Biomedical subjects

Franz X Vollenweider

Publications and source records attributed to Franz X Vollenweider.

At least 19 recordsLinked to original sources

PubMed2006

Clozapine enhances prepulse inhibition in healthy humans with low but not with high prepulse inhibition levels.

BACKGROUND: Atypical antipsychotics have been assessed for normalization effects on deficient sensory gating as indexed by prepulse inhibition (PPI) in schizophrenics with generally positive, although somewhat conflicting, results. METHODS: We tested the acute effect of clozapine on startle, PPI, and attention, working memory, and executive functioning in 28 healthy male volunteers with low versus high PPI levels using a placebo-controlled within-subject design. RESULTS: Clozapine significantly increased PPI levels obtained at short lead intervals of 60 and 120 msec in subjects with low PPI performance but showed no effect in subjects with high PPI. Clozapine also caused a mild cognitive impairment on attention and pattern recognition memory tests. No correlations between cognitive measures and PPI performance were found. Moreover, low and high PPI performers were shown to exhibit stable levels of PPI across three separate nondrug testing days. CONCLUSIONS: Clozapine increases sensorimotor gating in healthy subjects with low but not high PPI levels in a manner comparable to that seen in clozapine-treated schizophrenia patients. Healthy subjects with low PPI level in combination with genetic studies may provide a translational model to elucidate the neuronal basis of PPI deficits and to test the efficacy of novel antipsychotic medication.

Acoustic Stimulation↗

PubMed2006

The monotonic dependency of prepulse inhibition of the acoustic startle reflex on the intensity of the startle-eliciting stimulus.

Prepulse inhibition (PPI) of the acoustic startle reflex is a translational behavioural paradigm for the assessment of sensorimotor gating deficit which has been demonstrated in a number of neuropsychiatric conditions. PPI refers to the reduction of the reflexive startle response to a 'pulse' stimulus when its presentation is shortly preceded by a weak 'prepulse' stimulus. We have recently examined the expression of PPI as a function of the startle-eliciting 'pulse' stimulus intensity in mice and in humans. One major discrepancy that emerged was the finding that healthy human subjects, unlike normal mice, did not show a clear monotonic reduction of PPI magnitude (as indexed by % reduction in startle reactivity) with increasingly intense pulse stimulus. This lack of correspondence between species may potentially weaken the translational power of the PPI paradigm. Here, we re-examined this issue in 31 healthy subjects across three levels of pulse stimulus intensity (95, 105 and 115 dB). A clear linear reduction of PPI as a function of pulse intensity was revealed when subjects failing to respond to the lowest pulse stimulus were excluded. Inclusion of such non-responders, on the other hand, resulted in a trend towards an inverted U-shape function as reported previously. The present study thus clarifies an apparent divergence between mouse and man, and provides important qualification to the "First Law of Reflex Modification" proposed by Hoffman and Ison which suggests that the absolute reduction in startle reactivity resulting from a prepulse stimulus preceding the startle-eliciting pulse stimulus is fixed by the prepulse intensity regardless of the pulse stimulus intensity.

Acoustic Stimulation↗

PubMed2006

Effects of psilocybin on time perception and temporal control of behaviour in humans.

Hallucinogenic psilocybin is known to alter the subjective experience of time. However, there is no study that systematically investigated objective measures of time perception under psilocybin. Therefore, we studied dose-dependent effects of the serotonin (5-HT)2A/1A receptor agonist psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) on temporal processing, employing tasks of temporal reproduction, sensorimotor synchronization and tapping tempo. To control for cognitive and subjective changes, we assessed spatial working memory and conscious experience. Twelve healthy human volunteers were tested under placebo, medium (115 microg/kg), and high (250 microg/kg) dose conditions, in a double-blind experimental design. Psilocybin was found to significantly impair subjects' ability to (1) reproduce interval durations longer than 2.5 sec, (2) to synchronize to inter-beat intervals longer than 2 sec and (3) caused subjects to be slower in their preferred tapping rate. These objective effects on timing performance were accompanied by working-memory deficits and subjective changes in conscious state, namely increased reports of 'depersonalization' and 'derealization' phenomena including disturbances in subjective 'time sense.' Our study is the first to systematically assess the impact of psilocybin on timing performance on standardized measures of temporal processing. Results indicate that the serotonin system is selectively involved in duration processing of intervals longer than 2 to 3 seconds and in the voluntary control of the speed of movement. We speculate that psilocybin's selective disruption of longer intervals is likely to be a product of interactions with cognitive dimensions of temporal processing -presumably via 5-HT2A receptor stimulation.

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PubMed2005

Rapid visual information processing in schizophrenic patients: the impact of cognitive load and duration of stimulus presentation. A pilot study.

The inability to sustain attention has been proposed as a core deficit in schizophrenia. The Continuous Performance Task (AX-CPT) and the Rapid Visual Information Processing Task (RVP) are widely used neuropsychological tasks to measure sustained attention. The RVP displays numbers as stimuli, whereas the AX-CPT uses letters. Ten patients with chronic schizophrenia and 18 healthy control subjects were studied using four different versions of the RVP. The versions differed with regard to stimulus presentation time (600 vs. 1,200 ms) and the number of target sequences to be memorized: either one sequence (low cognitive load) or two sequences (high cognitive load). Schizophrenic patients showed a reduced number of hits only on the task version with 600 ms stimulus duration coupled with high cognitive load. The combination of high cognitive load and short stimulus duration created a critical performance breaking point for schizophrenic patients. This finding supports the hypothesis that patients have an impaired ability to coactivate different cognitive performances; thus the results favor the theory of impaired functional connectivity in schizophrenia.

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PubMed2005

On the feasibility to detect and to quantify prepulse-elicited reaction in prepulse inhibition of the acoustic startle reflex in humans.

The possibility that the prepulse stimulus typically employed in the studies of prepulse inhibition (PPI) can produce observable response has been questioned recently. Conflicting reports range from observations of prepulse-elicited startle reaction to a complete lack of detectable prepulse-elicited reactions in healthy volunteers. This controversy is subjected to critical examination in the present study. The ability of prepulse stimuli to induce PPI and to elicit measurable responses was examined in two separate experiments using prepulses ranging from 6 to 18dB above background (experiment 1), or 1 to 5dB above background (experiment 2). Three levels of pulse stimulus were employed: 95, 105 and 115dBA. Clear PPI and prepulse-elicited reaction were obtained in experiment 1, while neither effect was evident in experiment 2. Non-startle-eliciting prepulses that are of sufficient intensities to induce reliable PPI are associated with detectable and quantifiable response, confirming that direct evaluation of prepulse-processing is feasible and practical. This provides an additional measure of theoretical and potentially clinical relevance to PPI, and it ought to be included in future studies in patients as well as healthy subjects.

Acoustic Stimulation↗

PubMed2005

Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin.

Binocular rivalry occurs when different images are presented simultaneously to corresponding points within the left and right eyes. Under these conditions, the observer's perception will alternate between the two perceptual alternatives. Motivated by the reported link between the rate of perceptual alternations, symptoms of psychosis and an incidental observation that the rhythmicity of perceptual alternations during binocular rivalry was greatly increased 10 h after the consumption of LSD, this study aimed to investigate the pharmacology underlying binocular rivalry and to explore the connection between the timing of perceptual switching and psychosis. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine, PY) was chosen for the study because, like LSD, it is known to act as an agonist at serotonin (5-HT)1A and 5-HT2A receptors and to produce an altered state sometimes marked by psychosis-like symptoms. A total of 12 healthy human volunteers were tested under placebo, low-dose (115 microg/kg) and high-dose (250 microg/kg) PY conditions. In line with predictions, under both low- and high-dose conditions, the results show that at 90 min postadministration (the peak of drug action), rate and rhythmicity of perceptual alternations were significantly reduced from placebo levels. Following the 90 min testing period, the perceptual switch rate successively increased, with some individuals showing increases well beyond pretest levels at the final testing, 360 min postadministration. However, as some subjects had still not returned to pretest levels by this time, the mean phase duration at 360 min was not found to differ significantly from placebo. Reflecting the drug-induced changes in rivalry phase durations, subjects showed clear changes in psychological state as indexed by the 5D-ASC (altered states of consciousness) rating scales. This study suggests the involvement of serotonergic pathways in binocular rivalry and supports the previously proposed role of a brainstem oscillator in perceptual rivalry alternations and symptoms of psychosis.

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PubMed2005

Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors.

Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were tested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 microg/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggesting a primary involvement of the 5-HT1A receptor in the observed deficit. Based on physiological and pharmacological data, we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

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PubMed2005

MDMA affects both error-rate dependent and independent aspects of decision-making in a two-choice prediction task.

Decision-making, i.e. selecting an action from a number of alternatives when the outcome is uncertain, is a complex process that is important for everyday life. 3,4-Methylenedioxymethamphetamine (MDMA), also known as 'Ecstasy', is a widely used recreational drug that is known to increase serotonin (5-HT) and, to a lesser extent, dopamine (DA) in animals. This study examined whether MDMA alters decision-making in a way that depends on the degree of success and outcome.Forty-two normal, healthy volunteers were given placebo or 1.5mg/kg p.o. MDMA in a randomized crossover design. Subjects completed the two-choice prediction task 120min after administration of the drug. Decision-making characteristics were obtained at 20% error rate, 50% error rate or 80% error rate.MDMA affected decision-making via a process that is dependent on success or failure. Administration of MDMA increased the degree to which the previous response predicted the current response (mutual information) and the average response sequence predictability (average dynamical entropy) at low error rates. MDMA increased the degree to which the previous stimulus influenced the selection of the current response at 20%, 50% or 80% error rate. MDMA did not significantly alter basic response characteristics such as response latency or switching. Self-assessment of the psychological state induced by MDMA did not predict the MDMA induced decision-making patterns. These results support the hypothesis that acute administration of MDMA affects success-related response selection during decision-making.

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PubMed2005

The P3 in 'ecstasy' polydrug users during response inhibition and execution.

Substance abuse and associated externalizing disorders are characterized by behavioural disinhibition and low impulse control, with reduced neural inhibition postulated to be the common underlying brain mechanism. The P3 component of event-related potentials (ERPs) is a widely used neurophysiological measure thought to reflect inhibitory brain processes, but as yet has not been assessed in ecstasy users. We recorded ERPs evoked by a Continuous Performance Test (CPT) in 16 current ecstasy polydrug users and 17 controls. The CPT included conditions where a prepared motor response had to be executed (Go) or inhibited (NoGo). Both controls and ecstasy users showed normal, robust patterns of P3 anteriorization and delay in the NoGo compared to the Go condition. Ecstasy users had lower P3 amplitudes at midline electrodes and a less anterior location of NoGo P3 peaks. These effects became weaker after statistically controlling for age, educational level and lifetime cannabis use. While lower P3 amplitudes are consistent with higher levels of neural disinhibition in ecstasy polydrug users, the normal switch pattern between response execution and inhibition, and the less anterior location of the NoGo P3, do not indicate disturbed inhibitory brain mechanisms.

Adult↗

PubMed2005

Information-processing deficits and cognitive dysfunction in panic disorder.

OBJECTIVE: The plasticity of the startle reflex, including prepulse inhibition (PPI) and habituation, provides operational measures of information processing that are abnormal in several neuropsychiatric disorders characterized by deficits in suppression or inhibition of intrusive or irrelevant stimuli. Clinically, patients with panic disorder (PD) have been described as having difficulties in the inhibition of their response to sensory and cognitive events. Because such difficulties may be the result of failures in early stages of information processing, we hypothesized that startle reactivity, PPI and habituation are deficient in unmedicated patients with PD. Moreover, we tested whether there was a relation between startle reflex measures and dysfunctional cognition. METHODS: Fourteen unmedicated patients with PD (7 men, 7 women) and 28 healthy comparison subjects (14 men, 14 women) were recruited. Acoustic startle reactivity, habituation and PPI (30-ms, 60-ms, 120-ms, 240-ms and 2000-ms interstimulus intervals) were assessed in the patients with PD and the age-matched and sex-matched healthy controls. These data for unmedicated patients with PD were compared with those for 24 medicated patients with PD. Moreover, dysfunctional cognition in patients with PD was measured using the Body Sensations Questionnaire. RESULTS: Unmedicated patients with PD exhibited increased startle reactivity, reduced habituation and significantly reduced PPI in the 30-ms, 60-ms, 120-ms and 240-ms prepulse conditions. Furthermore, in unmedicated patients with PD, increased startle response and decreased habituation were correlated significantly with higher cognitive dysfunction scores, but this was not the case for PPI. CONCLUSIONS: These data indicate that the early stages of sensory information processing are abnormal in patients with PD in the absence of medication. The observed deficits in PPI and habituation could reflect a more generalized difficulty in suppressing or gating information in PD. The correlation between cognitive symptoms and higher startle response and deficient habituation supports the hypothesis that subjects with PD have abnormalities in the early stages of information processing that lead to a cascade of downstream effects on cognition.

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PubMed2004

Psilocybin impairs high-level but not low-level motion perception.

The hallucinogenic serotonin(1A&2A) agonist psilocybin is known for its ability to induce illusions of motion in otherwise stationary objects or textured surfaces. This study investigated the effect of psilocybin on local and global motion processing in nine human volunteers. Using a forced choice direction of motion discrimination task we show that psilocybin selectively impairs coherence sensitivity for random dot patterns, likely mediated by high-level global motion detectors, but not contrast sensitivity for drifting gratings, believed to be mediated by low-level detectors. These results are in line with those observed within schizophrenic populations and are discussed in respect to the proposition that psilocybin may provide a model to investigate clinical psychosis and the pharmacological underpinnings of visual perception in normal populations.

Adult↗

PubMed2004

Comparison of simultaneously recorded [H2(15)O]-PET and LORETA during cognitive and pharmacological activation.

The complementary strengths and weaknesses of established functional brain imaging methods (high spatial, low temporal resolution) and EEG-based techniques (low spatial, high temporal resolution) make their combined use a promising avenue for studying brain processes at a more fine-grained level. However, this strategy requires a better understanding of the relationship between hemodynamic/metabolic and neuroelectric measures of brain activity. We investigated possible correspondences between cerebral blood flow (CBF) as measured by [H2O]-PET and intracerebral electric activity computed by Low Resolution Brain Electromagnetic Tomography (LORETA) from scalp-recorded multichannel EEG in healthy human subjects during cognitive and pharmacological stimulation. The two imaging modalities were compared by descriptive, correlational, and variance analyses, the latter carried out using statistical parametric mapping (SPM99). Descriptive visual comparison showed a partial overlap between the sets of active brain regions detected by the two modalities. A number of exclusively positive correlations of neuroelectric activity with regional CBF were found across the whole EEG frequency range, including slow wave activity, the latter finding being in contrast to most previous studies conducted in patients. Analysis of variance revealed an extensive lack of statistically significant correspondences between brain activity changes as measured by PET vs. EEG-LORETA. In general, correspondences, to the extent they were found, were dependent on experimental condition, brain region, and EEG frequency.

Adult↗

PubMed2003

Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study.

RATIONALE: Serotonin (5-Hydroxytryptamine, 5-HT) receptors play an important role in perception, affect regulation and attention. Pharmacological challenge with the 5-HT(2A) agonist psilocybin (PY) is useful in studying the neurobiological basis of cognition and consciousness. OBJECTIVE: Investigation of dose-dependent effects of PY on psycho(patho)logical and physiological parameters. METHODS: Eight subjects received placebo (PL), and 45 ("very low dose, VLD"), 115 ("low dose, LD"), 215 ("medium dose, MD"), and 315 ("high dose, HD") microg/kg body weight PY. The "Altered States of Consciousness Rating Scale" (5D-ASC), the "Frankfurt Attention Inventory" (FAIR), and the "Adjective Mood Rating Scale" (AMRS) were used to assess the effects of PY on psycho(patho)logical core dimensions, attention, and mood. A 24-h electrocardiogram (EKG) was recorded and blood pressure was measured. Plasma concentrations of thyroid-stimulating hormone (TSH), prolactin (PRL), cortisol (CORT), adrenocorticotropic hormone (ACTH), and standard clinical chemical parameters were determined. RESULTS: PY dose dependently increased scores of all 5D-ASC core dimensions. Only one subject reacted with transient anxiety to HD PY. Compared with PL, MD and HD PY led to a 50% reduction of performance in the FAIR test. "General inactivation", "emotional excitability", and "dreaminess" were the only domains of the AMRS showing increased scores following MD and HD PY. The mean arterial blood pressure (MAP) was moderately elevated only 60 min following administration of HD PY. Neither EKG nor body temperature was affected by any dose of PY. TSH, ACTH, and CORT plasma levels were elevated during peak effects of HD PY, whereas PRL plasma levels were increased following MD and HD PY. CONCLUSION: PY affects core dimensions of altered states of consciousness and physiological parameters in a dose-dependent manner. Our study provided no cause for concern that PY is hazardous with respect to somatic health.

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PubMed2003

Behavioural dysregulation of decision-making in deficit but not nondeficit schizophrenia patients.

This study aimed to determine whether deficit but not nondeficit schizophrenia showed dysregulation of decision-making. In a two-choice prediction task, the subject is asked to predict whether a stimulus appears on the left or right side of a computer screen. Schizophrenia patients were divided into 12 patients with and 12 patients without deficit syndrome and compared to 12 healthy control subjects. Dynamical entropy and mutual information analyses were used to determine underlying strategies and the degree to which sequences of responses are nonrandom. When compared to controls, deficit but not nondeficit schizophrenia patients showed a dysregulation of decision-making characterized by an increased oscillation between highly predictable and highly unpredictable response sequences. Moreover, in deficit patients, the previous choice was more predictive of the current response. Therefore, the two-choice prediction task may be useful in differentiating between deficit and nondeficit schizophrenia.

Adult↗

PubMed2003

Deficits in prepulse inhibition and habituation in never-medicated, first-episode schizophrenia.

BACKGROUND: Prepulse inhibition (PPI) is the normal suppression of the startle reflex when an intense startling stimulus is preceded by a barely detectable prepulse. Habituation of the acoustic startle reflex is decrement in response when the same stimulus is presented repeatedly. These factors have been proposed as neurophysiologic measures of sensorimotor gating or filtering and discussed as trait-linked markers for information-processing deficits in schizophrenia-spectrum disorders. The aim of this study was to examine whether first-episode schizophrenia patients also exhibit deficits in PPI and habituation. METHODS: Never-medicated male schizophrenic and schizophreniform patients in their first psychotic episode (n=24) were compared with age-matched healthy men (n=21) in an acoustic startle paradigm assessing PPI (30-, 60-, 120-, 240-, and 2000-msec interstimulus intervals) and habituation. RESULTS: Compared with control subjects, first-episode patients exhibited significant deficits in both PPI in the 60-msec prepulse condition and startle habituation. Patients also exhibited less facilitation in the 2000-msec prepulse condition. CONCLUSIONS: In combination with other studies, these findings indicate that PPI and habituation may be sensitive intermediate phenotypic markers for information-processing deficits in schizophrenic patients.

Acoustic Stimulation↗

PubMed2003

Decision-making strategies by panic disorder subjects are more sensitive to errors.

BACKGROUND: Decision-making is a complex process, which can be assessed experimentally by the two-choice prediction task. Error-rate, i.e. the frequency of incorrect predictions during this task, is an important factor for the response selection during decision-making. This investigation examined whether the frequency of incorrect predictions has an augmented effect on the number of different strategies underlying decision-making in patients with panic disorder. METHODS: Patients with a DSM-IV diagnosis of panic disorder (PD; N=18), unipolar major depressive disorder (MDD; N=18) and normal comparison subjects (C; N=35) were tested with the two-choice prediction task using three error-rate conditions (20, 50, or 80%). The dynamical entropy of the response sequences was used to quantify the number of different strategies generated during the different error-rates. RESULTS: At 20% error-rates, panic disorder subjects when compared to MDD and C subjects generated more strategies and switched more frequently between strategies as measured by the dynamical entropy and the range of local dynamical entropies. Response bias measures during the two-choice prediction task and post-test self-assessment did not differ between panic disorder subjects and MDD or C subjects. LIMITATIONS: First, panic disorder subjects were medicated. Second, the frequency and intensity of panic attacks and the degree of avoidance behaviors, was not assessed. Third, subjects were tested once only. CONCLUSIONS: Panic disorder subjects show uniformly high response sequence unpredictability in the presence of low error-rates, which is consistent with continued search for an optimal response strategy even when the error-rate is low.

Adult↗

PubMed2003

The acoustic startle reflex and its modulation: effects of age and gender in humans.

The acoustic startle reflex and its modulation by prepulse inhibition (PPI) and habituation are used in many studies in different fields of neuropsychiatric research. The aim of this study was to examine the effects of age and gender on PPI, startle magnitude, and habituation in healthy human volunteers. Twenty-seven male and 28 female participants of four different age groups (range: 20-60 years) were investigated in an acoustic startle paradigm using a startle stimulus of 115 dB and a prepulse of 86 dB (16 dB over the white noise background) with five different lead intervals (30, 60, 120, 240, and 2000 ms). Seventeen males and 16 female participants were tested three times at monthly intervals. Aged participants showed significantly lower startle magnitude and significantly more habituation than younger participants, but there was no effect of age on PPI or prepulse facilitation. Moreover, there were no effects of gender on startle magnitude, PPI, prepulse facilitation, or habituation measures. Healthy males and females exhibited stable startle magnitudes and PPI across sessions. The results demonstrated that PPI and startle are reliable measures of sensory information processing in both genders and that startle magnitude and habituation are age-dependent measures.

Acoustic Stimulation↗

PubMed2003

Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia.

Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)--measures of auditory and visual context-dependent information processing--in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission.

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