O r i g i n a l P a p e r

Psychopathology 2015;48:376–385 Received: March 20, 2015 DOI: 10.1159/000438675 Accepted after revision: July 11, 2015 Published online: September 12, 2015

Ketamine-Induced

a, c a, c b a, c A l b e r t R. Powers I I I M a r k G. G a n c s o s E m i l y S. F i n n P e t e r T. M o r g a n a, c Philip R. Corlett a b Department of Psychiatry, Yale School of Medicine, Interdepartmental Neuroscience Program, Yale University, c and Connecticut Mental Health Center, New Haven, Conn. , USA

K e y W o r d s ner and offer an explanation grounded in predictive coding Ketamine · Hallucinations · Predictive coding · · models of perception and psychosis – the brain fills in ex- Computational psychiatry · Prediction · Psychosis pected perceptual inputs, and it does so more in situations of altered perceptual input. The altered perceptual input of the MRI scanner creates a mismatch between top-down per- A b s t r a c t ceptual expectations and the heightened bottom-up signals Background: Ketamine, the NMDA glutamate receptor an- induced by ketamine. Such circumstances induce aberrant tagonist drug, is increasingly employed as an experimental percepts, including musical and auditory verbal hallucina- model of psychosis in healthy volunteers. At subanesthetic tions. We suggest that these circumstances might represent doses, it safely and reversibly causes delusion-like ideas, a useful experimental model of auditory verbal hallucina- amotivation and perceptual disruptions reminiscent of the tions and highlight the impact of ambient sensory stimuli on aberrant salience experiences that characterize first-episode psychopathology. © 2015 S. Karger AG, Basel psychosis. However, auditory verbal hallucinations, a hall- mark symptom of schizophrenia, have not been reported consistently in healthy volunteers even at high doses of keta- mine. Sampling and Methods: Here we present data from a I n t r o d u c t i o n set of healthy participants who received moderately dosed, placebo-controlled ketamine infusions in the reduced stim- The introduction of phencyclidine (PCP) and its phar- ulation environment of the magnetic resonance imaging macological relative, ketamine, as anesthetic agents in the (MRI) scanner. We highlight the phenomenological experi- late 1950s and early 1960s was followed in short order by ences of 3 participants who experienced particularly vivid the recognition of their psychotomimetic effects [1] . In hallucinations. Results: Participants in this series reported the years since, ketamine has been employed as an ex- auditory verbal and musical hallucinations at a ketamine perimental model of psychosis, reproducing the positive dose that does not induce auditory outside of and negative symptoms of schizophrenia transiently, re- the scanner. Conclusions: We interpret the observation of versibly and safely in healthy nonpsychotic volunteers ketamine-induced auditory verbal hallucinations in the con- [2] . A noncompetitive NMDA (N-methyl-D -aspartate) text of the reduced perceptual environment of the MRI scan- receptor antagonist, ketamine has been instrumental in

© 2015 S. Karger AG, Basel Philip R. Corlett, PhD 0254–4962/15/0486–0376$39.50/0 Abraham Ribicoff Research Facilities Connecticut Mental Health Center E-Mail [email protected] 34 Park St., New Haven, CT 06511 (USA) www.karger.com/psp E-Mail philip.corlett @ yale.edu establishing a potential role for glutamatergic signaling in malities as hallucinations in standard scales like the Brief psychosis [3, 4] . Inconsistently present in the constella- Psychiatric Rating Scale (BPRS [14] ) while stating sepa- tion of ketamine-induced symptoms, however, are audi- rately that these may not represent true hallucinations tory verbal hallucinations, a hallmark of schizophrenia [10] , while others have maintained that true hallucina- described in 60–80% of patients [5, 6]. Here we evaluate tory experiences have not arisen in trials of ketamine ad- descriptions of perceptual abnormalities produced by ministration and that the perceptual effects of ketamine acute exposure to PCP and ketamine and present 3 cases are better characterized as illusions or sensory distortions of hallucinatory experiences with ketamine administra- [2, 7, 8] . tion in a functional neuroimaging setting. We attempt to Despite this seeming paucity of reports describing hal- explain the inconsistent presence of hallucinations fol- lucinations in the setting of controlled administration of lowing ketamine within a predictive coding framework. ketamine, several case reports do describe hallucinations Table 1 highlights the perceptual abnormalities re- during acute treatment with ketamine and in the hours, ported in placebo-controlled investigations of the aryl- days and weeks following dosing. One such case report cyclohexamine family of noncompetitive NMDA antago- describes vivid visual hallucinations associated with re- nists, of which ketamine and PCP are members. Notable covery from ketamine anesthesia [15] with spontaneous similarities among the studies include the amplification resolution and intact memories for the said phenomena or sharpening of sensory input [2, 7, 8] and alteration of (typically referred to as emergence phenomena [13] ). A the spatial and temporal relationships within or among similar emergence pattern was observed in another study individual sensory streams [1, 2, 9, 10] . Hallucinations are [16] meant to examine the rate of psychiatric adverse re- described only intermittently and, in many cases, vaguely actions in patients in a general hospital setting receiving enough for the discerning reader to suspect conflation intravenous ketamine at subanesthetic doses (mean = with sensory illusions – that is, distortions or amplifica- 0.19 mg/kg/h) for pain control. Here the authors reported tions of stimuli that are actually present [8, 11] . Some of hallucinations in 4 of 50 patients, although they did not the earliest accounts of PCP and ketamine responses de- elaborate further on the nature of these phenomena. In- scribe memory-driven dissociative experiences that were triguingly, these hallucinatory emergence phenomena rich in sensory detail. Luby et al. [1] described so-called have at times been reported to extend beyond the acute ‘hypnogogic states’ produced by PCP: phase of administration. One case report describes an in- cident in which an 11-year-old boy experienced a vivid The subjects reported feeling as though they were in some spe- visual hallucination of his grandmother at his bedside cific setting and were able to describe it in detail. While the reports typically had reference to past events, they were expressed as during emergence from ketamine anesthesia but also spo- though the experiences were taking place at the moment. radically for 5 days following initial recovery from anes- thesia while lying in bed [17] . In another pediatric case, The authors provide a striking example – a participant Meyers and Charles [18] describe the experience of a who experienced the full sensory array associated with a 3-year-old girl who reported malicious red and green scene from his childhood: lights in the room 30 min after recovery from ketamine anesthesia but continued to report similar phenomena at He stated that he was in his third-grade classroom, which he described elaborately, including the recognition of an old friend in least 1 day afterward and even developed fears of traffic the classroom. lights. In this case, nightmares involving her hallucina- tory experience persisted for 1 year after ketamine anes- This is echoed in a later description of prominent ei- thesia. Similarly, Fine and Finestone [19] report vivid detic imagery (but otherwise a lack of outright hallucina- dreams in 80% of patients given ketamine at anesthetic tions) by Stone and Pilowsky [12] during ketamine ad- doses and provide 3 cases of visual hallucinations in these ministration in healthy volunteers. Similarly, the earliest patients, who continued to experience flashback-like vi- descriptions of ketamine’s psychotomimetic effects in- sual disturbances in the weeks following administration. clude the presence of memory-like ‘frank hallucinations’, The first case is that of a vivid dream of riding a rocket although these are not characterized in more detail [13] . downward, with recurrence of these sensations for 3 Indeed, discerning such dissociative or illusory experi- weeks afterward, but only when descending a staircase. ences from ‘true’ hallucinations has posed a practical The second case was similar, with floating/flying sensa- problem in this literature. Some, like Newcomer et al. tions noted during recovery from ketamine and a 1-week [10] , solved the dilemma by rating all perceptual abnor- history of the same sensation afterward. The last case de-

Ketamine-Induced Hallucinations Psychopathology 2015;48:376–385 377 DOI: 10.1159/000438675 Table 1. Characteristics and findings of systematic studies of psychotomimetic properties of PCP and ketamine

Authors Year Design Sample NMDA Dose Perceptual findings [Ref.] antagonist

Luby 1959 Nonplacebo- 9 TD PCP 0.1 mg/kg i.v. for 12 min Perceived limb lengthening; feelings of flying; et al. [1] controlled PCP 9 SZ complete change in setting to past experience; administration ‘sensory experiences were overvalued if not eroticized’; mild diminution in auditory and visual acuity Lawes [7] 1963 2 × 3 dosage group 8 TD PCP Group A (n = 5): 5 mg p.o. Amplification or alteration in quality of sounds, vs. environmental Group B (n = 3): 10 mg p.o. sharpening of vision, room expansion; body stimulation level ‘lightness’; dose-response relationship observed Oye 1992 Double-blind 6 TD Ketamine S-ketamine: 0.05, 0.1, 0.15, 0.2 Blurred vision, visual field narrowing; et al. [60] crossover with mg/kg i.v. preoccupation with irrelevant environmental 4 doses of R-ketamine: 0.2, 0.4, 0.6, 0.8 stimuli; sound amplification 2 enantiomers, mg/kg i.v. 2 placebo doses Krystal 1994 Double-blind 19 TD Ketamine Low dose: 0.1 mg/kg i.v. Increased perceived intensity or closeness within et al. [2] placebo-controlled High dose: 0.5 mg/kg i.v. a discrete spatial field; no outright hallucinations 2-dose level noted crossover Vollenweider 1997 Within-subject 10 TD Ketamine Loading dose of 15 mg i.v. Visual illusions as well as complex hallucinations et al. [41] placebo-controlled racemic ketamine followed by present with S-ketamine administration; auditory counterbalanced continuous infusion of hyperacusis but no hallucinations noted trial 0.014 – 0.02 mg/kg/min Bowdle 1998 Single-blind 10 TD Ketamine Intravenous administration set Hallucinations as rated on a visual analog scale et al. [11] placebo-controlled to keep plasma concentration at (‘I heard voices or sounds that were not real’) crossover 0, 50, 100, 150, 200 ng/ml in differed significantly between ketamine and progressive steps saline and correlated with plasma concentration; these experiences are not described further Newcomer 1999 Double-blind 15 TD Ketamine Loading: 0.27, 0.081, 0.0243 Visual distortions (e.g. hands perceived as et al. [10] placebo-controlled mg/kg i.v. shrunken, ‘shadow of a body falling’ noted in 3-dose level Maintenance: 0.00225, window); no outright hallucinations noted 0.000675 and 0.0002025 mg/kg/min Lahti 2001 2 × 2 group by 18 TD Ketamine 0.3 mg/kg i.v. Formed auditory hallucinations (e.g. articulated et al. [40] placebo vs. drug 17 SZ voices) in SZ subjects (despite low levels of crossover positive symptoms outside drug administration), and in a minority of TD subjects; visual and olfactory hallucinations in both groups Gouzoulis- 2005 Double-blind 15 TD Ketamine Ketamine: 0.1 mg/kg i.v. (low) Limb lengthening and other somatic distortions; Mayfrank 2-drug, 2-dose and DMT and 0.2 mg/kg i.v. (high) visual hallucinations present in 1 subject on et al. [9] crossover DMT: 0.15 mg/kg (low) and ketamine; auditory distortions but no 0.3 mg/kg (high) hallucinations reported; DMT with more pronounced visual and auditory phenomena and musical hallucinations and whispers occurred in 2 cases; visual hallucinations on DMT were present in all subjects at high dose levels

Pomarol- 2006 Experimental case 15 TD Ketamine Intravenous administration set Increased sensitivity to noise and increased Clotet series for to keep plasma concentration at brightness of colors; loss of visual depth et al. [8] phenominological 100 ng/ml, then 200 ng/ml perception; alterations in perceived size, shape or description position of body parts; 1 participant reported sensing the presence of more people than were visibly present and hearing voices that were unable to be accounted for by those present

TD = Typically-developing; SZ = schizophrenia.

378 Psychopathology 2015;48:376–385 Powers III/Gancsos/Finn/Morgan/Corlett DOI: 10.1159/000438675 scribes vivid dreams of seeing faceless people around the Scale (PANSS [25] ), which is designed to assess positive, negative recovery bed followed by 1 week of experiencing the same and general psychotic symptoms. It should be noted that, unlike other uses of the PANSS in the setting of ketamine administration visions after lying down in bed. All of these experiences [10], our approach rated perception in the absence of physical resolved spontaneously after several months. stimulus (true hallucinations) on the P3 hallucinatory behavior Despite the well-documented nature of the perceptual item and did not take into account perceptual distortions or illu- disturbances often experienced with ketamine adminis- sions. It should also be noted that these ratings reflected phenom- tration, there remains significant discrepancy regarding ena in any of the sensory systems (auditory, visual, olfactory/gusta- tory, or somatic) and did not necessarily reflect the presence of the presence, characteristics and environmental settings auditory hallucinations (although see vignettes below, in which the necessary for the experience of hallucinations induced by hallucinations were primarily auditory, sometimes visual and so- NMDA antagonists. Here we present data from partici- matic and rarely olfactory/gustatory). pants taking part in a pharmacological functional neuro- We also report phenomenological descriptions from 3 partici- imaging study [20] , highlighting the phenomenological pants who experienced auditory verbal and musical hallucinations while in the MRI scanner on ketamine (rated on the PANSS as a experiences of 3 participants who experienced particu- score of 3 or higher). We only considered quantitative and qualita- larly vivid hallucinations, and discuss the implications of tive data from study visits when individuals were pretreated with these findings for the role of predictive coding in halluci- 0 mg of metabotropic glutamate receptor partial allosteric modula- nations. tor (thus, ‘placebo’ here refers to the period of saline infusion, which always preceded the period of ketamine infusion). Other clinical and neuroimaging data will be the subject of future reports.

M e t h o d s

The present data were drawn from a double-blind, placebo-con- R e s u l t s trolled, randomized, within-subject design. Subjects completed 3 visits, prior to which they were randomly assigned to pretreatment with a different dose of a partial allosteric modulator of metabo- Ketamine-Induced Symptoms tropic glutamate receptors (0 mg/placebo, 50 or 180 mg). In the Analysis of symptom scores was performed on the en- magnetic resonance imaging (MRI) scanner, during saline and ket- tire sample of 19 participants. Compared with ratings pri- amine administration, subjects completed a delayed spatial work- or to the infusion, ketamine induced positive, negative ing memory task described in detail in a prior publication [21] . and general symptoms ( fig. 1 ). Repeated-measures analy- Subjects sis of variance with drug (placebo/ketamine) and symp- All subjects provided informed consent approved by the Insti- tom (positive, negative and general) factors revealed a sig- tutional Review Board at Yale University. A total of 20 healthy, nificant main effect of drug (F 1, 19 = 45.8, p = 0.001) and neurologically and psychiatrically intact right-handed volunteers symptom (F 2, 38 = 263.2, p = 0.0001) and a significant drug (10 male) with a mean ± SD age of 27.5 ± 6.3 years were recruited × symptom interaction (F = 6.9, p = 0.004, applying from the local community by advertisement. Subjects were 1.8, 34.5 screened using an initial telephone interview and subsequent per- Huyhn-Feldt correction for nonsphericity of the covari- sonal interview. Psychiatric or physical illness, head injury, drug ance matrices). Post hoc tests revealed that ketamine en- or dependence, and smoking were excluding factors, as gendered more positive than negative symptoms (t = 2.9, were family history of psychiatric illness and alcohol problems. d.f. = 19, p = 0.008) and more general than negative (t = 13.3, d.f. = 19, p = 0.0001) or positive symptoms (t = 13.3, Infusion Protocol Subjects were administered racemic ketamine (1 mg/ml; Bed- d.f. = 19, p = 0.0001). For the purposes of the present ford Laboratories) intravenously via initial bolus (0.23 mg/kg to be study, we examined the positive symptoms more closely administered over 1 min) followed by subsequent continuous infu- with a similar analysis – repeated-measures analysis of sion of 0.58 mg/kg/h for 75 min. Prior studies from our laboratory variance with drug (placebo/ketamine) and symptom di- using very similar infusion paradigms consistently produced plasma mension (delusions, hallucinations, conceptual disorga- ketamine levels during infusion of approximately 200 ng/ml [22] and reliably and transiently produced positive symptoms, negative nization, hostility, persecution, excitement, grandiosity, symptoms and cognitive impairments redolent of schizophrenia and unusual thought content). This revealed a main effect [23]. This infusion approach produces stable effects across repeated of drug (F1, 19 = 36.4, p = 0.0001) and symptom dimension test days on most behavioral outcome measures [24] a n d d o e s n o t (F5, 92 = 8.4, p = 0.009) and a significant drug × symptom appear to be associated with persisting negative effects [23] . dimension interaction (F1, 19 = 8.79, p = 0.008, applying Clinical Measures Huyhn-Feldt correction). Post hoc tests revealed that hal- Subjects underwent clinical rating scales before and after infu- lucinations were the most common symptom, with hal- sions. Here we focused on the Positive and Negative Syndrome lucination scores exceeding those of the other PANSS

Ketamine-Induced Hallucinations Psychopathology 2015;48:376–385 379 DOI: 10.1159/000438675 25 Placebo Ketamine

20

15

10

Total PANSS subscale score PANSS Total 5

0 a Positive Negative General

4.0

3.5

3.0

2.5

2.0 Fig. 1. Ketamine-induced symptoms. a To- tal PANSS subscale scores for all 19 par- 1.5 ticipants tested after placebo and ketamine 1.0 administration. b PANSS component component score PANSS scores for all positive symptoms (P1–P7) 0.5 and 1 general symptom dimension (G9). 0 Analysis revealed a main effect of drug (F 1, 19 = 36.4, p = 0.0001) and symptom di- mension (F 5, 92 = 8.4, p = 0.009) and a sig- P7: hostility P1: delusions nificant drug × symptom dimension inter- P4: excitement P5: grandiosityP6: persecution P3: hallucinations action. Post hoc tests revealed that halluci- P2: disorganization nations were the most common symptom, with hallucination scores exceeding those b G9: unusual thought content of the other PANSS items. Error bars = 1 SEM.

items (e.g. P3, hallucinatory behavior, vs. P1, delusions, fore the infusion. As the infusion began, she felt that the t = 5.01, d.f. = 19, p = 0.001). computer screen in front of her turned into a soccer pitch and she could see the players on it. She described Case Descriptions how the head coil transformed into a soccer goal. She Case 1 : Subject 23 (Hallucinations Component Score, felt transported to a specific soccer game, the 2005 FIFA P3 = 5, Total Positive Symptoms Score = 16) Champion’s League Final in Istanbul, Turkey, between This 21-year-old female graduate student volun- Liverpool FC and AC Milan – believing she was there. teered for our research study and passed our screen for She could hear the Liverpool fans in the crowd singing safety and appropriateness of participation. She de- ‘You’ll Never Walk Alone’. She felt irritated because in scribed herself as a soccer fan and had been watching a the first half of the game Liverpool conceded 3 goals, but lot of soccer the day before the infusion (including a she knew what would happen after half-time (Liverpool penalty shoot-out in the World Cup). One of the au- scored 3 goals to tie the game and won in a penalty thors (P.R.C.) had discussed this shoot-out with her be- shoot-out) and felt superior to the others in the crowd

380 Psychopathology 2015;48:376–385 Powers III/Gancsos/Finn/Morgan/Corlett DOI: 10.1159/000438675 around her because they did not know this and she that although he was stationary in the scanner, he was also would not share it with them. moving. He described the noise of the scanner turning into music and that the music changed his vision – he Case 2 : Subject 30 (Hallucinations Component Score, heard the Nutcracker Suite and saw the wooden soldiers, P3 = 5, Total Positive Symptoms Score = 16) he heard Yellow Submarine by the Beatles and saw the This 21-year-old female graduate student volunteered animated characters from that movie, and he heard the and qualified for our research study. When the infusion entirety of the album Diamond Dogs by David Bowie. began and her first blood sample was drawn (for plasma ketamine assay), she became concerned that something had gone awry with the experiment. She thought that she D i s c u s s i o n might have died and that her left arm had disappeared. She reported thinking more about life and its purpose and that Despite its reputation as a hallucinogen, subanesthetic her philosophy was ‘somewhere between Dr. Who and the ketamine does not consistently produce frank hallucina- Matrix’ (she had been watching Dr. Who the day before). tions. We report 3 cases of placebo-controlled ketamine She asked: ‘What if existence isn’t real? What if everyone administration that produced frank musical and auditory is a figment of my imagination?’ She described having less verbal hallucinations accompanied by dissociation and a control over her thoughts and that one of the authors loss of insight. The experiences of these 3 participants, (P.R.C.) had taken control of her thoughts whilst she stood while discussed in detail here because of the finer points back. At the same time, she described being able to predict of their phenomenology, are consistent with the larger the trials of a working memory task before they happened. sample of subjects participating in this paradigm and thus She felt disconnected from her body and she imagined she represent a departure from the historically inconsistent was talking whilst in the scanner, receiving the infusion. inclusion of hallucinations among the symptoms pro- When told that she had not been talking during the infu- duced by ketamine. sion, she related that her thoughts were being broadcast We now attempt to reconcile these disparate reports out loud. She reported hearing the voices of friends and by considering how hallucinations arise within the infor- family members talking, reassuring her about her future. mation-processing hierarchy of the brain and why the She described how the noise of the MRI scanner came to relatively sparse sensory environment of the MRI scanner sound like drums and then more complete music – music might be particularly conducive to the genesis of halluci- she had not heard before. Overall, she rated her experi- nations under ketamine. A number of recent works [26– ences as pleasant and enjoyable. 28] have posited a Bayesian framework for understanding the relationship between top-down predictive coding and Case 3 : Subject 42 (Hallucinations Component Score, bottom-up inference in perceptual processing. We pro- P3 = 4, Total Positive Symptoms Score = 17) pose that ketamine perturbs the balance between priors, This 30-year-old male real estate agent participated in prediction errors and their precision [29] , such that bot- our study having passed our screening telephone call and tom-up noise is enhanced and top-down priors attempt in-person interview. He described the ketamine infusion to accommodate the noise [27] . There are rodent [30] and as being ‘like a tidal wave’ that made him think more human [31] data that support this notion. about black holes and cosmology. He described feeling Additionally, quantitative approaches to ketamine’s confused and ‘befuddled’, which made him distrust the effects on sensory processing have produced results that study team that was working with him but at the same match qualitative reports of sensory amplification. time feeling that we were his ‘oldest and best friends’. He Plourde et al. [32] determined that, unlike most general described the world becoming ‘spaghetti-like’ – vertical anesthetics, ketamine produces an increase in auditory lines pervaded his vision. His inner speech, the thoughts event-related gamma-band oscillations in patients ad- in his head, became very clear at times and dulled at oth- ministered anesthetic doses. Similar increases in gamma- ers. Being in the scanner, he saw part of his face reflected band oscillations have also been demonstrated in somato- in the mirror used to present tasks and felt he looked dis- sensory-evoked potentials in subjects administered sub- torted, as though he had undergone plastic surgery (‘I anesthetic ketamine [13] . In the context of predicted looked like Joan Rivers’). He felt at times he was being normal ambient input, top-down priors can be mobi- brainwashed (‘like in A Clockwork Orange ’ – the novel by lized, resulting in delusion-like interpretations of aber- Anthony Burgess and the movie by Stanley Kubrick) and rant salience, but not hallucinations [27] ( f i g . 2 , l e f t p a n -

Ketamine-Induced Hallucinations Psychopathology 2015;48:376–385 381 DOI: 10.1159/000438675 Environmental conditions Normal stimulus level Low stimulus level Normal perceptual balance Enhanced signal detection Increased false alarms – Overinterpreted stimuli

Increased sensory salience Hallucinations Delusion-like ideas + Ketamine

Low High Low High Glutamate signaling Dopamine/acetylcholine signaling (signal) (gain)

Fig. 2. Influence of environmental conditions and ketamine ad- (darkened downward arrow). In the presence of ketamine (bottom ministration on perceptual processing. In the absence of ketamine panels), which blocks NMDA-mediated top-down signaling and and under everyday environmental conditions (top left panel), boosts AMPA-mediated bottom-up signaling (bottom left panel; there is a balanced equilibrium between bottom-up (upward ar- narrow downward arrow, widened upward arrow), increased sen- row) and top-down (downward arrow) processing in perceptual sory salience is observed and delusion-like ideas result. However, inference. If environmental information is minimized, resulting in in the setting of minimized environmental stimulation, the (nor- a decreased signal (via bottom-up AMPA-dependent glutamate mally adaptive) increased gain on top-down priors seen in this set- signaling; top right panel, narrowed upward arrow), improved ting combines with increased bottom-up prediction errors to pro- perceptual performance is achieved by increasing the (neuromod- duce experience-related hallucinations. ulator-mediated) gain on top-down priors in perceptual inference

els). However, in the reduced perceptual environment of neural firing within its optimal dynamic range [28] . Sim- the MRI scanner ( fig. 2 , right panels), perceptual expecta- ilar phenomena have been described in the auditory sys- tions are already being violated, which triggers prediction tem. Indeed, most investigations of musical hallucina- error responses that are exacerbated by ketamine. A more tions have focused on their tendency to arise in the con- robust top-down response is mounted (as a result of the text of deafferentation of the central auditory processing sensory isolation) and hallucinations result. We have pro- hierarchy via sensory deprivation or, most commonly, posed that this enhanced top-down response is mediated progressive sensorineural hearing loss [35–37] . However, by the slow neuromodulators dopamine and acetylcho- recent work has investigated musical hallucinations oc- line [27] , which have been shown to mediate attentional curring in the setting of cochlear implantation [38, 39] . In gain on incoming sensory information [33] and encode the most recent study only 7 of the 18 patients reporting salience of environmental stimuli [34] . musical hallucinations had such experiences before co- Efforts in computational modeling of perception have chlear implantation [38] . The remainder (61%) devel- had some success using simple neural network models to oped the phenomenon following the operation. Of these help explain the occurrence of hallucinations in cases of 7, many reported that cochlear implant placement had sensory deprivation like Charles-Bonnet syndrome [28] , made the musical hallucinations less prominent, but 2 re- in which deafferentation of lower levels of the visual pro- ported that they became louder with implantation [38] . cessing hierarchy gives rise to homeostatic mechanisms We speculate that implantation introduces new sensory that increase excitability of the network and result in inputs that have yet to be properly accommodated by top- spontaneous activation of complex perceptual represen- down priors and, during that process, musical hallucina- tations in deep association layers. This is plausible given tions arise as attempts to accommodate the new inputs in the model’s performance in rapid deafferentation and the a system accustomed to the absence of bottom-up infor- rapid effects of homeostatic mechanisms meant to keep mation. If true, this process would predict the observation

382 Psychopathology 2015;48:376–385 Powers III/Gancsos/Finn/Morgan/Corlett DOI: 10.1159/000438675 of hallucinations in ketamine under conditions of sparse studies definitively noting the absence of true hallucina- sensory input, as described here. tions in the presence of ketamine. With this framework in mind we may return to the The data analyzed here are derived from only one of case reports reviewed in the introduction and in table 1 . several studies in which ketamine was administered It is notable that most reports of true hallucinatory phe- during fMRI data acquisition. Unfortunately, the major- nomena follow emergence from higher-dose ketamine ity of these [42–49] do not specifically address percep- anesthesia (as reviewed in Introduction). In those studies tual abnormalities in subjects, providing only general employing placebo-controlled subanesthetic ketamine it PANSS scores. Other studies, similar to those noted is often unclear whether reports and ratings of hallucina- above, do report an increased rate of auditory percep- tions were in fact illusions (distortions of stimuli that tual abnormalities under ketamine but do not differenti- were actually present [10] ). However, among the 10 stud- ate between frank hallucinations and sensory distor- ies of controlled ketamine administration listed, we may tions or illusions [50, 51] . Two studies have specifically identify 4 that reported the occurrence of true hallucina- commented on the occurrence of hallucinations in an tions in any sensory modality [9, 11, 40, 41] . The first of fMRI setting [52, 53], noting an increased rate of percep- these studies [41] took place in a PET scanner and report- tual abnormalities during ketamine administration, but ed complex visual (but not auditory) hallucinations. Giv- both separately describing an absence of frank halluci- en the relatively quiet and visually open nature of PET nations in subjects. It is notable that in both studies the scans compared with MRI scanners, this observation may ketamine infusion rate (target plasma concentration of be consistent with the model proposed here. Lahti et al. 100 ng/ml [52] and continuous infusion of 0.25 mg/ [40] administered ketamine to individuals with a diagno- kg/h) was markedly lower than that used here (0.58 mg/ sis of schizophrenia and to typically developing controls. kg/h) and may represent a dose-related manipulation of Crucially, while controls were noted not to experience the system we propose – as NMDA blockade/AMPA po- true hallucinations, patients were noted to experience tentiation increases with dose, so do the prediction error well-formed hallucinations (such as voices) – a fact that signals propagated up the hierarchy, further increasing may be related to altered dopaminergic signaling in these the need for top-down influence to explain them and individuals. Similar conclusions on the role of neuro- resulting in hallucinations. However, further studies modulators in hallucinations may be drawn from the in- will be required to fully test the effect of ketamine dose vestigation by Gouzoulis-Mayfrank et al. [9] of the psy- upon hallucination propensity under conditions of rela- chological impact of S-ketamine and the serotonergic tive sensory deprivation. hallucinogen N,N-dimethyltryptamine (DMT), which We note that the observations made here pertain to highlighted the relative prevalence of visual hallucina- acute intoxication with ketamine. Less is known about tions and pervasiveness of auditory hallucinations during chronic exposure. Lim [54] described a case series of 2 DMT administration, with only one occurrence of visual patients with chronic exposure to ketamine, averaging hallucination (cartoons running across a computer 4–5 months, who report enhanced sensation of environ- screen), during S-ketamine administration at the highest mental stimuli (e.g. taste, smells, music) observed in dose tested. Unfortunately, a washout period was includ- many acute studies but also report the occurrence of true ed and no effect of order was observed, although given the auditory, visual and tactile hallucinations with chronic model proposed here one may speculate that the preva- use. Chronic exposure leads to tolerance to subanesthetic lence of hallucinations under ketamine would increase ketamine [55] . In prior work we speculated that acute and even in subclinical plasma concentrations of DMT. Last- chronic ketamine differ in their impact on processes of ly, Bowdle et al. [11] conducted a single-blind placebo- learning and inference [29] . That is, acute ketamine is controlled crossover study with controlled plasma con- transient and reversible. As such, it impacts sensory infer- centrations of ketamine and noted that plasma concen- ences and, whilst on board, vitiates perception. However, tration of ketamine correlated significantly with a visual as it is metabolized, its synaptic effects subside and it does analog scale rating on the item ‘I heard voices or sounds not have long-lasting effects on learning (it does not en- that were not real’, but findings were not elaborated upon gender long-term changes in perceptual priors). Howev- beyond this and no details are available in the manuscript er, chronic ketamine abuse appears not only to engage detailing the environment in which participants pro- homeostatic changes in glutamate signaling, but it also duced these ratings. Similarly, scanty detail regarding the alters slower monoaminergic and cholinergic function environmental stimulus level is made available in those [56, 57] . These neuromodulators appear to code the gain

Ketamine-Induced Hallucinations Psychopathology 2015;48:376–385 383 DOI: 10.1159/000438675 on perceptual and learning prediction errors, that is, the A c k n o w l e d g m e n t s volatility or expected uncertainty of those parameters. A.R. Powers 3rd was supported by the Integrated Mentored Pa- Longer-term changes in those parameters may broaden tient-Oriented Research Training (IMPORT) in Psychiatry grant the perceptual possibility space and induce what Hoff- (5R25MH071584-07) as well as the Clinical Neuroscience Research man has referred to as a ‘listening attitude’ – broadly, Training in Psychiatry grant (5T32MH19961-14) from the NIMH. once a threshold of hallucinatory experiences has been Additional support was provided by the Yale Detre Fellowship for surpassed, the patient ‘expects’ to hallucinate (although Translational Neuroscience. Data from the original study were ob- tained with the support of the Wellcome Trust and the Bernard not necessarily consciously). We believe this process is Wolfe Health Neuroscience fund. The study was conducted at the dopamine driven and secondary to prolonged aberrant Wellcome Trust Clinical Research Facility and the Wolfson Brain glutamate and GABA signaling [27, 29] . D2 dopamine an- Imaging Centre (Addenbrooke’s Hospital, Cambridge, UK) and tagonists do not reverse the acute effects of ketamine [58] . within the Behavioral and Clinical Neuroscience Institute support- ed by the Medical Research Council and the Wellcome Trust. P.R. However, consistent with our hypothesis, D2 antagonism Corlett was supported by the Connecticut State Department of does seem to ameliorate symptoms in ketamine abuse Mental Health and Addiction Services. He was funded by an [59] . IMHRO/Janssen Rising Star Translational Research Award and In summary, we report qualitative and quantitative CTSA grant (UL1 TR000142) from the National Center for Re- data that suggest ketamine administration in the MRI search Resources (NCRR) and the National Center for Advancing scanner induces auditory hallucinations at a dose that Translational Science (NCATS), components of the National Insti- tutes of Health (NIH), and NIH roadmap for Medical Research. would not induce such symptoms outside of the scanner. The contents of the study are solely the responsibility of the authors We believe that this observation may have a bearing on and do not necessarily represent the official view of the NIH. our use of ketamine to model psychotic symptoms and our understanding of those symptoms in terms of the bal- ance between top-down and bottom-up signaling in the D i s c l o s u r e S t a t e m e n t Bayesian brain. P.R. Corlett consults for Otsuka Pharmaceuticals.

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Ketamine-Induced Hallucinations Psychopathology 2015;48:376–385 385 DOI: 10.1159/000438675