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J Psychopharmacol OnlineFirst, published on March 20, 2009 as doi:10.1177/0269881109103227

Original Papers

Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis

Journal of Psychopharmacology 00(00) (2009) 1–10 © The Author(s), 2009. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav ISSN 0269-8811 10.1177/0269881109103227

J Daumann Department of Psychiatry and Psychotherapy, University of Cologne, Germany. D Wagner Department of Psychiatry and Psychotherapy, University of Cologne, Germany. K Heekeren Department of Psychiatry and Psychotherapy, University of Cologne, Germany. A Neukirch Department of Psychiatry and Psychotherapy, University of Cologne, Germany. CM Thiel Institute of Medicine, Research Centre Jülich, Germany. E Gouzoulis-Mayfrank Department of Psychiatry and Psychotherapy, University of Cologne, Germany. Abstract Deficits in attentional functions belong to the core cognitive symptoms in schizophrenic patients. Alertness is a nonselective attention component that refers to a state of general readiness that improves stimulus processing and response initiation. The main goal of the present study was to investigate cerebral correlates of alertness in the human 5HT2A agonist and N-methyl-D-aspartic acid (NMDA) antagonist model of psychosis. Fourteen healthy volunteers participated in a randomized double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. A target detection task with cued and uncued trials in both the visual and the auditory modality was used. Administration of DMT led to decreased blood oxygenation level-dependent response during performance of an alertness task, particularly in extrastriate regions during visual alerting and in

temporal regions during auditory alerting. In general, the effects for the visual modality were more pronounced. In contrast, administration of S-ketamine led to increased cortical activation in the left insula and precentral gyrus in the auditory modality. The results of the present study might deliver more insight into potential differences and overlapping pathomechanisms in schizophrenia. These conclusions must remain preliminary and should be explored by further fMRI studies with schizophrenic patients performing modality-specific alertness tasks.

Introduction

only few neuroimaging studies have focused on the neural network underlying alertness and their results are partially contradictory. For the visual modality, alerting effects were primarily found in right visual cortex, left premotor cortex, left insula and left fronto-parietal areas (Coull, et al., 2001; Sturm and Willmes, 2001). For auditory target detection, right lateralized parietal and frontal activations were detected (Sturm and Willmes, 2001). Most recently, Thiel and Fink (2007) demonstrated bilateral activation in extrastriate, posterior parietal and frontal brain areas with peak activations in the inferior occipital gyrus under conditions of visual alerting and activation of bilateral superior temporal cortices and bilateral frontal brain regions under conditions of auditory alerting. To our knowledge, no published functional neuroimaging findings of alertness in schizophrenia are currently available.

Deficits in attentional functions belong to the core cognitive symptoms in schizophrenic patients (Addington and Addington, 1998). Following psychological and neuropsychological theories, at least four attentional functions can be separated, which are as follows: alertness as the ability to control arousal and response readiness, sustained attention and vigilance for long time maintenance of activation, selective attention to separate irrelevant from relevant features of a task and divided attention to share attentional resources between different aspects of a task (Posner and Petersen, 1990; Van Zomeren and Brouwer, 1994). Accordingly, alertness is the most basic aspect of attention intensity probably constituting the basis for the more complex aspects of attentional functions. To date

Key words alertness; dimethyltryptamine; experimental psychosis; ketamine; pharmacological fMRI

Corresponding author: J Daumann, PhD, Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, 50924 Cologne, Germany. Email: [email protected]

Downloaded from jop.sagepub.com at PENNSYLVANIA STATE UNIV on March 5, 2016

2 DMT and ketamine model of psychosis

However, some behavioural studies have tested the functional integrity of the alerting, orienting and executive control systems in patients. Based on broader definitions of schizophrenia, early studies indicated that patients do present impaired performance on tasks involving responses to warning signals (Zahn, et al., 1963). These findings are consistent with the notion that schizophrenic patients exhibit an alerting deficit. More recently, it has been demonstrated that patients with schizophrenia and/or schizophrenia-spectrum disorders display sustained attention deficits using the identical pairs version or degraded stimulus version of a continuous performance test (CPT, Cornblatt and Malhotra, 2001). Although, this can be interpreted as indicative of an alerting impairment, successful performance on the more difficult forms of the CPT involves several processes, including working memory, which rather is an executive control function (Michie, et al., 2000). Taken together, it is well accepted that schizophrenia is associated with attentional deficits (Goldberg and Gold, 1995). However, attention is often defined so broadly that impaired performance on virtually any task could be interpreted as evidence for a deficit in attention. Additionally, the overall degree of attentional impairments varies strongly across different studies and group of patients (Palmer, et al., 1997). Hence, differences in the tasks used across the different studies, as well as the biological heterogeneity of the schizophrenic disorder, different medications, and aspects of the age of onset and long-term course may account for the contradictory results. With respect to these above-mentioned methodological issues, human experimental studies with hallucinogenic drugs are fairly accepted as a valuable, complementary research strategy to studies with patient populations. Pharmacological challenges with hallucinogens have often been used as models for psychosis, although there is some controversy as to the closeness of these models to schizophrenia (Snyder, 1988; Gouzoulis-Mayfrank, et al., 1998, 1999; D’Souza, et al., 1999; Carpenter, 1999). Intraindividual comparisons of the off- and on-drug state help to minimize the variability of data and offer a unique opportunity to study fundamental neurobiological mechanisms of psychoses. Interestingly, the two major classes of hallucinogens (phencyclidine (PCP)-type: glutamate NMDA-receptor antagonists and lysergic acid diethylamide (LSD)-type: serotonin 5-HT2A receptor agonists or partial agonists) have somewhat different psychotropic profiles, and therefore, they may model different aspects or types of schizophrenia. The NMDA antagonist state (PCP, ketamine) is thought to be an appropriate model for undifferentiated or disorganized psychoses with both positive and negative symptoms, while the 5-HT2A agonist state (LSD, dimethyltryptamine (DMT), psilocybin) may be an appropriate model for the paranoid subtype of schizophrenia (Javitt and Zukin, 1991; Krystal, et al., 1994; Abi-Saab, et al., 1998; GouzoulisMayfrank, et al., 2005; Daumann, et al., 2008). In the present study, functional magnetic resonance imaging (fMRI) was used to examine the neural correlates of S-ketamine- and DMT-induced psychotic states in healthy individuals while they performed a target-detection task measuring

the most basic aspect of attention intensity. Within the same sample and during the same substance administration, we recently demonstrated that inhibition of return (IOR), a complex attentional function comprising spatial orienting of attention, was significantly blunted after DMT, but not S-ketamine. In contrast, administration of S-ketamine, yet not DMT, yielded a stronger signal increase in cortical regions involved in the modulation of IOR (Daumann, et al., 2008). However, in spite of its simplicity, IOR cannot be accounted for by a single mechanism and involves both sensory and attentional components as well as motor and oculomotor modules (Berlucchi, 2006). Therefore, our recent findings cannot unambiguously be associated with an attentional effect. With the present study, we aim at further clarifying how the neural correlates of the most basic, nonconfounded aspect of attention is modulated by the two major classes of hallucinogens. Additionally, we intended to investigate whether the potential drug-induced neural modulations of alertness is modality specific by differentiating between visual and auditory cues. Based on our previous findings, we expected more pronounced performance impairments with DMT administration. Furthermore, we expected ketamine-induced stronger signal increases in cortical regions involved in the modulation of alertness.

Materials and methods Participants Fourteen healthy right-handed volunteers (8 men; mean age 32.1 years, range: 26–42) with no current physical and no current or previous history of neurological or psychiatric disorder (Axis I according to DSM-IV criteria, American Psychiatric Association (APA), 1994) were included in the study. Within the same day and during the same substance administration subjects participated in two different attentional experiments, one investigating IOR (Daumannn, et al., 2008), and one studying alertness, which is dealt with in the present article. Therefore, we refer to the corresponding article for a detailed description of the current sample (Daumann, et al., 2008). The study was carried out in accordance with the Declaration of Helsinki and was approved by the ethics committee at the Medical Faculty of the University of Cologne, Germany and the Federal Health Administration (Bundesinstitut für Arzneimittel und Medizinprodukte, Bundesopiumstelle Berlin, Germany). Written informed consent was obtained from all subjects following detailed description of the experimental procedures and assurance that they could withdraw from the study at any time without having to explain the reasons.

Drugs The appropriate dosages for both DMT and S-ketamine were already applied in a recently published study (GouzoulisMayfrank, et al., 2005). The individual dosages were titrated


DMT and ketamine model of psychosis

during every experiment within the defined ranges so as to obtain relatively uniform psychopathological profiles across subjects. The two dose regimens were as follows: (1) DMT: bolus injection of 0.15 mg/kg over 5 min followed by a break of 1 min, followed by continuous infusion with 0.01– 0.01875 mg/kg/min for over 20 min and (2) S-ketamine: bolus injection of 0.1 mg/kg over 5 min, followed by a break of 1 min, followed by continuous infusion with 0.0066– 0.015625 mg/kg/min for over 20 min. With these doses the psychological effects of both drugs developed fully within about 10 min from the start of the injection and were then kept relatively constant over the fMRI scanning session. The dose was determined as to evoke more profound alterations including true psychotic symptoms such as hallucinations and transient delusional misinterpretations of the experimental situation. The individual dosages were titrated during every experiment within the defined range as to obtain similar intensities of psychopathological effects for both substances. Hence, this procedure enabled us to obtain psychological effects of comparable intensity within each dose regimen despite the interindividual differences in responsiveness to these drugs. The decision for increasing or decreasing the rate of infusion was made by an experienced psychiatrist, who was blind to the substance used.

Study design Subjects were scanned on two separate days at least 14 days apart with a placebo and an active drug condition on each day (double-blind, randomized order between and within sessions) with 2–3 h break between both conditions. Subjects were at all times in the company of an experienced psychiatrist, who was blind to the substance used (Placebo, DMT or S-ketamine). The drugs were administered by a second physician. This physician was located in an adjacent room, was not blind to the substance and changed the infusion upon order of the psychiatrist. The administering physician did not communicate with the research team in a manner that either team members or the subjects knew if he administers placebo or the active drug (double-blind). Drugs were administered intravenously by an automatic infusion pump (Perfusor®, B. Braun, Melsungen, Germany), which allowed graded rate changes. Within a few minutes of stopping the drug infusion the psychological effects disappeared. For further details of the study design, we refer our recently published article (Daumann, et al., 2008).

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assessment of positive symptoms (Andreasen, 1984), the scale for the assessment of negative symptoms (Andreasen, 1983) and, finally, the schizophrenia proneness instrument – adult version (Schultze-Lutter, et al., 2007). For a detailed description of the particular subscales, we refer to our recently published article (Daumann, et al., 2008).

Stimuli and fMRI paradigm A target-detection task with visual targets and visual, auditory or no warning cues to capture neural correlates of phasic alertness was used. The advantage of studying phasic alertness – induced by warning cues in neuroimaging studies rather than investigating increases or decreases of tonic alertness over the course of the experiment – is that uncued trials can be used as an adequate control condition. Visual stimuli were projected onto a screen in front of the participant in the MRI scanner. Viewing distance was about 29 cm. Auditory stimuli were presented by electrostatic headphones that passively shielded the subjects from scanner noise. The baseline condition was a display consisting of a central box with the fixation cross in it and two peripheral boxes (Figure 1). The visual warning cue consisted of a frame within the central box appearing for 100 ms. The auditory warning cue was a 500-Hz sine tone, presented to both ears. The target was an X and appeared for 100 ms in one of the peripheral boxes. In unwarned trials, the cue stimulus was omitted, giving no indication that a target would subsequently appear. Two different cue-target intervals (400 and 700 ms) were used to reduce temporal orienting towards the target; that is, volunteers had only approximate information

Psychopathological evaluation and clinician ratings Psychological effects were assessed using two self-rating scales: the hallucinogenic rating scale HRS (Strassman, et al., 1994) and the APZ-OAV (Abnormer psychischer Zustand = altered state of consciousness, Dittrich, et al., 1985). Furthermore, four psychiatric scales for the assessment of schizophrenia-like symptoms were used which are as follows: the brief psychiatric rating scale (Overall and Gorham, 1962), the scale for the

Figure 1 Timing within a trial: Example here illustrates a trial with a visual warning cue. Trial starts with the warning cue (100 ms). After a variable cue-target interval (400–700 ms) a target stimulus (X) appears for 100 ms within one of the two peripheral boxes. Subjects are asked to respond with a button press as soon as they detect the target. The next trial starts after 1400 or 1100 ms.



on when the target was going to appear. The length of the cue-target intervals chosen was comparable to prior studies on warning-cue-induced alertness (Coull, et al., 2001; Fan, et al., 2002; Robertson, et al., 1998; Witte, et al., 1997). The order of trial types was randomized as was the occurrence of left and right targets so that stimulus–response compatibility could not affect our measures of alerting. The experiment consisted of 200 trials each presented randomly with an intertrial-interval of 2000 ms. About 44 out of these trials were baseline trials (null events) with no cue or target occurring. The remaining 156 trials consisted of no cue, audio cue or visual cue stimuli appearing with equal probability. In the cued trials, the target followed either 400 or 700 ms after cue onset either in the right or the left box with equal probability. Subjects were instructed to maintain fixation to the centrally located cross throughout the experiment and to covertly detect any peripheral target as fast as possible. Volunteers made responses with the right index finger on a button of a keypad placed on the right of their body. It has previously been shown that the responding hand can interact with activations observed in visuospatial tasks (Fink, et al., 2000). Nevertheless, it was chosen not to use both hands in this experiment for reasons of comparability with prior cued target–detection tasks, which all used the right hand for responding (Thiel and Fink, 2007; Corbetta and Shulman, 2002; Coull, et al., 2001). Before scanning, subjects were informed about the different conditions. A short training was performed before each scanning session. In an additional run, subjects were scanned while performing a covert orienting of attention task (COVAT) with nonpredictive peripheral cues, which has been reported previously (Daumann, et al., 2008).

Data acquisition A Sonata MRI system (Siemens, Erlangen, Germany) operating at 1.5 T was used to obtain T2*-weighted echoplanar images (EPI) with blood oxygenation level-dependent (BOLD) contrast (matrix size: 64 × 64, pixel size: 3.12 × 3.12 mm2). The 172 volumes of 24 four-mm-thick axial slices were acquired sequentially with a 0.8-mm gap (repetition time = 2.5 s, echo time = 66 ms). For anatomic reference, we additionally obtained a T1-weighted 3-D inversion recovery sequence (imaging parameters: TR = 2200 ms, TE = 4 ms, TI = 400 ms, flip angle = 15°). Head movements were minimized in all subjects using foam pads and Velcro straps. Images were acquired using a standard head coil. The first five volumes were discarded to allow for T1 equilibration effects. Images were spatially realigned to the first volume to correct for head movements, interpolated in time (temporal realignment to the middle slice) and normalized to a standard EPI template volume (resampled to 2 × 2 × 2 mm3 voxels). The data were then smoothed with a Gaussian kernel of 8 mm full-width-half maximum to accommodate intersubject anatomical variability. Raw time-series were detrended by the application of a high-pass filter (cut-off period: 128 s).

Data analyses Psychological effects and cognitive performance were analyzed by means of repeated-measure analysis of variance (ANOVA) and paired t-tests implemented in SPSS 15.0 software (SPSS Inc., Chicago, Illinois). For this purpose, median reaction times (RTs) were, at first, calculated for each trial type and drug condition in each subject. Trials with RTs less than 100 ms (3.4%) or exceeding 1000 ms (3.9%) were excluded because they were considered either anticipatory or most likely to be due to brief periods of general inattention to the task. The remaining 92.7% of trials were used in the statistical analyses. Median RT values of the remaining trials were calculated for each subject, drug condition and type of trial. P-values ≤ 0.05 were considered significant. Functional imaging data were analyzed with Statistical Parametric Mapping software (SPM2, Wellcome Department of Cognitive Neurology, London, UK) implemented in Matlab 7 (Mathworks Inc., Sherborn, Massachusetts) employing a random effects model. At the first level, all four sessions (twice placebo, S-ketamine, DMT) were incorporated into one design matrix. For each session 12 event types were defined which are as follows: short stimulus onset asynchrony (SOA) + visual cue + right target, short SOA + visual cue + left target, short SOA + audio cue + right target, short SOA + audio cue + left target, short SOA + no cue + right target, short SOA + no cue + left target, long SOA + visual cue + right target, long SOA + visual cue + left target, long SOA + audio cue + right target, long SOA + audio cue + left target, long SOA + no cue + right target, and long SOA + no cue + left target. This design matrix was specified applying the hemodynamic response function to every event type. In order to explore differences between the active drug and placebo conditions, the computed contrasts of each subject were entered into two separate within-subjects second-level analyses (paired t-tests for placebo and active drug condition). All random-effects analyses contrasts were computed with the commonly used height threshold of P < 0.001 (uncorrected on a voxel level). Minimum cluster size was set to 20 voxels. Because the Montreal Neuroscience Institute (MNI) brain template coordinates do not accurately match the brain of Talairach and Tournoux (1988), we used the Matlab function mni2tal by M. Brett for the nonlinear transformation of MNI to Talairach coordinates.

Results Psychological effects All subjects who entered the study completed both experimental days without any complications. Both the drugs induced psychotic symptoms similar to schizophrenic manifestations (data not shown). Only a few psychopathological and clinical differences between both drugs reached statistical significance. For a detailed description of these effects, we refer to our previously published investigation (Daumann, et al., 2008).



Cognitive performance Cognitive performance is presented in Figure 2. Performance for both placebo conditions did not differ and was, therefore, pooled, as well as performance for the 400 ms and the 700 ms SOA condition and as performance for targets in the right and left visual field. An initial 3 × 3 repeated measures ANOVA with the factors drug (DMT, S-ketamine, placebo) and cue (visual cue, auditory cue, no cue) revealed significant main effects for drug [F(2,12) = 14.34, P = .001] and cue [F(2,12) = 37.72, P < 0.000]. The interaction between drug and cue was also significant [F(4,10) = 13.91, P < 0.000]. The post-hoc tests showed that RTs under DMT did not differ significantly from RTs under S-ketamine over all cue conditions (DMT vs S-ketamine: P = 0.355), whereas RTs under both drugs differed significantly from RTs under placebo (DMT vs placebo: P = 0.002, S-ketamine vs placebo, P = 0.006). Furthermore, RTs in visual cued trials did not differ significantly from RTs in acoustically cued trials (visual cue vs auditory cue: P = 0.537), while RTs in both visually and acoustically cued trials differed significantly from RTs in no-cue trials (visual cue vs no cue: P < 0.000, auditory cue vs no cue: P < 0.000). Additionally, we found a significant main effect of drug in regard to the cue effect (Figure 2) both in the visual and in the auditory modality [F(2,12) = 17.74, P < 0.000 and F(2.12) = 10.55, P = 0.002, respectively]. In both modalities,

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pair-wise comparisons revealed no significant differences of the cue benefit between the S-ketamine and the placebo condition (in the visual modality: S-ketamine vs placebo: P = 0.380; in the auditory modality: S-ketamine vs placebo: P = 0.201), whereas the cue benefit was significantly smaller under DMT compared with both S-ketamine and placebo in both modalities (in the visual modality: DMT vs S-ketamine: P < 0.000; DMT vs placebo: P = 0.001; in the auditory modality: DMT vs S-ketamine: P = 0.003; DMT vs placebo: P = .001).

Imaging results Effects of the task for the placebo condition: Brain regions significantly involved in alerting are summarized in Table 1. Brain areas involved in visual alerting are given in Figure 3. They were identified by comparing BOLD activity in trials with visual warning cues versus uncued trials under placebo. The contrast yielded activity in left and right extrastriate areas with peak activations in the middle occipital gyrus. Additional significant activations were found in the right inferior occipital gyrus, in bilateral posterior parietal cortex, in right fusiform gyrus and in the right inferior and middle temporal gyrus. Neural correlates of auditory alerting are also given in Figure 3. BOLD effects were isolated by comparing BOLD activity for conditions with auditory warning cues versus uncued trials under placebo. This contrast revealed significant neural activation in bilateral middle temporal gyrus, in bilateral superior temporal gyrus, in right inferior temporal gyrus and in the bilateral subgyral temporal lobes. Additional significant activations were found in the left middle frontal gyrus and in the right inferior frontal gyrus. Further significant activations were found in the left amygdala, left putamen, right claustrum, left thalamus, right culmen and left precuneus.

Effects of the task for the substance conditions

Figure 2 Behavioural data. Above: Mean (±SE) reaction times (RTs) for each cue-condition and drug treatment. Below: Cue benefit (RTnocue − RTcued; mean ± SE, *indicates significant differences) for each drug treatment in the visual and in the auditory cue modality.

In order to explore the modulation of the alerting network by DMT and S-ketamine only those regions are displayed that showed significant effects under placebo. In the DMT condition, significantly less activation was found after visual cues in contrast to the placebo-condition (Figure 4). In the visual modality, the effects of DMT were evident in the left inferior (x = −28, y = −100, z = −10, Z = 3.24) and right middle occipital gyrus (x = 28, y = −88, z = 4, Z = 3.92), in the right inferior temporal gyrus (x = 50, y = −66, z = 2, Z = 4.05), in the left cuneus (x = −20, y = −102, z = 0, Z = 4.35) and in the right culmen (x = 34, y = −52, z = −22, Z = 4.13). In the auditory cue condition, effects of DMT were found in the right middle temporal gyrus (x = 62, y = −24, z = −2, Z = 3.94). In the S-ketamine condition significantly increased activation after auditory cues were found in contrast to the placebocondition in the corresponding alertness-network (Figure 4). Effects of S-ketamine were found in the left insula (x = −38, y = 0, z = 14, Z = 4.08) and left precentral gyrus (x = −50, y = −12, z = 10, Z = 4.93). In the visual modality, no



Table 1 Regions significantly involved in alerting during placebo conditions (cue vs no cue, P < 0.001, uncorrected on a voxel level, minimum cluster size: 20 voxels) Region Visual alerting Middle occipital gyrus Inferior occipital gyrus Posterior parietal cortex Fusiform gyrus Inferior temporal gyrus Middle temporal gyrus Auditory alerting Middle temporal gyrus Superior temporal gyrus Inferior temporal gyrus Subgyral temporal lobe Middle temporal gyrus Right inferior frontal gyrus Amygdala Putamen Claustrum Thalamus Culmen Precuneus

Side

x

y

z

Z-score

R L R R L R R R

38 −38 32 42 −44 −38 48 36

−90 −70 −88 −64 −80 −48 −66 −60

4 8 −6 −18 −16 −18 2 −14

4.72 3.84 3.70 4.55 4.24 4.71 4.50 3.94

R L R L R R L R R L L R R R L

64 −60 66 −50 52 44 −38 −60 44 −28 −30 26 −14 12 −16

−38 −48 −34 −54 −30 −12 −10 −36 18 −4 −12 20 −10 −44 −62

4 8 20 10 −18 −12 −14 24 4 −16 −6 −4 14 −16 46

4.24 4.73 3.93 4.34 4.65 4.47 3.68 4.83 3.79 4.28 4.15 3.98 3.97 3.91 3.89

Coordinates (x, y, z) correspond to the Talairach atlas (Talairach and Tournoux, 1988).

significant differences were found in the S-ketamine condition compared to placebo.

Discussion The purpose of the present investigation was to study the pharmacological modulation of visual and auditory alertness in two different pharmacological models of psychosis in humans. Psychotomimetic doses of the serotonergic hallucinogen DMT and the antiglutamatergic hallucinogen S-ketamine were administered to healthy volunteers in a randomized, doubleblind, cross-over experimental design. Overall, all subjects tolerated the procedures and no serious immediate or delayed adverse effects were observed after the experiments. The administration of both hallucinogens was followed by alterations of perception, affect and cognition, which were comparable to many symptoms of patients with schizophrenia. The overall intensity of the hallucinogenic effects of both drugs was similar, albeit visual alterations were more pronounced after DMT and phenomena resembling negative symptoms of schizophrenia were more prominent after S-ketamine. In general, both DMT and S-ketamine slowed down reaction times significantly, whereas the analysis of cue benefits revealed an

attentional impairment particularly accompanied by DMT administration. This finding confirms a variety of evidence that attention and serotonin are functionally and anatomically intertwined. For example, it has been shown that 5-HT depletion leads to an impairment of Go–NoGo tasks requiring attentional set shifting and related inhibition of attentional set (Rubinsztein, et al., 2001). More relevantly, the 5-HT1a/2a agonist psilocybin has been shown to impair attentional functions in a COVAT (Gouzoulis-Mayfrank, et al., 2002), as well as attentional tracking abilities (Carter, et al., 2005). For the placebo conditions, neural correlates of visual alertness were found in bilateral extrastriate areas with peak activations in inferior and middle occipital regions. In analogy, we found an alerting-related increase of BOLD response in higher-level auditory cortices when using an auditory alertness task. These modality-specific neural mechanisms correspond to recent findings observed in a similar target-detection task presented in a blocked design (Thiel and Fink, 2007). Contrarily, in our event-related study, we found no inferior parietal or frontal brain areas in the visual modality and only marginal left-sided frontal response in the auditory modality. However, for an event-related design, the lack of frontal and parietal BOLD response with warning-cue-induced alertness has already been noticed (Giessing, et al., 2004). To explain this



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Figure 3 BOLD response during the task under placebo administration (cue – no cue). Above: In the visual alerting condition, the contrast yielded activity in left and right extrastriate areas with peak activations in the middle occipital gyrus. Below: In the auditory alerting condition, the contrast revealed significant neural activation primarily in temporal regions. P < .001 (uncorrected on a voxel level), minimum cluster size: 20 voxels.

discrepancy, it has been proposed that blocked and event-related approaches differ in their sensitivity to capture transient and sustained activations. Thus, alertness-related parietal and frontal activations may rather be associated with sustained than transient increase in neural activity after a warning cue is provided. For both modalities, DMT led to diminished activation within the underlying alertness-network in comparison to placebo conditions. For the visual modality, peaks of this hypoactivation were found in inferior and middle occipital regions, and for the auditory modality, peaks were found in inferior and middle temporal regions. These effects were more pronounced in the right hemisphere. Comparable pharmacological fMRI studies with serotonergic agonists are currently not available. However, suitable evidence comes from an early fluor-18-fluorodeoxyglucose positron emission tomography (FDG-PET) study with a word association task under psilocybin administration also revealing a decreased metabolism during task performance in the left posterior cingulate, the right anterior cingulate, the occipital cortex and the right putamen (Gouzoulis-Mayfrank, et al., 1999). In general, psilocybin is known to activate both 5-HT1A and 5-HT2A receptor subtypes. However, the majority of the drug’s subjective effects are generally attributed to activation of the 5-HT2A receptor (Nichols, 2004; Vollenweider, et al., 1998). Linking the observed hypoactivation with DMT in the present study to schizophrenia, it might be hypothesized that this finding corresponds to a multitude of studies on acute schizophrenic patients suggesting diminished capacity to activate task-associated regions upon cognitive demand (Cohen, et al., 1987; Weinberger, et al., 1988; Buchsbaum, et al., 1990; Andreasen, et al., 1992). Alternatively, it might be possible that the hallucinogen-induced visual disturbances with DMT administration compete with activation required for alertness (Gouzoulis-Mayfrank, et al., 2005). This may have led to diminished activation in the corre-

Figure 4 Above: BOLD response during the task under placebo in contrast to DMT in visual alerting (cue – no cue). Middle: BOLD response during the task under placebo in contrast to DMT in auditory alerting (cue – no cue). Below: BOLD response during the task under S-ketamine in contrast to placebo in auditory alerting (cue – no cue). Note that in each case only those regions are displayed that show a significant alerting effect under placebo, P < 0.001 (uncorrected on a voxel level), minimum cluster size: 20 voxels.

sponding network. However, given the lack of corresponding literature, these conclusions might be considered preliminarily. Furthermore, for the auditory modality, administration of S-ketamine led to increased activation in the left insula and precentral gyrus. This finding is in line with a number of studies suggesting increased cortical activation during cognitive performance under ketamine administration (Honey, et al., 2004, 2005; Northoff, et al., 2005; Fu, et al., 2005; Daumann, et al., 2008). Remarkably, ketamine administration did not significantly impair task performance in these studies. Similarly, a task-specific effect of S-ketamine on brain activation was found in the present study while, at least, the cue benefit did not significantly differ. This finding may facilitate the attribution of the fMRI alterations to an effect of the drug. Frequently, in pharmacological imaging studies, groups differ in both task performance and drug condition. Therefore, imaging findings cannot unambiguously be associated with one of these factors since neural activity may reflect differences in task performance rather than assessing a drug effect. In the present study, however, matched performance across drug conditions (similar cuebenefit in the ketamine and placebo condition) allows the interpretation that alterations in BOLD response are likely to reflect a drug effect. This is particularly interesting since pharmacological fMRI studies may serve as a sensitive tool for detecting subtle cognitive changes that may not be seen behaviourally. Hence, it



may be speculated that the task-related hyperactivity during S-ketamine administration indicates compensatory mechanisms in order to maintain constant cognitive performance. Linking these findings to schizophrenia it may, at first glance, seem surprising that ketamine is accompanied by increased BOLD response, as hypofrontality has been the more common outcome (Fu and McGuire, 1999). However, several functional neuroimaging studies in psychotic patients have revealed increased prefrontal activation, particularly in patients with florid symptoms (Volkow, et al., 1986; Cleghorn, et al., 1992; Ebmeier, et al., 1993; McGuire, et al., 1993; Shergill, et al., 2000). Furthermore, several functional imaging studies have found no differences in prefrontal activation between patients and healthy controls during cognitive processing (Frith, et al., 1995; Fletcher, et al., 1996; Curtis, et al., 1999; Dye, et al., 1999; Spence, et al., 2000; Fu, et al., 2005) and even hyperfrontality in patients (Stevens, et al., 1998; Manoach, et al., 1999). Finally, increased regional blood flow in the anterior cingulate was reported by Lahti, et al. (1995) in a group of schizophrenic patients in remission who were reexperiencing their usual psychotic symptoms while receiving ketamine. Even though the present study does not concern frontal activity, given the widespread distribution of NMDA receptors over the human brain, it may be hypothesized that similar patterns apply to temporal cortices. The neural effects of ketamine in healthy individuals, as a matter of course, are not fully comparable to the abnormalities of longstanding disrupted brain circuits as in schizophrenia. Remarkably, this pattern was not found in the visual modality of the present study. Cortical activation did not significantly differ in the S-ketamine and the placebo condition in this modality. However, it may be taken into account that the impact of ketamine on visual perception, in general, is not as strongv as the impact on auditory perception (GouzoulisMayfrank, et al., 2005). Hence, it might be possible that, in terms of auditory alertness, more brain capacity is required to perform on a comparable level because of the greater visual disturbances. Given the lack of visual disturbances under ketamine administration, it might be possible that visual alertness remains relatively unaffected in terms of neuronal activation in comparison to placebo administration. This finding might give a valuable link for further research on schizophrenic patients using modality-specific alertness tasks. Given the common finding that auditory perception is often stronger impaired than visual perception in most schizophrenic patients similar neuronal mechanisms could be accompanied (Mueser, et al., 1990). There are some limitations in interpreting the present data, which are outlined below. First, we cannot fully exclude the possibility that our imaging findings were associated with an unspecific effect of drug on cerebral blood flow. However, recent studies suggest that ketamine administration rather results in an altered BOLD response specific to the cognitive task (Northoff, et al., 2005) or the emotional stimuli (Abel, et al., 2003) presented than in a nonspecific global effect on cerebral blood flow per se. Further support for this argument comes from animal studies, which also suggest that ketamine

has no effects on vascular mechanisms beyond its specific effects on neural activation (Burdett, et al., 1995). The same may hold true also for DMT. Secondly, human as well as animal studies suggest that ketamine not only affects the glutamatergic system. In humans, for example, it increases dopamine levels in the striatum (Vollenweider, et al., 2000), reduces acetylcholine release (Grunwald, et al., 1999) and also binds to 5-HT2 receptors (Kapur and Seemann, 2002). Furthermore, in rodents acute administration of ketamine increased the release of dopamine in the prefrontal cortex (Moghaddam, et al., 1997). In addition, we cannot rule out the possibility that the poorer cognitive performance, in particular for the DMT condition, might, in part, be responsible for the corresponding imaging findings. Moreover, the statistical analyses do not justify in claiming differential patterns of brain response for DMT and ketamine. To perform the direct comparison and to show the difference maps between both substances, a considerable larger sample would have been required in order to perform multiple subtractions of different event types and substance conditions. Additionally, administration of drug and placebo on the same day might be regarded as a potential confound. However, in a previous study, we assessed neither psychological nor psychopathological residual effects nor residual effects regarding the blood plasma levels 2 h after the administration of the two different drugs (Gouzoulis-Mayfrank, et al., 2005). Nevertheless, we cannot rule out the possibility of residual effects. Finally, because of the small sample size we did not control for multiple comparisons. Therefore, our findings should be regarded as preliminary. In conclusion, administration of DMT led to hypoactivity, particularly in extrastriate regions during visual alerting and in temporal regions during auditory alerting. In general, the effects for the visual modality were more pronounced. In contrast, administration of S-ketamine led to increased cortical activation in the left insula and precentral gyrus in the auditory modality. This is of typical interest since it extends our recent findings on IOR by application of a task reflecting the most basic, nonconfounded aspect of attention (Daumann, et al., 2008). Hence, pharmacological fMRI might be a profound tool to distinguish cortical activations during the most basic aspect of attention modulated by the two distinct types of drugs. This might deliver more insights into the mechanisms of potential different subtypes of schizophrenia. It might be hypothesized that the findings of the present study may indicate different pathomechanisms underlying varying characteristics of schizophrenic symptoms possibly depending on whether visual perception or auditory perception is more affected. Needless to say, these conclusions must remain preliminary and should be explored by further fMRI studies with schizophrenic patients performing modalityspecific alertness tasks.

Acknowledgements This work was supported by a grant to E. Gouzoulis-Mayfrank from the German Research Foundation (Deutsche Forschungsgemeinschaft DFG, Project No. 6 of a DFG clinical researcher group KFO 112/1/-1, Go 717/5-1).



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