- Changes in brain connectivity have been linked to changes in strate that the ventral caudate and the superior temporal gyrus, synaptic plasticity (Stampanoni Bassi et al., 2019) and might be which are often associated with emotional regulation and reward necessary for the initiation of mechanisms – at the brain and neu- processing presented with increased connectivity with the occipi- ronal level – that would mediate the antidepressant effects of the tal lobe and the precuneus (Yang and Wang, 2017) whereas the drug. NA, also involved in reward processing, showed increased con- When brain networks were examined separately, acute keta- nectivity with several brain areas including the bilateral caudate, mine administration produced changes in the connectivity of the the medial OFC and the rostral ACC (Gong et al., 2017). The DMN, the executive control network as well as networks that insula, however, a key region for interoceptive awareness and play an important role in the initiation of sedation and uncon- emotional regulation (Namkung et al., 2017), presented with sciousness. The increased connectivity of these networks under decreased connectivity with brain regions that are part of the acute ketamine administration could be associated with the fronto-limbic circuitry (Guo et al., 2015). Some of these areas anaesthetic effects of the drug seen at higher doses. However, where connectivity changes have been identified such as striatal several studies that specifically focused on connectivity changes areas and the ACC present with lower glucose metabolism (Su within the DMN network, a network that is particular interest to et al., 2014; Wei et al., 2016) as measured by PET in patients with depression, failed to report any significant differences after acute MDD indicating that these brain areas are promising targets for ketamine administration (Kleinloog et al., 2015; Mueller et al., pharmacological agents such as ketamine that alter glutamatergic 2018; Niesters et al., 2012). signalling. Within the group of regions associated with emotional regula- When DMN connectivity was examine and compared between tion and cognition and presented with increased connectivity treatment-naïve individuals and HC, increases were identified under ketamine, the hippocampus has been the most examined. between the different DMN subsystems as well as between the Research studies have identified increases in hippocampal con- DMN and the rest of the brain (Zhu et al., 2017). Increased DMN nectivity with several brain regions including the insula, the pre- activations have been linked to increased rumination, a very cuneus, and the parietal cortex after ketamine administration prominent characteristic of depression which persists in remis- compared to placebo (Grimm et al., 2015). This increase in hip- sion. Increased rumination is associated with overgeneral memory pocampal connectivity has been linked with ketamine’s effects 20 Brain and Neuroscience Advances on Long-Term Potentiation (Yan et al., 2019) and synaptic plas- with improvements in anhedonia and anxiety and further underlie ticity, a candidate mechanism for ketamine’s antidepressant the importance of the glutamatergic modulation of these brain action (Kavalali and Monteggia, 2020). Moreover, since the hip- areas for the antidepressant effects of the drug. pocampus mediates cognitive and spatial processing functions, this altered connectivity of the hippocampus could offer a poten- Limitations tial explanation for the cognitive impairments that are observed during acute ketamine administration (Corlett et al., 2007). Most of the studies that have looked at the acute effects of keta- mine in healthy volunteers have investigated ketamine as a model The delayed and antidepressant effects of ketamine on of psychosis. In order to validate their hypotheses, these studies brain connectivity. The antidepressant effects of ketamine are have selected to focus on brain regions that have been previously detectable 2 h after the administration of the drug, peak at 24-h identified in research as important for psychosis. These regions, post-infusion, and could last up to 1 week after a single ketamine however, do not necessarily overlap with the brain areas that are infusion (REF). Ketamine’s antidepressant action, if mirrored in key to the understanding of depression. Trying to reconcile the the brain as a normalisation of the changes in connectivity findings of the acute ketamine connectivity studies with those of observed in depression, would be expected to reverse some of the depression was therefore challenging. In addition, these studies changes in connectivity observed between MDD and HCs. often use bolus-infusion techniques for ketamine administration, The studies that have looked at the antidepressant effects of where the dose and duration of the infusion vary from study to ketamine on depressed individuals have shown that the decreased study, whereas when used as an antidepressant, a slow infusion is connectivity that was identified during the placebo session was given, usually over 40 min. The precise impact of these different reversed by ketamine. Specifically, GBC was found reduced in infusion regimens has not been directly compared, but it seems MDD compared to healthy participants that was increased 24-h the strength of the psychotomimetic effects may be reduced with post-ketamine administration (Abdallah et al., 2017); this find- the slower infusion (Ballard and Zarate, 2020). ing, however, failed replication (Kraus et al., 2020). The drug Moreover, our stringent inclusion criteria aiming to bypass effects on brain connectivity seem to persist even longer than the confounding effects of antidepressant medication on brain 24 h since the decrease in the connectivity between the DMN and structure (Dusi et al., 2015) greatly limited the number of studies the insula that was identified for MDD patients compared to HCs included in our review and so we decided not to exclude any was smaller 48 h after ketamine administration but returned to studies based on a sample size criterion. This mainly impacted baseline 10 days past the ketamine infusion (Evans et al., 2018). the HC studies where there were a number of smaller studies (e.g. Ketamine produced increases in the connectivity of striatal n = 12, 14, 17 and 18). Small sample sizes in neuroimaging and regions (Mkrtchian et al., 2020) with the dorsolateral and ventro- especially pharmacology studies that involve healthy volunteers lateral PFC, the pregenual ACC and the OFC in depressed indi- have been a great concern in the field and could obscure true viduals, while decreases were observed for the same set of brain finding. In addition, different connectivity methodologies have regions in healthy volunteers. Moreover, the increases and been used to examine the differences in brain connectivity decreases in the connectivity of the amygdala and the hippocam- between healthy individuals and treatment-naïve depressed pus also lasted for more than 24 h and were detectable after mul- patients as well as the acute and delayed effects of ketamine and tiple ketamine infusion (Vasavada et al., 2021). this would also be a confounding factor that could potentially In healthy volunteers, however, our literature search revealed explain inconsistencies in the results of these studies. that 24-h post-ketamine administration, the connectivity of the Most of the studies with drug-naïve depressed patients that DMN decreased compared to the placebo session (Scheidegger have been included in our review recruited either first-episode et al., 2016) and the connectivity between the pACC and dPCC depressed participants or patients with MDD without any history also decreased 24-h post-ketamine (Lehmann et al., 2016). This of treatment. The number of studies that failed to explicitly iden- potentially differential effect that the drug produces in depressed tify whether the patients received treatment or not was also strik- and healthy participants is rather interesting since it indicates that ing. The majority of those studies were also conducted with an ketamine’s antidepressant effects could be specific to networks exclusively Chinese sample perhaps limiting the generalisation and deficits that are present in MDD and could be associated with of these findings. Furthermore, no follow-up studies that we are neurotransmitter deficits that are observed in depression. aware of have looked at treatment response in those samples. We Several studies have looked at the delayed effects of keta- could thus assume that those studies consist of both treatment mine, 2–24 h post-administration in depressed individuals and responders as well as treatment-resistant patients. The resting- have used PET imaging to assess changes in glucose metabolism. state studies that have looked at ketamine as an antidepressant Most of the findings of those studies show effects in limbic areas mainly focus on treatment-resistant patients since the clinical such as the amygdala (increased glucose metabolism post-keta- efficacy of ketamine has been most studies in these cases. The mine) (Carlson et al., 2013) and the hippocampus (decreased glu- putative neuronal differences characterising these sub-groups are cose metabolism post-ketamine) (Nugent et al., 2014), brain currently unknown. Whether ketamine would have a differential areas that present with altered connectivity in depression and are effect on responders and non-responders to conventional antide- thus potential targets for pharmacological modulation. Although pressant treatment requires further investigation. only two studies so far have looked at the effects of ketamine on Finally, there is evidence that in pharmacological MRI and the striatum (Mkrtchian et al., 2020), the amygdala and the hip- especially with NMDA receptor antagonists (acute ketamine pocampus (Vasavada et al., 2021), the fact that the drug produces administration), the tight relationship between the neuronal detectable and long-lasting changes in the connectivity of these activity and regional blood flow is disrupted (Golanov and Reis, areas is rather promising, Some of these changes also correlate 1996; Långsjö et al., 2004). This makes the interpretation of the Kotoula et al. 21 results of acute ketamine studies challenging since they could, at ORCID iDs least partly, be attributed to the vascular effects of the drug Vasileia Kotoula https://orcid.org/0000-0002-6391-0285 (Iannetti and Wise, 2007). 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Resting-state connectivity studies as a marker of the acute and delayed effects of subanaesthetic ketamine administration in healthy and depressed individuals: A systematic review:

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Abstract

Acute ketamine administration has been widely used in neuroimaging research to mimic psychosis-like symptoms. Within the last two decades, ketamine has also emerged as a potent, fast-acting antidepressant. The delayed effects of the drug, observed 2–48 h after a single infusion, are associated with marked improvements in depressive symptoms. At the systems’ level, several studies have investigated the acute ketamine effects on brain activity and connectivity; however, several questions remain unanswered around the brain changes that accompany the drug’s antidepressant effects and how these changes relate to the brain areas that appear with altered function and connectivity in depression. This review aims to address some of these questions by focusing on resting-state brain connectivity. We summarise the studies that have examined connectivity changes in treatment-naïve, depressed individuals and those studies that have looked at the acute and delayed effects of ketamine in healthy and depressed volunteers. We conclude that brain areas that are important for emotional regulation and reward processing appear with altered connectivity in depression whereas the default mode network presents with increased connectivity in depressed individuals compared to healthy controls. This finding, however, is not as prominent as the literature often assumes. Acute ketamine administration causes an increase in brain connectivity in healthy volunteers. The delayed effects of ketamine on brain connectivity vary in direction and appear to be consistent with the drug normalising the changes observed in depression. The limited number of studies however, as well as the different approaches for resting-state connectivity analysis make it very difficult to draw firm conclusions and highlight the importance of data sharing and larger future studies. Keywords Ketamine, resting state, acute ketamine changes, delayed ketamine effects, major depressive disorder Received: 30 December 2020; accepted: 24 September 2021 by commonly prescribed antidepressant medication (Berman Introduction et al., 2000). While current antidepressant medications typically Ketamine is a N-methyl-d -aspartate receptor (NMDA) receptor take several weeks to produce a detectable clinical effect, antagonist which is commonly prescribed as an anaesthetic and is also used recreationally. In research, ketamine has been widely Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology used as a model of psychosis in both animal as well as human and Neuroscience, King’s College London, London, UK studies (Frohlich and Van Horn, 2014). Within minutes of admin- GKT School of Medical Education, London, UK istration, subanaesthetic doses of ketamine produce strong dis- University of Sussex, Brighton, UK sociative effects that have been described as psychosis-like symptoms (Krystal et al., 2005). Several studies have investi- Corresponding authors: gated these acute effects of ketamine in the brain which include Vasileia Kotoula, Centre for Neuroimaging Sciences, Institute of widespread increases in metabolism, blood flow and blood oxy- Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK. gen level–dependent (BOLD) signal (Bryant et al., 2019; Lally Email: vasileia.kotoula@kcl.ac.uk et al., 2015; Mueller et al., 2018). During the last two decades, ketamine has emerged as a potent, fast-acting antidepressant, Mitul Mehta, Centre for Neuroimaging Sciences, Institute of Psychiatry, currently licenced for Treatment-Resistant Depression (Schwartz Psychology and Neuroscience, King’s College London, London SE5 8AF, et al., 2016; Zarate et al., 2006). The antidepressant effects of UK. ketamine appear to be different compared to the effects produced Email: mitul.mehta@kcl.ac.uk Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Brain and Neuroscience Advances ketamine’s antidepressant action has been detected within hours 2 h post its administration (delayed effects). A total of 15 studies of drug administration and can last on average, up to 1 week after looking at the acute effects of ketamine in healthy participants a single infusion (Zarate et al., 2006). were identified whereas only three studies that reported the Several studies have focused on the molecular mechanisms delayed effects of ketamine in healthy participants were found. that may underlie the antidepressant effects of ketamine in the Finally, we searched for studies that have administered ketamine brain (for review, see Zanos and Gould, 2018). At the systems’ as an antidepressant treatment and have used resting-state MRI to level, the delayed effects that accompany the antidepressant examine the brain changes during the antidepressant effects time action (2–24 h after infusion) are only now beginning to be window. The terms we have used for this search were ‘antide- understood. Several key outstanding questions need to be pressant’ and ‘ketamine’, ‘depression’ and ‘resting state’. A total addressed in order to comprehend ketamine’s antidepressant of five studies fulfilled our research criteria and are included in effects in the brain. Are the brain areas sensitive to acute drug this review. In addition to our online search, we also used refer- administration different from those areas that are sensitive to the ence lists from the identified articles, reviews and meta-analyses delayed effects? Are the brain changes produced by ketamine to find additional articles not indexed by PubMed. The number of directly targeting areas affected in depression or is ketamine’s studies which fulfilled the inclusion criteria of this review was antidepressant action demonstrated in a more indirect manner? relatively low, and therefore, we decided not to use a sample size At the systems’ level, neuroimaging studies are beginning to criterion in decisions to exclude studies. This allowed a more chart these effects. While important insights may be gained from complete overview of the published literature, but this limitation other modalities, such as positron emission tomography (PET) or should be taken into account when the results of those studies are task-based magnetic resonance imaging (MRI), this review will presented, and conclusions are drawn. However, this mainly focus on the resting-state studies since this methodology has affected the healthy volunteer studies. We also did not exclude been more widely employed to examine not only the connectivity any studies based on the connectivity methodology that they changes observed in major depressive disorder (MDD) but also have followed as long as sufficient details about the data process- the acute and delayed effects of ketamine’s administration in ing and analysis were provided in the appropriate section. All the healthy and depressed volunteers. articles in this article were judged by all the authors to meet rigor- In this systematic literature review, we aim to (1) summarise ous scientific standards. Figure 1 provides a summary of all the reported changes in connectivity in unmedicated patients with studies that were identified, screened and selected to be part of depression, (2) present reported effects of ketamine on brain con- this review. nectivity in healthy participants and (3) report the effects of keta- mine on brain activity in patients with depression. For the purpose Results of this review, we use the term ‘delayed effects’ to describe any post-acute changes in brain connectivity that occur 2 h to 2 weeks Connectivity changes in treatment-naïve MDD after the drug’s administration. When those ‘delayed effects’ con- patients cern MDD patients, they also reflect the antidepressant actions of the drug. By describing the patterns of brain connectivity in Subcortical regions of interests depression and ketamine’s effects on the healthy and depressed Subcortical brain areas – namely, the ventral caudate (Yang and brain, we hope to identify potential systems-level mechanisms Wang, 2017), the nucleus accumbens (ΝA) (Gong et al., 2017) for ketamine’s delayed effects which can serve as candidates for and the amygdala (Wei et al., 2016) – were used as seed regions understanding rapid-acting antidepressant mechanisms. to investigate connectivity changes in depressed patients com- pared to healthy controls (HCs). The ventral caudate, bilaterally, showed increased Methods Functional Connectivity (FC) with the right cuneus in the We followed the PRISMA guidelines for a systematic review and MDD group (n = 40) compared to healthy participants (n = 36). performed a Medline and Web of Science search for articles up to However, the FC of the right ventral caudate with the right 1 September 2020. Overall, we conducted three main searches. middle temporal gyrus and the left ventral caudate with the Our first search focused on the identification of studies that have right superior parietal lobule and right superior frontal gyrus used resting-state MRI to investigate connectivity in treatment- was significantly reduced in MDD patients (Yang and Wang, naïve depressed patients. For that purpose, we have used the 2017). When the functional coupling of the reward circuits in search terms ‘depression’, ‘drug-naïve’, ‘treatment-free’ ‘resting patients with MDD (80 patients and 43 HCs) was examined, state’ and ‘imaging’. Studies with participants who were in their the right NA presented with decreased positive FC with the left in the first-episode depressed and drug-naïve or chronically superior temporal gyrus, insular lobe, bilateral middle orbital depressed but with no history of antidepressant treatment were frontal cortex (OFC), left medial OFC and rostral anterior cin- included in our review. A total of 12 studies that fulfilled our gulate cortex (ACC) (Gong et al., 2017). Negative FC between research criteria were identified and included in this review. In the NA, the bilateral dorsal medial prefrontal cortex (DMPFC) order to identify studies that examined the acute and delayed and the left dorsal ACC was also identified in the HC group effects of ketamine with the use of resting-state MRI, we entered and was significantly reduced in depression (Gong et al., the search terms ‘ketamine’, ‘healthy’, ‘resting state’ and ‘imag- 2017). The connectivity of the bilateral amygdala with the ven- ing’. We then separated those studies into those that have scanned tral prefrontal cortex (VPFC) as well as the dorsal lateral pre- participants right after the administration of the drug (acute frontal cortex (DLPFC) was also reduced in the MDD group effects) and those that have studied the effects of the drug at least (49 patients and 50 HCs) (Wei et al., 2016). Kotoula et al. 3 Figure 1. The PRISMA flow diagram shows the process that was followed in order to identify relevant publications for our literature review. From the 166 studies initially identified, 35 fulfil our inclusion criteria and are described in our review. areas including the superior and inferior frontal gyrus, the pre- Cortical region of interests. When the between connectivity of central gyrus and OFC presented with decreased connectivity 90 region of interests (ROIs) was examined and compared with frontal and parietal cortical areas as well as the fusiform between depressed and healthy volunteers, several cortical gyrus and the precuneus (for more details see Table 1). regions presented with increased connectivity in MDD (n = 15) The insula bilaterally presented with decreased connectivity in compared to HCs (n = 37). These areas included, the left hippo- the depressed (n = 44) compared to healthy individuals (n = 44) campus which presented with increased connectivity with the with the left middle frontal gyrus, left superior temporal gyrus and right parahippocampal gyrus, the right inferior frontal gyrus left superior temporal pole as well as the middle occipital gyrus which presented with increased connectivity with the right infe- (Guo et al., 2015). Negative FC was found between the left hip- rior OFC, as well as the right cuneus that was hyperconnected to pocampus and the bilateral middle frontal gyrus, the right hip- the left superior occipital gyrus (Tao et al., 2013). Brain areas that pocampus and the right inferior parietal lobule as well as the right presented with decreased connectivity between the MDD and HC cerebellum. The magnitude of negative FC was smaller in MDD group included the bilateral insula which presented with (n = 42) compared to the control subjects (n = 32) (Cao et al., 2012). decreased connectivity with the bilateral putamen. Several brain 4 Brain and Neuroscience Advances Table 1. Connectivity studies with MDD, drug-naïve volunteers are summarised in this table based on the connectivity methodology that each study has used. The methodology, aims and hypotheses as well as a brief description of the main findings are included for each study. Connectivity analysis in treatment-naïve, MDD patients Seed-based functional connectivity Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Yan et al. First-episode, drug- 33 ROIs were selected to examine DMN within-network FC using To identify abnormal FC patterns DMN connectivity (2019) naïve MDD patients, LMM (Linear Mixed Models) associated with the DMN across First-episode, drug-naïve patients > HC – no significant difference. n = 318. Reproducibility of the analysis assessed by: cohorts and investigate whether First-episode, drug-naïve patients > first-episode, on-meds patients – con- HC, n = 394. Using different atlases episode type, medication status, nectivity within the DMN. These patients form Finer parcellations illness severity and illness dura- First-episode, drug-naïve patients > recurrent, on-meds patients – con- part of a larger cohort Performing meta-analysis instead of LMM tion contributed to abnormali- nectivity within the DMN. of 1300 MDD patients Use of global signal regression ties. Exploratory analysis (826 female). Use of scrubbing in addition to 24 motion parameters First-episode, drug-naïve patients < HC – connectivity within the VN. Exploratory network analysis of within and between connectivity First-episode, drug-naïve patients < recurrent, on-meds patients – connec- included: tivity between the VN and the SMN and between the SMN and DAN. Visual Network (VN) Sensory Motor Network (SMN) Dorsal Attention Network (DAN) Ventral Attention Network (VAN) Subcortical Network (SN) Frontoparietal Network (FN) Yang and First-episode MDD The seeds selected for the FC analysis included: MDD patients would express MDD > HC Wang patients, n = 40 (21 Bilateral Ventral Caudate (VC) greater abnormalities in the Right VC with the right Occipital Lobe, Cuneus (2017) males). Superior Temporal Gyrus (STG) VC and increased connectivity Left VC with the right Occipital Lobe, Cuneus Three participants were The time course of these seed regions was correlated with the between the STG and the cuneus Left STG with the left Parietal Lobe, the Precuneus, the right Angular Gyrus, excluded. entire brain. and precuneus. the left Occipital Lobe and the Cuneus HC, n = 36 (17 males). MDD < HC Four participants were Right VC with the right Middle Temporal Gyrus excluded. Left VC with the right Superior Parietal Lobule and the right Superior Frontal Gyrus Gong et al. First-episode MDD The left and right Nucleus Accumbens (NA) were used as seeds and Dysfunctional reward circuits in MDD < HC (2017) patients, n = 80 (33 examine separately. the NA would contribute to cog- Left NA with the left Bilateral Caudate, the left Medial and Middle Orbital males). The time course of the seed regions was correlated with the rest nitive deficits in depression. Frontal Cortex, the left Rostral ACC, the left Superior Temporal Gyrus and the Five participants were of the brain. Insular Lobe. excluded. Right NA with the left Superior Temporal Gyrus, the Insular Lobe, the Bilateral HC, n = 43 (23 males). Middle Orbital Frontal Cortex, the right ACC and the left Medial Orbital Cortex. One participant was MDD > HC excluded. Right NA with the right Bilateral Dorsal Medial Prefrontal Cortex and the left Dorsal ACC. Guo et al. MDD patients, n = 44 The time course of the bilateral insular cortex seeds was correlated Altered rsFC of the insula with MDD < HC (2015) (22 males). with the rest of the brain. the rest of the brain between Right Insula with the left Middle Frontal Gyrus, the left Superior Temporal HC, n = 44 (20 males). MDD patients and controls. Gyrus and the right Putamen. Left Insula with the right Middle Occipital Gyrus, the left Superior Temporal Pole and the right Middle Occipital Gyrus. (Continued) Kotoula et al. 5 Table 1. (Continued) Connectivity analysis in treatment-naïve, MDD patients Seed-based functional connectivity Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Guo et al. MDD patients, n = 44 The time course of the Bilateral Crus I was correlated with the rest Increased Crus I-DMN connectiv- MDD > HC (2015) (22 males). of the brain. ity. Right Crus I with the right Inferior Frontal Cortex, the right Superior Tempo- HC, n = 44 (20 males). ral Pole, the bilateral MPFC and the left Middle Temporal Gyrus. Cao et al. MDD patients, n = 42 The time course of the Bilateral hippocampal seeds was corrected Abnormal FC pattern of the hip- MDD > HC (2012) (18 males). with the rest of the brain. pocampus with the cortical-limbic Left Hippocampus with the Bilateral Middle Frontal Gyrus. HC, n = 32 (17 males). circuits in MDD. Right Hippocampus with the right Inferior Parietal Lobule and the right Cerebellar Tonsil. ICA (independent component analysis) Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Zhu et al. MDD patients, n = 37 ICA was conducted and a template of the DMN was used to exam- Dissociated connectivity pattern Within the DMN (2012) (17 males). ine connectivity changes between the two groups. between anterior and posterior MDD > HC Five participants were parts of the DMN. Dorsal MPFC/Ventral ACC, Ventral MPFC and the Medial Orbital PFC. excluded. MDD < HC HC, n = 37. PCC/Precuneus, Right AG and the left AG/Precuneus. Four participants were excluded. Veer et al. MDD patients, n = 23 The following ICA networks were identified and compared between Altered connectivity in the Within the Medial Visual Network* (RSN3) MDD < HC (2010) (8 males). the two groups: resting-state network (RSN) that Four participants were Primary Visual Network. includes brain areas associated Lingual Gyrus with the rest of the network. Within the Auditory Network** (RSN12) excluded. Lateral Visual Network. with affective (ventral PFC, limbic HC, n = 19 (8 males). Medial Visual Network. areas) and cognitive (lateral PFC, MDD < HC parietal areas) as well as net- Amygdala and Left Insula with the rest of the network and the right Sensory–Motor Network. Right Lateral Network. works that show corticostriatal Superior Temporal Gyrus. connectivity. MDD > HC (within the network) Left Lateral Network. Precuneus. Right Inferior Frontal Gyrus. Between the Task Positive (attention and working memory) Ventral Stream Network. Medial Temporal Network. Network***(RSN11) and the rest of the brain MDD < HC Salience Network. Task Positive Network. The left Frontal Pole with the rest of the network. Auditory Network. Default Mode Network. (Continued) 6 Brain and Neuroscience Advances Table 1. (Continued) ROI-to-ROI Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Zhu et al. First-episode MDD The following ROIs of the DMN were defined and included: MDD patients would exhibit Between the DMN ROIs (2017) patients, n = 33 (14 Anterior medial Prefrontal Cortex (MPFC). altered connectivity in the DMN Within system connectivity in the DMPFC subsystem males). Posterior Cingulate Cortex (PCC). subsystems. MDD > HC – DMPFC-Temp and TPJ-LTC. Two participants Dorsal Medial Prefrontal Cortex (DMPFC) Inter system connectivity between the DMPFC and Medial Temporal Lobe (MTL) excluded due to head Temporo-parietal junction (TPJ). subsystems motion. Lateral Temporal Cortex (LTC). MDD > HC – TPJ-PHC (inter-system connectivity between the DMPFC and HC, n = 33 (15 males). Temporal Pole (TempP). MTL subsystems), LTC-PHC (inter-system connectivity between the DMPFC One participant Ventral MPFC. and MTL subsystems), TempP-vMPFC (inter-system connectivity between excluded due to head Retrosplenial cortex (Rsp). the DMPFC and MTL subsystems), TempP-pIPL (inter-system connectivity motion. posterior Inferior Parietal Lobule (pIPL). between the dMPFC and MTL subsystems), TempP-Rsp (inter-system connec- Parahippocampal Cortex (PHC). tivity between the DMPFC and MTL subsystems), TempP-PHC (inter-system Hippocampal Formation (HF). connectivity between the DMPFC and MTL subsystems). The three DMN subsystems were defined as Within the DMN subsystems Midline core: anterior MPFC and PCC. MDD > HC – DMPFC subsystem. DMPFC subsystem: DMPFC, TPJ, LTC and TempP. Between the DMN subsystems MTL subsystem: vMPFC, pIPL, Rsp, PHC, HF. MDD > HC – DMPFC subsystem – MTL subsystem. Wei et al. First-episode MDD Correlation analysis between the bilateral amygdala ROI and Altered connectivity between the MDD < HC (2016) patients, n = 49 (17 bilateral PFC mask including Brodmann area 9–12, 24, 25, 32 and amygdala – PFC and amygdala Amygdala – VPFC and DLPFC. males). 44–47. – DLPFC in MDD. HC, n = 50 (17 males). Tao et al. First-episode MDD Connectivity analysis To unambiguously identify key MDD > HC (2013) patients, n = 15 (8 The whole brain was parcellated in 90 ROIs based on the anatomi- connections which are modified Left Hippocampus – Right Parahippocampal Gyrus, Right Inferior Frontal males). cal labelling atlas and the time series of these ROIs were compared in depressed patients. Gyrus – Right Inferior Orbitofrontal Cortex, Right Medial Frontal Gyrus HC, n = 37 (8 males). between the two groups. – Right Inferior Frontal Gyrus, Right Cuneus – Left Superior Occipital Gyrus and the Right Superior Orbitofrontal Cortex – Right Inferior Orbitofrontal Cortex. MDD < HC Bilateral Insula – Bilateral Putamen, Left Superior Frontal Gyrus – Right Insula, Left Precentral Gyrus – Left Inferior Frontal Gyrus, Right Inferior Frontal Gyrus – Right Supramarginal Gyrus, Left Precentral Gyrus – Left Inferior Parietal Lobule. Right Lingual Gyrus – Right Fusiform Gyrus, Right Angular Gyrus – Right Precuneus and the Left Superior Orbitofrontal Cortex – Left Inferior Orbitofrontal Cortex. (Continued) Kotoula et al. 7 Table 1. (Continued) Other connectivity techniques Study Subjects Methodology Summary of results Connectivity analysis Aims/hypothesis Wang et al. First-episode MDD ALFF (Amplitude of Low-Frequency Fluctuations) and fALFF (frac- Altered low frequency amplitude ALFF results (2012) patients, n = 18 (9 tional ALFF) analysis was performed and differences between the found widely across brain regions MDD > HC males). two groups were explored. linked with PFC, temporal, pari- Right Fusiform Gyrus, Right Anterior Lobe of the Cerebellum and the Right HC, n = 18 (9 males). etal, occipital and limbic regions. Posterior Lobe of the Cerebellum. MDD < HC Left Inferior Temporal Gyrus, Bilateral Inferior Parietal Lobule and the Right Lingual Gyrus. fALFF results MDD > HC Right Precentral Gyrus, Bilateral Fusiform Gyrus, Bilateral Anterior Lobes of the Cerebellum and the Bilateral Posterior Lobes of the Cerebellum. MDD < HC Left Dorsolateral Prefrontal Cortex, Bilateral Medial Orbitofrontal Cortex, Bilateral Middle Temporal Gyrus, Left Inferior Temporal Gyrus and the Right Inferior Parietal Lobule. Zhang et al. First-episode MDD Graph connectivity theory trying to examine the topological Disrupted topological organisa- MDD > HC (2011) patients, n = 31 (8 organisation of functional brain networks in MDD and compare tion of intrinsic functional brain Decreased path length and increased global efficiency imply a disturbance males). them to HC. networks. of the normal global integration of whole-brain networks. One participant was Increased nodal centralities were observed in the Caudate Nucleus and the excluded. DMN. HC, n = 64(30 males). Decreased nodal centralities were observed in the Temporal Lobes and the One participant was Occipital Lobes. excluded. *The Medial Visual Network comprised of areas of the medial occipital cortex. **The Auditory Network comprised of a functional assembly of regions of the auditory cortex extending into pre- and post-central gyri and more ventral areas such as the insula and temporal poles bilaterally, the media PFC as well as the amygdala. ***The Task Positive network included the lateral parietal cortex, temporal-occipital junction and the precentral gyrus. DMN: default mode network; DLPFC: dorsal lateral prefrontal cortex; ACC: anterior cingulate cortex. 8 Brain and Neuroscience Advances sample of 24 healthy participants. When cortico-limbic connec- Brain networks. Using Independent Component Analysis tivity was examined (n = 23) between the subgenual Anterior (ICA), Veer et al. (2010) identified three networks with whose Cingulate Cortex (sgACC) and the hippocampus and the amyg- significantly altered connectivity between treatment-naïve dala, no significant changes were identified between the ket- depressed individuals (n = 23) and HCs (n = 19). Specifically, amine and placebo sessions (Scheidegger et al., 2016). Moreover, within the auditory network, the functional connectivity of the in a study by Anticevic and colleagues (n = 19), Global Brain amygdala with the left insula was significantly decreased in the Connectivity (GBC) was used to study connectivity of the PFC depressed group. For the attention/working memory network, and voxels within that region and increased connectivity was referred to as the task positive network, the connectivity of the found between the superior frontal gyrus and the middle frontal frontal poles with this network was also reduced in the MDD gyrus (Anticevic et al., 2015) in ketamine compared to placebo. group compared to healthy volunteers. Finally, within the visual The acute effects of ketamine’s administration on corticohip- network, the lingual gyrus was less strongly connected with the pocampal connectivity were examined by Khalili-Mahani et al. rest of the network, in the MDD patients compared to the HCs. (2015). In this study of 12 participants, the hippocampus was The changes in connectivity between and within these networks segmented into three anatomical regions: body, head and tail and in depression could relate to some of the emotional as well as the connectivity of those regions was correlated with the rest of cognitive deficits often observed in depressed patients (Veer the brain. Acute ketamine administration increased the connec- et al., 2010). tivity between the hippocampal body (bilateral) and the superior The default mode network (DMN) was the main focus of part of the precuneus, the premotor cortex and the lateral visual three resting-state studies since increased connectivity within cortices, compared to placebo (Khalili-Mahani et al., 2015). that network has been linked to depression. A study looking at the Hippocampal connectivity under ketamine was also examined overall connectivity within the DMN revealed that compared to (n = 19) focusing on the left hippocampus and decreased connec- HC subjects (n = 37), depressed patients (n = 32) showed increased tivity between that seed region and several brain areas including resting-state functional connectivity within this network. Some the ACC, the PCC and the insula (Kraguljac et al., 2017) was decreases, however, were also identified within this network identified. Finally, Zacharias et al., have used the PCC/precuneus between the posterior cingulate cortex (PCC) and the precuneus/ as a seed region to examine the connectivity of the DMN with the right Angular Gyrus(AG) as well as the left AG and the precu- rest of the brain in a sample of 24 healthy volunteers. Ketamine neus (Zhu et al., 2012). compared to placebo increased the connectivity between the seed In another study of the same sample by Zhu et al., 11 pre- region and the medial Prefrontal Cortex (mPFC). Decrease con- defined ROIs were used in order to assess in more detail the con- nectivity was observed between the PCC/precuneus and the nectivity within the DMN and revealed increased FC within the interparietal lobe, bilaterally (Zacharias et al., 2019). DMN (Zhu et al., 2017). Finally, in a very large study (Yan et al., 2019), DMN connectivity in cohort of 318 first-episode drug- naïve patients no significant changes were found in DMN con- Networks. The majority of studies – seven out of fifteen – that nectivity when that group was compared to HCs (n = 266). examined the effects of acute ketamine administration on connec- Interestingly, when the treatment-naïve patients were compared tivity focused on brain networks. Bonhomme and colleagues to medicated first-episode MDD patients, decreased DMN con- assessed FC changes (n = 14) induced by different doses of ket- nectivity was found in the treatment group. A summary of those amine in brain networks related to consciousness including the studies based on the connectivity methodology that they have DMN, the right and left executive control network, the salience net- used is also available in Table 1. work, the auditory network, the sensorimotor network and visual network. Ketamine, when administered in doses that were relevant for this review, reversed the significant anticorrelations that were Acute effects of ketamine administration on identified between the DMN and three brain clusters (see Table 2). brain connectivity – healthy volunteers Moreover, within the DMN, ketamine produced a breakdown of connectivity and there was a significant correlation between the Subcortical ROIs. The acute effects of ketamine on fronto- depth of sedation and decreased connectivity of the mPFC with the striato-thalamic connectivity with the rest of the brain, revealed DMN (Bonhomme et al., 2016). that ketamine, compared to placebo, increased the connectivity When the connectivity of the thalamus hub network (n = 35) (n = 21) between the dorsal caudate and the thalamus bilaterally, and the cortico-thalamic network were examined, significant as well as the ventral striatum and the superior and inferior ven- increases were identified when acute ketamine was compared to tromedial prefrontal cortex and the frontopolar cortex (Dandash placebo. Specifically, ketamine increased connectivity between et al., 2015). Ketamine-induced increases in the connectivity the thalamus hub network and a cluster extending from the supe- correlated with the changes in positive psychosis symptoms as rior parietal lobule towards the temporal cortex. In the cortico- well as the dissociative effects that accompany acute ketamine thalamic network, ketamine increased the connectivity of the administration. post-central gyrus with the ventromedial region of the thalamus as well as the temporal lobe with medial dorsal nucleus (Höflich Cortical ROIs. Four studies have used cortical seeds to investi- et al., 2015). gate the acute effects of ketamine’s administration in brain con- Niesters et al. (2012) showed that acute ketamine adminis- nectivity. Specifically, when the connectivity between the dorsal tration (n = 12) increased the connectivity between the medial lateral PFC and the hippocampus was examined, ketamine visual network and the thalamus, the occipital cortex, the pri- increased the connectivity between the dorsal lateral PFC (left mary and secondary somatosensory cortex. In the same study, and right) and the left hippocampus (Grimm et al., 2015) in a increase connectivity was also identified between the auditory Kotoula et al. 9 Table 2. Studies investigating changes in brain connectivity after acute ketamine administration in healthy volunteers are summarised in this table. The methodology, aims and hypotheses as well as a brief description of the main findings are included for each study. Acute effects of ketamine’s administration on resting-state fMRI in healthy volunteers GBC (Global Brain Connectivity) Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Anticevic Pharmacological Intravenous administration GBC focusing only on the PFC and voxels Acute ketamine administra- Pharmacological imaging et al. (2015) imaging of racemic ketamine via bolus within that region. tion would be associated Ketamine > Placebo HC, n = 19 males. (0.23 mg/kg over 1 min) fol- with PFC functional hyper- L/R Superior Frontal Gyrus and R Middle Frontal Gyrus. Early Course and lowed by continuous infusion connectivity. No regions showed connectivity decrease following ketamine administration. Chronic Schizophrenia, (0.58 mg/kg over 1 h). Explore the differences in Comparison of early course (EC-SCZ) and chronic schizophrenia (C-SHZ), high High Risk and Healthy PFC connectivity across risk (HR) and healthy control (HC). Control Comparison schizophrenia stages. Right Superior Lateral Prefrontal Cortex EC-SCZ, n = 28. Ketamine’s effects would HC > C-SCZ and EC-SCZ > C-SCZ C-SCZ, n = 20. resemble early course but Superior Medial Prefrontal Cortex HR, n = 21. not chronic schizophrenia. EC-SCZ > HC, HR > HC, EC-SCZ > C-SCZ HC, n = 96 Ketamine’s effects on PFC connectivity appear to be more relevant to earlier than later stages of schizophrenia. Driesen et al. HC, n = 22 (14 males). Intravenous administration GBC analysis of the whole brain – cor- Acute ketamine administra- GBC analysis (2013) of racemic ketamine via bolus relation with positive, negative and tion would alter cortical Ketamine > Placebo (0.23 mg/kg over 1 min) fol- cognitive symptoms as captured by the functional connectiv- Increase in connectivity occurred across all voxels in the brain and no lowed by continuous infusion PANSS. ity during rest and that discrete clusters of increased GBC were identified within this pattern. (0.58 mg/kg over 1 h). would relate to psychosis Increased GBC under ketamine in the: L/R Paracentral Lobule, L/R Posterior symptoms. Areas, L Middle Occipital Gyrus, L Parietal Operculum, L Insula, L Precentral Gyrus, L Medial Frontal Gyrus, R Middle Frontal Gyrus predicts positive symptoms. Increased GBC under ketamine in the: Dorsal Anterior Striatum, Medial Anterior Striatum and Thalamus predicts negative symptoms. No correlations were found between changes in GBC and cognitive symptoms. (Continued) 10 Brain and Neuroscience Advances Table 2. (Continued) ROI-to-ROI analysis Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Grimm et al. HC, n = 24 (12 males). Humans Humans Acute ketamine administra- Humans (2015) Rats, n = 9. Steady-State intravenous keta- ROI-to-ROI connectivity analysis tion would increase the Ketamine > Placebo mine infusion of 0.5 mg/kg. between the dorsal lateral PFC and PFC-HC connectivity in the Right dorsal lateral PFC and left Hippocampus and Left dorsal lateral PFC Resting-State scanning 20- the hippocampus bilaterally. human and rat brain. and left Hippocampus. min post-infusion. Animals Animals Animals ROI-to-ROI connectivity analysis Ketamine > Placebo Subcutaneous injection of between the left and right prelimbic Left Prelimbic Cortex and left Hippocampus, Left Prelimbic Cortex and S-ketamine. cortex and the hippocampus bilaterally. right Hippocampus and Right Prelimbic Cortex and left Hippocampus. Scheidegger HC, n = 23 (12 males). Intravenous administration of S- ROI-to-ROI cortico-limbic connectivity Ketamine infusion would Cortico-limbic Connectivity analysis et al. (2016) ketamine via bolus (0.12 mg/kg) Seed regions include the bilateral decrease reactivity in the No significant changes in cortico-limbic functional connectivity between followed by continuous infusion pregenual ACC (Anterior Cingulate amygdalo-hippocampal ketamine and placebo. (0.25 mg/kg/h). Cortex), the bilateral hippocampus complex, during processing BOLD change signal correlations and the bilateral amygdala. of negative stimuli. During Ketamine administration: Percentage changes in the BOLD signal This reduction would be % BOLD signal changes to negative pictures positively correlated with during an emotional faces task were cor- reflected in changes in functional connectivity to the pregenual ACC and bilateral Amygdala. related with cortico-limbic connectivity functional connectivity to No significant correlation between % BOLD change for positive or neutral changes. the pregenual ACC. stimuli and connectivity changes. ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Zacharias HC, n = 24 males. Intravenous administration of S- Functional connectivity of the Default Frontal decrease of DMN Default Mode Network Connectivity et al. (2019) ketamine (0.1 mg/kg) for 5 min. Mode network with the rest of the brain functional connectivity to Ketamine < Placebo Infusion stopped for 1 min and was assessed using the PCC/precuneus parietal brain regions. PCC/precuneus – Medial Prefrontal Cortex. continued at 0.015625 mg/kg/ as a core region. Ketamine > Placebo min for a maximum of 1 h with a PCC/precuneus – Left and Right Interparietal Lobe. 10% reduction in the dose every 10 min. Bonhomme HC, n = 14 (9 males). Intravenous administration of Functional Connectivity was assessed in To explore the effects Default Mode Network Connectivity et al. (2016) Six excluded from the racemic ketamine following the specific networks which included: of ketamine at different Ketamine > Placebo analysis. Domino protocol. Default Mode Network (DMN). anaesthetic doses on brain Cluster 1: Right Supramarginal gyrus, Bilateral Somatosensory cortex and Ketamine target concentrations Right and Left Executive Control Network. connectivity. Insula Cortex. progressively increased by steps Salience Network. Cluster 2: Bilateral Premotor Cortes, Ventral ACC and Dorsal ACC. of 0.5 μγ/mL until deep sedation Auditory Network. Cluster 3: Left Supramarginal Gyrus, Somatosensory Association Cortex, was achieved. Sensorimotor Network. Insular Cortex, Primary Auditory Cortex and Subcentral Area. Visual Network. Networks were identified using specific ROIs and the activation in these regions was correlated to the rest of the brain. Resting-State data were acquired in the absence of ketamine, during light keta- mine sedation and ketamine-induced unresponsiveness. (Continued) Kotoula et al. 11 Table 2. (Continued) ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Intravenous ketamine administra- Corticostriatal functional connectivity was Ketamine would reduce the Corticostriatal Functional Connectivity Dandash HC, n = 21 (10 males). et al. (2015) Two excluded from the tion using a three-compartment characterised in relation to the following functional connectivity in the Ketamine > Placebo pharmacokinetic model to achieve bilateral seed regions: dorsal fronto-striato-thalaminc Dorsal Caudate – L/R Thalamus and Ventral Striatum – L Superior Ventro- analysis. a standard plasma concentration Dorsal Caudate. circuit. medial Prefrontal Cortex, Ventral Striatum – L Frontopolar Cortex, Ventral of 100 ng/mL using a computerised Ventral Striatum/Nucleus Accumbens. Striatum – L Inferior Ventromedial Prefrontal Cortex. pump. Dorsal-Caudal Putamen. Correlation with psychosis symptom scales Ventral-Rostral Putamen. Higher ketamine-induced functional connectivity between: the L Ventral Striatum Changes in connectivity were also corre- – L Superior Ventromedial Prefrontal Cortex and R Dorsal Caudate – R Midbrain. lated with in positive psychotic symptoms Correlated with higher ΔBPRS scores (RSPS) and the brief rating scale (BPRS) as Higher ketamine-induced functional connectivity between: the L Ventral well as dissociative symptoms (CADSS) Striatum – L Inferior Ventromedial Prefrontal Cortex and L Dorsal Caudate – L Ventromedial Thalamus and Subthalamic Nuclei. Correlated with higher ΔCADSS scores Higher ketamine-induced functional connectivity between: the L Dorsal Cau- date – L Ventrolateral Prefrontal Cortex and R Dorsal Caudate – R Midbrain. Höflich et al. HC, n = 35 (18 males). Intravenous administration of S- Analysis 1 To explore the involvement of Analysis 1 (2015) Five excluded from ketamine (5 mg/mL) using a 1-min Seed-based analysis of the thalamus specific functional connec- Ketamine > Placebo analysis. bolus of 11 mg/kg followed by a hub network including: tions of the thalamus in the Increased connectivity between the thalamus hub network and a bilateral maintenance infusion of 0.12 mg/ L/R Thalamus. schizophrenia-like state. cluster extending from the superior parietal lobule towards the temporal kg for 19 min. Cingulate Cortex. cortex, including post and precentral gyri. Lingual Gyrus. These changes start at 2.5-min post-infusion and remain for 17.5 min after The time course of these seed regions the end of the infusion. was correlated with the entire brain. Analysis 2 Analysis 2 Ketamine > Placebo Seed-based analysis of the cortico- Increased connectivity of the post-central gyrus with the ventromedial thalamic network including: region of the thalamus as well as the temporal seed region with the medial Motor cortex/Supplementary Motor Area. dorsal nucleus. Somatosensory cortex. Temporal lobe. Posterior Parietal Cortex. Occipital Lobule. Khalili- HC, n = 12 male. Intravenous administration The hippocampus was segmented into To investigate ketamine’s Emergence of connectivity between the hippocampal head and the insula, Mahani et al. of S-ketamine, 20 mg/70 kg/h three anatomical regions: body, head, effects on the biomarkers of medial visual and posterior parietal cortices (2015) for the first 60 min followed tail and the time series of these regions stress, including corticohip- Ketamine > Placebo by 40 mg/70 kg/h for another were correlated with the rest of the pocampal connectivity. L/R hippocampal body – superior part of the precuneus, L/R hippocam- 60 min. brain. pal body – premotor cortex and L/R hippocampal body – lateral visual cortices. Niesters et al. HC, n = 12 male. Intravenous administration Networks of Interest Resting-state fMRI would be Medial Visual Network Connectivity (2012) of S-ketamine, 20 mg/70 kg/h Medial Visual Network (NOI1). able to detect ketamine- Ketamine > Placebo for the first 60 min followed Lateral Visual Network (NOI2). induced alterations in large- NOI1: R Frontal Lobe, L Thalamus, R Primary Somatosensory cortex, L by 40 mg/70 kg/h for another Auditory-Somatosensory Network scale network patterns that Secondary Somatosensory cortex, L Occipital cortex, L Optic radiation, R 60 min. (NOI3). would involve brain areas Supramarginal Gyrus, R Cerebellum. Acquisition of data occurred Sensorimotor Network (NOI4). associated with analgesia, Auditory and Somatosensory Network Connectivity during the last 10 min of the Default Mode Network (NOI5). ketamine’s side effects and Ketamine > Placebo low-dose administration and Executive Saline Network (NOI6). pain processing. NOI3: R Hippocampus, L Precuneus, R Primary Visual Cortex, L Orbito- the last 10 min of the high-dose Visual-Spatial Network (NOI7). frontal Cortex, L Premotor Cortex, R Middle Temporal Gyrus, R Thalamus, administration. Working Memory Network (NOI8). L Primary Auditory Cortex, L/R Caudate Nucleus, L Anterior/Posterior Cingulate Cortex, L Lateral Occipital Cortex, L Amygdala, L Superior Lon- gitudinal Fasciculus, R Insula, R Occipital Cortex and L Cerebellum. (Continued) 12 Brain and Neuroscience Advances Table 2. (Continued) ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypotheses Kraguljac HC, n = 19 male. Intravenous bolus (0.27 mg/ The left hippocampus was used as seed Ketamine’s administration Left hippocampal connectivity et al. (2017) kg over 10 min) infusion, fol- and time series from that regions were would result in fronto-tem- Ketamine < Placebo lowed by a continuous infusion correlated with the rest of the brain. poral and temporo-parietal Left Hippocampus: Anterior Cingulate Cortex, Medial Prefrontal Cortex, (0.25 mg/kg/h flow rate of functional dysconnectivity. Middle Cingulate, Bilateral Hippocampus, Right Insula, Posterior Cingu- 0.02 mL/s). late Cortex, Lingual Gyrus and Calcarine Sulcus. Resting-state scans started 45 min after the start of the challenge and lasted for 7.5 min. Mueller et al. HC, n = 17. Intravenous bolus infusion Seeds were selected to represent five brain To examine ketamine’s Executive Control Network Connectivity Analysis (2018) (0.1 mg/kg) of S-ketamine, fol- networks and their mean BOLD time series effects on the Default Mode Ketamine < Placebo lowed by a continuous infusion was correlated with the rest of the brain Network, the Dorsal Atten- DLPFC and Bilateral Calcarine Fissure of 0.015625 mg/kg/min for Seeds include: tion Network, the Executive Ketamine > Placebo maximum 1 h with a 10% dosage Posterior Cingulate Cortex for the Control Network and the DLPFC and Left Anterior Cingulum and Left Superior Frontal Gyrus. reduction every 10 min. Default Mode Network. Salience Network. Salience Network Connectivity Analysis Bilateral Intraparietal sulcus for the Ketamine < Placebo Dorsal Attention Network. Insular Cortex and Right Calcarine Fissure. Bilateral DLPFC for Executive Control Correlation with clinical symptoms Network. Connectivity between the fronto-insular cortex (Salience Network) and the Bilateral fronto-insular cortex for the right calcarine fissure correlates with negative symptoms as captured by Salience Network. the PANSS. The PANSS and 5D-ASC were administered before and after ketamine and the delta score was correlated with changes in ketamine-induced changes in connectivity. Within network connectivity Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis To assess the influence of Converging results between the different approaches show that Spies et al. HC, n = 35 (18 males). Intravenous administration of Functional connectivity of within and (2019) Five excluded from S-ketamine (5 mg/mL) using between all main brain networks was ketamine on functional con- Esketamine < Placebo assessed using different methodological nectivity using multiple FC Within the left Visual Network and between the left Visual Network and analysis. a 1-min bolus of 11 mg/kg followed by a maintenance infu- approaches to evaluate the effect of estimation methods. the right Visual Network. esketamine on rsFC. sion of 0.12 mg/kg for 19 min. Kleinloog HC, n = 5. Intravenous administration Within connectivity was examined in The connectivity within the Within Network Connectivity Analysis et al. (2015) of S-ketamine, 20 mg/70 kg/h those networks: DMN and specifically that Connectivity between the sensory motor network and a cluster containing for the first 60 min followed Medial Visual Network. of the posterior cingulate the PCC and the Precentral Gyrus significantly correlated with subjective by 40 mg/70 kg/h for another Occipital Visual Network. cortex would be associated effects of perception under ketamine. 60 min. Lateral Visual Network. with the psychotomimetic Acquisition of data occurred Default Mode Network. effects. during the last 10 min of the Cerebellum Network. low-dose administration and Sensorimotor Network. the last 10 min of the high-dose Auditory Network. administration. Executive Control Network. Right Frontoparietal Network. Left Frontoparietal Network. Changes in connectivity were also correlated with subjective effects. (Continued) Kotoula et al. 13 Table 2. (Continued) Pattern recognition connectivity networks Joules et al. HC, n = 18. Intravenous administration Node connectivity and pattern recogni- To identify spatial patterns Node Connectivity Analysis (2015) of racemic ketamine, 1 min tion techniques of whole-brain connectivity Ketamine > Placebo bolus infusion of 0.12 mg/ underlying the effects of Basal Ganglia and Cerebellum kg/h followed by a steady state ketamine. Ketamine < Placebo 0.31 mg/kg/h. Occipital Cortex, Temporal Cortex, Medial Temporal Cortex and Frontal Cortex Delayed effects of ketamine administration on resting-state fMRI in healthy volunteers ROI-to-ROI Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Lehmann HC, n = 17. Steady-state infusion of Connectivity between the posterior The psychotomimetic experi- Ketamine < Placebo et al. (2016) 0.25 mg/kg of S-ketamine. ACC (pACC) and dorsal PCC (dPCC) was ences of ketamine might Reduced connectivity between the pACC and dPCC. assessed. be related to changes in Correlation with psychotomimetic changes The activation of these regions was also functional connectivity 24 h The stronger the psychotomimetic effects, the more reduced the resting- correlated with psychotomimetic effects after its administration. state connectivity between the pACC and dPCC. as captured by the ‘5D-ASC’ scale. Participants were scanned 24 h after the ketamine/placebo administration. ROI to whole brain Scheidegger HC, n = 17. Steady-state infusion of 0.25 ROI to whole-brain connectivity analysis To investigate pharmaco- Seed-Based Analysis et al. (2012) mg/kg of S-ketamine. was conducted using the following key logical changes in functional Ketamine < Placebo network regions as seeds: connectivity in the healthy Default Mode Network Connectivity of the Bilateral PCC with the Bilateral Bilateral DLPFC – Cognitive Control brain as a model for DMPFC, posterior ACC and mPFC. Network. ketamine’s antidepressant Affective Network Connectivity of the sgACC with the right DMPFC. Bilateral PCC – Default Mode Network. actions. Connectivity of the Dorsal Nexus with the PCC sgACC – Affective Network. Connectivity between the dorsal nexus* and the whole brain was assessed. Participants were scanned 24 h after the ketamine/placebo administration. (Continued) 14 Brain and Neuroscience Advances Table 2. (Continued) ROI to whole brain Li et al. HC, n = 61. Steady-state infusion of 0.5 mg/ Seed-based FC at the dPCC. A data-driven investigation FC Results (2020) kg of S-ketamine or saline. fALFF to assess whole-brain activity of ketamine – induced ef- 1 h post-ketamine compared to placebo – no significant changes. changes from baseline to 1 and 24 h. fects at 1 and 24 h. 24 h post-ketamine compared to placebo Participants underwent two MRI ses- Decreased FC between the dPCC and the DMPFC (strongest finding), sions: the inferior frontal gyrus and the vMPFC and pgACC and increased FC Day 1: baseline scan (20 min prior to between the dPCC and the precuneus. infusion) and 1 h after infusion. fALFF Results Day 2: 24 h post-infusion 1 h post-ketamine compared to placebo Increased fALFF in the ventral PCC and decreased fALFF in the bilateral inferior occipital gyri. 24 h post-ketamine compared to placebo – no significant changes. Post-hoc seed based analysis in the vPCC 1 h post-ketamine compared to placebo Decreased FC between the vPCC and the midcingulate cortex. 24 h post-ketamine compared to placebo – no significant changes. *The dorsal nexus seed was created by overlapping voxels that showed significant changes in both the posterior and subgenual cingulate cortices. fMRI: functional magnetic resonance imaging; PFC: prefrontal cortex; BOLD: blood oxygen level–dependent; PCC: posterior cingulate cortex; DMN: default mode network; fALFF: Fractional amplitude of low-frequency fluctuation. Kotoula et al. 15 Table 3. Acute and delayed (2 h to 2 weeks post-drug administration) changes in brain connectivity after ketamine administration in MDD patients are summarised in this table. The studies are classified based on their connectivity methodology and a brief description of the aims, hypotheses and main findings are included for each study. Delayed effects of ketamine’s administration on resting-state fMRI in depressed volunteers Single dose GBC (Global Brain Connectivity) Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Kraus MDD, n = 33. Intravenous admin- GBC analysis of the whole To independently replicate Whole-brain GBC at baseline et al. HCs, n = 22. istration of racemic brain as well as intra-PFC the finding of disrupted MDD < HC (2020) Patients were treatment- ketamine (0.5 mg/ GBC. GBCr in individuals with Bilateral MCC and ACC spreading to the superior medial frontal cortices. resistant and in a current kg over 40 min) via a Participants were scanned at MDD. Intra-PFC GBC at baseline depressive episode at the steady-state, continu- baseline and on day 2 and to examine the specific MDD < HC time of the scan. ous infusion. day 10 after the ketamine effects of pre-processing Right superior frontal cortex and Right middle frontal cortex. All patients were medica- and placebo infusion. strategies on GBCr. No effects of ketamine vs placebo were observed in GBCr, 24-h post-ketamine administration. tion free for 2 weeks before randomisation and for the duration of the study. Abdal- MDD, n = 18. Intravenous admin- GBC analysis of the whole Patients with MDD in a cur- MDD group-pre ketamine lah et al. HC, n = 25. istration of racemic brain. rent depressive episode will Widespread dysconnectivity in MDD compared to HC in the PFC. (2017) Patients had a chronic and ketamine (0.5 mg/ Participants received a show reduced PFC GBCr. MDD group post-ketamine treatment-refractory illness. kg over 40 min) via a baseline rs-fMRI scan. Mood normalisation, fol- Ketamine increased GBCr in the lateral PFC and reduced GBC in the left cerebellum. Following ketamine, 56% steady-state, continu- MDD patients underwent a lowing ketamine treatment, MDD group post-ketamine of MDD patients achieved ous infusion. repeated rs-fMRI scan 24-h would parallel a normalisa- Responders > non-responders response. post-ketamine infusion. tion in the functional con- Bilateral Caudate, Right lateral PFC and Left middle Temporal Gyrus. nectivity. ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Mkrtch- See Evans et al., 2018. See Evans et al., ROI analysis of bilateral stri- Ketamine would increase HCs vs MDD ian et al. 2018. atal subregions including: functional connectivity Baseline compared to Day 2, increased connectivity after ketamine (2020) Ventral Striatum (VS). within the fronto-striatal VS – left dorsolateral Prefrontal Cortex, DC – right ventrolateral Prefrontal Cortex, DCP – Dorsal Caudate (DC). circuitry of Treatment pregenual Anterior Cingulate Cortex and VRP – Orbital Frontal Cortex. Dorsal Caudate Putamen Resistant Depressed (TRD) Baseline compared to Day 2, ketamine decreased connectivity in the same brain areas as in the (DCP). participants but decrease MDD group, described above. Ventral-Rostral Putamen in HVs. Relationship between connectivity changes and CRP: (VRP). These effects would be Increased CRP levels correlated with decreased connectivity between the VRP–Orbital Frontal Inflammatory biomarkers associated with ketamine- Cortex, in HCs. (CRP), anhedonia (SHAPS) induced changes in inflam- Relationship between connectivity changes and SHAPS scores on Day 2: and depression scores matory response. Reduction in SHAPS scores correlated with increased connectivity between the DC – right (MADRS) were examined ventrolateral Prefrontal Cortex, post-ketamine in the MDD group. in relation to connectivity Relationship between connectivity changes and SHAPS scores on Day 10: changes. Reduction in SHAPS scores correlated with post-ketamine increases in the connectivity between the DC – right ventrolateral Prefrontal Cortex in the MDD group. (Continued) 16 Brain and Neuroscience Advances Table 3. (Continued) ROI to whole brain Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Intravenous admin- ROI analysis of the DMN differences between HCs vs MDD Evans MDD, n = 33. et al. HC, n = 25. istration of racemic Salience Network (SAL). the MDD and HC subjects Baseline ketamine (0.5 mg/ Central Executive Network would be reduced after Right dorsolateral PFC (BA6 and BA9) and Left postcentral gyrus (insula to BA43). (2018) Patients were treatment- resistant and experiencing kg over 40 min) via (CEN). ketamine administration, Baseline, Day 2 and Day 10, both for increased DMN connectivity with: a depressive episode at a steady-state, con- Default Mode Network particularly in regions Right precentral gyrus and Bilateral post-central gyrus for both the ketamine and placebo the time of the scan. tinuous infusion. (DMN). associated with SAL and sessions. All patients were medica- The study was a Participants were scanned at CEN. Day 2 of the ketamine session tion free for 2 weeks placebo-controlled, baseline and on Day 2 and Smaller difference between the HCs and MDD in connectivity between the DMN and the before randomisation and cross over design. Day 10 after the ketamine insula which normalised at Day 10. for the duration of the and placebo infusion. The ACC showed increased connectivity in the HCs compared to MDDs that was still apparent study. at Day 10 but not present during the Baseline scan or the placebo Day 2 scan. Following ketamine admin- Day 10 of the ketamine session istration depression scores Increased connectivity of the right supramarginal gyrus (BAs 22 and 39) in subjects with were reduced for MDD MDD compared to HCs. patients and remained Ketamine Day 2 > Placebo Day 2 significantly improved for MDD group 2 days post-infusion. Right and left insula, the Middle frontal gyrus (BA31), Post-central gyrus (BA5) and the Occipital gyrus (BAs 18 and19). HC group Left thalamus, the Cingulate cortex (BA24), the Cuneus (BA18) and the Right middle frontal gyrus (BAs 6, 8 and 9). Ketamine day 10 < Placebo Day 10 MDD group Occipital gyrus and Left dorsolateral prefrontal cortex (BA 9). Ketamine Day 10 < Placebo Day 10 MDD group Right post-central gyrus (BA 40). (Continued) Kotoula et al. 17 Table 3. (Continued) Repeat dose ROI to network Study Subjects Methodology Summary of results Infusion protocol Connectivity analysis Aims/hypothesis Vasavada MDD, n = 44. Intravenous admin- Two bilateral ROIs were Functional connectivity MDD vs HCS et al. HC, n = 50. istration of racemic selected: between the amygdala and/ Baseline (2021) Patients were treatment- ketamine (0.5 mg/ Amygdala. or hippocampus and cortical Increased connectivity between the right amygdala and right CEN in HCs compared to MDD patients. resistant and experiencing kg over 40 min) via a Hippocampus. RSNs would be deficient No changes in hippocampal connectivity between HCs and MDD patients. a depressive episode at the steady-state, continu- And the connectivity of the in depression and restored MDD group time of the scan. ous infusion. ROI with the: by ketamine in patients Ketamine T2 compared T1 All patients were allowed The study was a Default Mode Network. with TRD. Decreased connectivity of amygdala to left CEN. to remain on stable placebo-controlled, Central Executive Network. Post-hoc analyses investi- Increased negative connectivity of right hippocampus to left CEN. antidepressant medication cross-over design. Salience Network was gated cross-sectional dif- Ketamine T3 compared to T1 (unchanged for 6 weeks MDD patients received examined. ferences between patients Increased connectivity of right amygdala to right CEN. prior to scanning). four ketamine infusion MDD patients we scanned at: and control subjects and Decreased connectivity of left amygdala with SN. Depressive scores signifi- in 2–2.5 weeks. Baseline (T1-44 patients). correlations with longitudi- Increased negative connectivity of right hippocampus to left CEN. cantly decreased after the This study employed 24 h post the first infusion nal change in FC in order to Correlation of connectivity changes with symptoms’ improvement four ketamine infusions. an open label experi- (T2-43 patients) 24–72 h post understand the antide- Acute change in functional connectivity between the left amygdala and the Salience Network mental design. the fourth infusion (T3-39 pressant response under after the first infusion correlated with post-treatment improvement in the BIS (Behavioural patients). ketamine. Inhibition System) scale. HCs were scanned at: The same effect was observed at the end of the treatment. Baseline (T1-30 participants). Acute change in functional connectivity between the hippocampus and the right Central Execu- 2 weeks after the first scan tive Network correlated with changes in the SHAPS (Snaith–Hamilton Pleasure Scale) scale after – 17 participants. the first infusion. 18 Brain and Neuroscience Advances and somatosensory network and brain regions including the (sgACC). The connectivity of the dorsal nexus with the rest of hippocampus, the precuneus, the thalamus, the caudate nucleus, the brain was also examined. Ketamine decreased connectivity the anterior and PCC as well as the insula and cerebellum (for between the bilateral PCC (DMN seed) and the bilateral DMPFC, details, see Table 2) (Niesters et al., 2012). In a study by Spies posterior ACC and mPFC, compared to placebo. Decreased con- et al., various methodological approaches were used to examine nectivity was also identified between the sgACC (affective net- the acute effects of ketamine on brain connectivity (n = 35) work seed) and the right DMPFC whereas the dorsal nexus compared to placebo. Decreased connectivity within the left presented with decreased connectivity with the PCC (Scheidegger visual network and between the left and right visual network et al., 2012). A summary of those studies can be found in Table 2. was the common finding between the different methodologies (Spies et al., 2019). Antidepressant effects of ketamine Increases as well as decreases following acute ketamine administration (n = 17) were also identified when the FC between administration on brain connectivity – MDD the executive control network and the salience network (SN) with patients the rest of the brain was examined and compared to placebo. The Most studies investigating the effects of ketamine in MDD DLPFC was used as a seed region to examine connectivity patients focus on 24 h past the drug administration, when keta- between the executive control network and the rest of the brain, mine’s antidepressant effects peak. Abdallah and colleagues and it was shown that ketamine decreased the connectivity found that before the ketamine administration, patients with between the DLPFC and the bilateral calcarine fissure. MDD present with decreased GBC in the PFC compared to HCs. Connectivity was increased, following ketamine administration, When connectivity was assessed 24-h post-ketamine administra- between the DLPFC and the left anterior cingulum and the left tion, MDD patients presented with increased connectivity in the superior frontal gyrus. Decreased connectivity was identified lateral PFC and reduced GBC in the left cerebellum. Moreover, between the insular cortex – a seed region for the SN – and the when the MDD patients were classified as ketamine responders right calcarine fissure. This decrease in connectivity correlated and non-responders, it was shown that responders had increased with negative symptoms as captured by the PANSS (Mueller GBC in the bilateral caudate, the right lateral PFC and the left et al., 2018). A positive correlation between the sensory motor middle temporal gyrus (Abdallah et al., 2017). network and a cluster containing the PCC and subjective effects Another study looked at the delayed effects of ketamine, com- of perception under ketamine was also identified in another study pared to placebo, 2 days and 10 days after the ketamine adminis- examining the psychotomimetic effects of several pharmacologi- tration on MDD patients and HCs. An ROI approach was used in cal compounds including ketamine, this study however, had a order to assess connectivity changes in the SN, the central execu- very small sample size (n = 5) (Kleinloog et al., 2015). tive control network and the DMN. At baseline, MDD patients exhibited decreased connectivity between the DMN and the right Global connectivity and pattern recognition tech- dorsolateral PFC (BA6 and BA9) and the left postcentral gyrus niques. When GBC was assessed at a whole-brain level, ket- (insula to BA43). When the effects of ketamine were compared amine (n = 22) produced a significant increase across all voxels in to placebo, 48 h (day 2) after the drug administration, between the brain (Driesen et al., 2013), compared to placebo. Moreover, MDD and HCs, smaller differences in the connectivity between increases in GBC in several cortical and subcortical brain areas the DMN and the insula were identified for the two groups which predicted the presence of positive symptoms or the absence of normalised at day 10. In contrast, the ACC showed increased negative symptoms as measured by the PANSS. Pattern recogni- connectivity in the HCs compared to MDDs at day 2 that was still tion techniques were also used to compare ketamine and placebo apparent at day 10 and was not present at baseline scans or the (n = 18) and it was shown that ketamine produced a pattern of placebo session (Evans et al., 2018). brain activations that could be discriminated from placebo with Using the same data set, Kraus and colleagues used GBC in high accuracy (Joules et al., 2015). The nodes that appeared to order to assess connectivity changes in MDD patients com- have a strong presence in the pattern were subcortical nodes pared to HCs and examine the effects of ketamine. At baseline, including the caudate, thalamus and cerebellum. These showed MDD patients had decreased GBC at the middle Cingulate increased connectivity on ketamine, whereas the cortical nodes Cortex (MCC) and the ACC. When the GBC was examined on average showed decreased connectivity on ketamine. specifically at the PFC, it was shown that at baseline MDD patients had decreased connectivity in the right superior frontal cortex and the right middle frontal cortex. However, no signifi- Delayed effects of ketamine administration cant changes were observed between the ketamine and placebo on brain connectivity – healthy volunteers sessions in MDD patients (Kraus et al., 2020). The same data set was also used to assess the effects of ketamine on striatal Two studies have investigated the delayed (24-h post-administra- connectivity. It was shown that 2 days after the ketamine tion) effects of ketamine in healthy volunteers (n = 24) using administration, MDD patients presented with increased con- resting-state fMRI. The first study examined the connectivity nectivity between the different striatal seeds and areas of the between the pACC and dPCC, and it was shown that 24-h post- prefrontal cortex, ACC and OFC. Decreased connectivity was ketamine connectivity reduced between those two brain areas. identified, after ketamine in healthy volunteers. Increased con- Moreover, the reduction in connectivity between these two areas nectivity between the dorsal caudate and the ventromedial pre- correlated with increased acute psychotomimetic symptoms frontal cortex, 2 days and 10 days after ketamine, also correlated (Lehmann et al., 2016). The second study (n = 17) used as seeds with a reduction in anhedonia in the MDD group (Mkrtchian key brain areas of the cognitive control network (bilateral et al., 2020). DLPFC), the DMN (bilateral PCC) and the Affective Network Kotoula et al. 19 Finally, in a study by Vasavada et al., the effects of four keta- recall and a bias towards negative affect and is not currently tar- mine infusions on the connectivity of the amygdala and the hip- geted successfully by commonly prescribed antidepressants pocampus with the Central Executive Network (CEN), the DMN (Jones et al., 2008). It is striking, however, that only two of the and the SN were examined and compared to placebo. Decreased thirteen studies identified in treatment-naïve depressed individu- connectivity between the amygdala and the left CEN as well as als have reported significant changes in DMN connectivity. In the increased negative connectivity between the right hippocampus study by Yan et al., when a very large sample of first-episode, and the left CEN was identified when connectivity was assessed treatment-naïve individuals were compared to HC, connectivity 24 h after the first infusion and was compared to baseline. This within the DMN did not differ between the two groups. Most increase in hippocampal connectivity predicted decreases in interestingly, when DMN connectivity was compared between the anhedonia. When the effects of ketamine on connectivity were first-episode, treatment-naïve patients and first-episode patients assessed 24–72 h after the fourth infusion and were compared to receiving treatment at the time of the scan, it was shown that the baseline, ketamine increased the connectivity between the amyg- medicated patients exhibited significantly reduced connectivity. dala and the right CEN as well as the negative connectivity This result could indicate that some of the previous research find- between the right hippocampus and the left CEN and decreased ings about the DMN showing significantly altered connectivity the connectivity between the left amygdala and the SN and this between depressed patients and HCs could partly be attributed to change predicted improvements in anxiety (Vasavada et al., antidepressant treatment (Yan et al., 2019). The long-term and 2021). A summary of those studies can be found in Table 3. short-term effects of antidepressant treatment on brain connectiv- ity are not very well-understood and could, along with methodol- ogy inconsistencies, explain why in this review there in no great overlap between the brain areas that present with altered connec- Discussion tivity in treatment-naïve depressed individuals and the treatment- Drug-naïve MDD connectivity research resistant depressed patients who are recruited in the ketamine studies when they are compared to control individuals. It is thus The studies that investigate connectivity changes in MDD drug- crucial for research studies to properly report the medication sta- naïve patients (Table 1) can be divided into two groups. The first tus of their participants. group includes studies that examine brain regions which are important for emotional regulation and cognition such as the hip- pocampus, fronto-limbic areas, the caudate and the NA (Cao Ketamine’s effects in healthy volunteers et al., 2012; Gong et al., 2017; Yang and Wang, 2017). The sec- ond group comprises of only two studies that look at the DMN Acute ketamine effects in healthy volunteers. In general, connectivity by examining this network as a whole (Zhu et al., acute ketamine administration in healthy volunteers caused an 2012) and by selecting DMN seeds for connectivity analyses overall increase in brain connectivity (Anticevic et al., 2015; Dri- (Zhu et al., 2017). esen et al., 2013). This was a consistent finding despite the differ- In order to examine the brain regions that are important for ent methodologies used by different studies. An overall increase emotional regulation, which appears to be problematic in depres- in brain connectivity during the ketamine infusion (acute ket- sion and investigate how their connectivity might differ between amine administration) was associated the positive and negative patients and HCs, most studies have used seed-to-whole-brain symptoms psychosis-like symptoms produced by the drug. connectivity approaches. The findings of these studies demon- Changes in brain connectivity have been linked to changes in strate that the ventral caudate and the superior temporal gyrus, synaptic plasticity (Stampanoni Bassi et al., 2019) and might be which are often associated with emotional regulation and reward necessary for the initiation of mechanisms – at the brain and neu- processing presented with increased connectivity with the occipi- ronal level – that would mediate the antidepressant effects of the tal lobe and the precuneus (Yang and Wang, 2017) whereas the drug. NA, also involved in reward processing, showed increased con- When brain networks were examined separately, acute keta- nectivity with several brain areas including the bilateral caudate, mine administration produced changes in the connectivity of the the medial OFC and the rostral ACC (Gong et al., 2017). The DMN, the executive control network as well as networks that insula, however, a key region for interoceptive awareness and play an important role in the initiation of sedation and uncon- emotional regulation (Namkung et al., 2017), presented with sciousness. The increased connectivity of these networks under decreased connectivity with brain regions that are part of the acute ketamine administration could be associated with the fronto-limbic circuitry (Guo et al., 2015). Some of these areas anaesthetic effects of the drug seen at higher doses. However, where connectivity changes have been identified such as striatal several studies that specifically focused on connectivity changes areas and the ACC present with lower glucose metabolism (Su within the DMN network, a network that is particular interest to et al., 2014; Wei et al., 2016) as measured by PET in patients with depression, failed to report any significant differences after acute MDD indicating that these brain areas are promising targets for ketamine administration (Kleinloog et al., 2015; Mueller et al., pharmacological agents such as ketamine that alter glutamatergic 2018; Niesters et al., 2012). signalling. Within the group of regions associated with emotional regula- When DMN connectivity was examine and compared between tion and cognition and presented with increased connectivity treatment-naïve individuals and HC, increases were identified under ketamine, the hippocampus has been the most examined. between the different DMN subsystems as well as between the Research studies have identified increases in hippocampal con- DMN and the rest of the brain (Zhu et al., 2017). Increased DMN nectivity with several brain regions including the insula, the pre- activations have been linked to increased rumination, a very cuneus, and the parietal cortex after ketamine administration prominent characteristic of depression which persists in remis- compared to placebo (Grimm et al., 2015). This increase in hip- sion. Increased rumination is associated with overgeneral memory pocampal connectivity has been linked with ketamine’s effects 20 Brain and Neuroscience Advances on Long-Term Potentiation (Yan et al., 2019) and synaptic plas- with improvements in anhedonia and anxiety and further underlie ticity, a candidate mechanism for ketamine’s antidepressant the importance of the glutamatergic modulation of these brain action (Kavalali and Monteggia, 2020). Moreover, since the hip- areas for the antidepressant effects of the drug. pocampus mediates cognitive and spatial processing functions, this altered connectivity of the hippocampus could offer a poten- Limitations tial explanation for the cognitive impairments that are observed during acute ketamine administration (Corlett et al., 2007). Most of the studies that have looked at the acute effects of keta- mine in healthy volunteers have investigated ketamine as a model The delayed and antidepressant effects of ketamine on of psychosis. In order to validate their hypotheses, these studies brain connectivity. The antidepressant effects of ketamine are have selected to focus on brain regions that have been previously detectable 2 h after the administration of the drug, peak at 24-h identified in research as important for psychosis. These regions, post-infusion, and could last up to 1 week after a single ketamine however, do not necessarily overlap with the brain areas that are infusion (REF). Ketamine’s antidepressant action, if mirrored in key to the understanding of depression. Trying to reconcile the the brain as a normalisation of the changes in connectivity findings of the acute ketamine connectivity studies with those of observed in depression, would be expected to reverse some of the depression was therefore challenging. In addition, these studies changes in connectivity observed between MDD and HCs. often use bolus-infusion techniques for ketamine administration, The studies that have looked at the antidepressant effects of where the dose and duration of the infusion vary from study to ketamine on depressed individuals have shown that the decreased study, whereas when used as an antidepressant, a slow infusion is connectivity that was identified during the placebo session was given, usually over 40 min. The precise impact of these different reversed by ketamine. Specifically, GBC was found reduced in infusion regimens has not been directly compared, but it seems MDD compared to healthy participants that was increased 24-h the strength of the psychotomimetic effects may be reduced with post-ketamine administration (Abdallah et al., 2017); this find- the slower infusion (Ballard and Zarate, 2020). ing, however, failed replication (Kraus et al., 2020). The drug Moreover, our stringent inclusion criteria aiming to bypass effects on brain connectivity seem to persist even longer than the confounding effects of antidepressant medication on brain 24 h since the decrease in the connectivity between the DMN and structure (Dusi et al., 2015) greatly limited the number of studies the insula that was identified for MDD patients compared to HCs included in our review and so we decided not to exclude any was smaller 48 h after ketamine administration but returned to studies based on a sample size criterion. This mainly impacted baseline 10 days past the ketamine infusion (Evans et al., 2018). the HC studies where there were a number of smaller studies (e.g. Ketamine produced increases in the connectivity of striatal n = 12, 14, 17 and 18). Small sample sizes in neuroimaging and regions (Mkrtchian et al., 2020) with the dorsolateral and ventro- especially pharmacology studies that involve healthy volunteers lateral PFC, the pregenual ACC and the OFC in depressed indi- have been a great concern in the field and could obscure true viduals, while decreases were observed for the same set of brain finding. In addition, different connectivity methodologies have regions in healthy volunteers. Moreover, the increases and been used to examine the differences in brain connectivity decreases in the connectivity of the amygdala and the hippocam- between healthy individuals and treatment-naïve depressed pus also lasted for more than 24 h and were detectable after mul- patients as well as the acute and delayed effects of ketamine and tiple ketamine infusion (Vasavada et al., 2021). this would also be a confounding factor that could potentially In healthy volunteers, however, our literature search revealed explain inconsistencies in the results of these studies. that 24-h post-ketamine administration, the connectivity of the Most of the studies with drug-naïve depressed patients that DMN decreased compared to the placebo session (Scheidegger have been included in our review recruited either first-episode et al., 2016) and the connectivity between the pACC and dPCC depressed participants or patients with MDD without any history also decreased 24-h post-ketamine (Lehmann et al., 2016). This of treatment. The number of studies that failed to explicitly iden- potentially differential effect that the drug produces in depressed tify whether the patients received treatment or not was also strik- and healthy participants is rather interesting since it indicates that ing. The majority of those studies were also conducted with an ketamine’s antidepressant effects could be specific to networks exclusively Chinese sample perhaps limiting the generalisation and deficits that are present in MDD and could be associated with of these findings. Furthermore, no follow-up studies that we are neurotransmitter deficits that are observed in depression. aware of have looked at treatment response in those samples. We Several studies have looked at the delayed effects of keta- could thus assume that those studies consist of both treatment mine, 2–24 h post-administration in depressed individuals and responders as well as treatment-resistant patients. The resting- have used PET imaging to assess changes in glucose metabolism. state studies that have looked at ketamine as an antidepressant Most of the findings of those studies show effects in limbic areas mainly focus on treatment-resistant patients since the clinical such as the amygdala (increased glucose metabolism post-keta- efficacy of ketamine has been most studies in these cases. The mine) (Carlson et al., 2013) and the hippocampus (decreased glu- putative neuronal differences characterising these sub-groups are cose metabolism post-ketamine) (Nugent et al., 2014), brain currently unknown. Whether ketamine would have a differential areas that present with altered connectivity in depression and are effect on responders and non-responders to conventional antide- thus potential targets for pharmacological modulation. Although pressant treatment requires further investigation. only two studies so far have looked at the effects of ketamine on Finally, there is evidence that in pharmacological MRI and the striatum (Mkrtchian et al., 2020), the amygdala and the hip- especially with NMDA receptor antagonists (acute ketamine pocampus (Vasavada et al., 2021), the fact that the drug produces administration), the tight relationship between the neuronal detectable and long-lasting changes in the connectivity of these activity and regional blood flow is disrupted (Golanov and Reis, areas is rather promising, Some of these changes also correlate 1996; Långsjö et al., 2004). This makes the interpretation of the Kotoula et al. 21 results of acute ketamine studies challenging since they could, at ORCID iDs least partly, be attributed to the vascular effects of the drug Vasileia Kotoula https://orcid.org/0000-0002-6391-0285 (Iannetti and Wise, 2007). 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Journal

Brain and Neuroscience AdvancesSAGE

Published: Nov 15, 2021

Keywords: Ketamine; resting state; acute ketamine changes; delayed ketamine effects; major depressive disorder

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