Wouter Hulstijn

Drug-induced stimulation and suppression of action monitoring in healthy volunteers.

RationaleAction monitoring has been studied extensively by means of measuring the error-related negativity (ERN). The ERN is an event-related potential (ERP) elicited immediately after an erroneous response and is thought to originate in the anterior cingulate cortex (ACC). Although the ACC has a central role in the brain, only a few studies have been performed to investigate directly the effects of drugs on action monitoring. A recent theory argues that the mesencephalic dopamine system carries an error signal to the ACC, where it generates the ERN.MethodsERPs and behavioral measurements were obtained from 12 healthy volunteers performing an Eriksen Flankers task. On each of the 4 test days, the stimulant d-amphetamine, the sedative lorazepam, the antidepressant mirtazapine, or a placebo was orally administered in a double-blind, four-way crossover design.ResultsThe indirect dopamine agonist amphetamine led to a strong enlargement of ERN amplitudes without affecting reaction times. Lorazepam and mirtazapine both showed slowing of responses, but only lorazepam led to reduced ERN amplitudes.ConclusionsAdministration of amphetamine leads to stimulated action monitoring, reflected in increased ERN amplitudes. This result provides evidence for dopaminergic involvement in action monitoring and is in line with differences in ERN amplitude found in neuropsychiatric disorders also suggesting dopaminergic involvement. The different effects for lorazepam and mirtazapine are probably caused by the neurobiological characteristics of these two types of sedation. Action monitoring is suppressed after administration of lorazepam, because the GABAergic pathways directly inhibit ACC functioning, whereas the histaminergic pathways of mirtazapine do not innervate the ACC directly.

Effects of antipsychotic and antidepressant drugs on action monitoring in healthy volunteers.

Humans need to monitor their actions continuously to detect errors as fast as possible and to adjust their performance to prevent future errors. This process of action monitoring can be investigated by measuring the error-related negativity (ERN), an ERP component elicited immediately after an error. In the current study, we investigated action monitoring after administration of the classic antipsychotic haloperidol (2.5 mg), the atypical antipsychotic olanzapine (10 mg), and the antidepressant paroxetine (20 mg), a selective serotonin reuptake inhibitor. Healthy volunteers (N = 14) were administered the three compounds and placebo in a randomized, double-blind, single-dose, four-way cross-over design. All participants performed a speeded two-choice reaction task, while event-related potentials and behavioral measurements were obtained. Both haloperidol and olanzapine significantly reduced ERN amplitudes. After paroxetine, the ERN was not different from placebo. N2 congruency effects were not affected by treatment condition. Only olanzapine demonstrated behavioral effects, namely a slowing of responses, an increase in error rates, and the absence of performance adjustments. The attenuated ERNs after the dopamine antagonist haloperidol are in line with the presumed role of dopamine in action monitoring. Haloperidol is thought to block dopaminergic signaling, thus reducing ERN amplitudes. On the other hand, the effects of olanzapine are mainly caused by its sedative side effects, leading to a decline in motivation and appraisal of errors. Finally, the absence of any effects after paroxetine suggests that serotonin transmission does not play a direct role in regulating mechanisms related to action monitoring.

Neural dynamics of error processing in medial frontal cortex.

Adaptive behavior requires an organism to evaluate the outcome of its actions, such that future behavior can be adjusted accordingly and the appropriate response selected. During associative learning, the time at which such evaluative information is available changes as learning progresses, from the delivery of performance feedback early in learning to the execution of the response itself during learned performance. Here, we report a learning-dependent shift in the timing of activation in the rostral cingulate zone of the anterior cingulate cortex from external error feedback to internal error detection. This pattern of activity is seen only in the anterior cingulate, not in the pre-supplementary motor area. The dynamics of these reciprocal changes are consistent with the claim that the rostral cingulate zone is involved in response selection on the basis of the expected outcome of an action. Specifically, these data illustrate how the anterior cingulate receives evaluative information, indicating that an action has not produced the desired result.

Psychomotor slowing and planning deficits in schizophrenia

The relative contribution of cognitive and motor processing to psychomotor slowing in schizophrenia was investigated using three tasks: a simple line-copying task and a more complex figure-copying task, both following a reaction paradigm, and a standard psychomotor test, the Digit Symbol Test (DST). Various movement variables of the task performances were derived from recordings made with the aid of a digitizing tablet. The patients with schizophrenia appeared to be about one-third slower in their total performance time on all three tasks when compared with healthy controls, which suggests a general psychomotor slowing in this group. When itemized over the various movement variables, this slowing was found in both initiation time and movement time in the copying tasks and in the DST in the time to match the symbol and the digit, but not in writing the digit. Furthermore, in the figure-copying task it was found that increased figure complexity or decreased familiarity prolonged the initiation time. These latency increases were not significantly larger for the schizophrenia group as a whole, but only for a subgroup of patients with higher scores on negative symptoms. Regarding reinspection time, the effects of familiarity were larger in the schizophrenia group as a whole. These group findings suggest that patients tend to plan their actions less in advance, which, in the case of the more complex or unfamiliar task conditions, is a less sophisticated planning strategy. Given the longer latencies in patients with more severe negative symptoms, it seems that these patients have problems with turning a plan into action. The present study provides evidence of psychomotor slowing and planning deficits in schizophrenia.

Fine motor retardation and depression

New computerized techniques allow the precise measurement of psychomotor retardation in patients with a major depressive episode (MDE). One such technique is the analysis of writing and drawing behaviour during figure copying tasks. In the present study, 22 inpatients with an MDE were compared to 22 normal controls. Three tasks were used: the drawing of lines and simple figures, the copying of complex figures and a task in which figures had to be rotated. Objectives were to provide support for earlier findings that the patients were slower than the controls and to explore the cognitive and motor processes involved. Two strategies were applied: analysis of the reaction time and movement time and their different components, and manipulation of the cognitive and motor demands. Patients showed considerable retardation with most of the kinematic variables. Motor deficits and cognitive slowing down contributed to this retardation. Cognitive difficulties increased with increasing complexity of the task.

Retardation in depression: assessment by means of simple motor tasks

BACKGROUND Psychomotor retardation in depression has mostly been assessed with tasks requiring both cognitive and motor processes. This study tested whether retardation could be measured if the cognitive demands of the task were minimal. METHODS 30 inpatients with a major depressive episode were compared one week after the start of antidepressant treatment, to 30 healthy control persons, matched for age, sex and educational level. Tests consisted of ten simple drawing tasks. The kinematics of drawing movements were recorded using a specially designed pen, a graphics tablet and a personal computer. RESULTS Patients showed marked motor slowing on all the tasks: longer movement durations, longer pauses and lower velocities. CONCLUSIONS Psychomotor retardation in depressed patients treated with antidepressants occurs during drawing tasks, in which the cognitive demands are minimal and less than those required in the figure copying tasks used in our previous studies. LIMITATIONS The use of co-medication can have influenced the results, although no correlations were found between the use of medication and the kinematic variables. CLINICAL RELEVANCE Detailed registration and analysis of drawing movements enable a more precise diagnosis of psychomotor disturbances in depressed patients.

Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers.

Ampakines act as positive allosteric modulators of AMPA-type glutamate receptors and facilitate hippocampal long-term potentiation (LTP), a mechanism associated with memory storage and consolidation. The present study investigated the acute effects of farampator, 1-(benzofurazan-5-ylcarbonyl) piperidine, on memory and information processes in healthy elderly volunteers. A double-blind, placebo-controlled, randomized, cross-over study was performed in 16 healthy, elderly volunteers (eight male, eight female; mean age 66.1, SD 4.5 years). All subjects received farampator (500 mg) and placebo. Testing took place 1 h after drug intake, which was around Tmax for farampator. Subjects performed tasks assessing episodic memory (wordlist learning and picture memory), working and short-term memory (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Information processing was assessed with a tangled lines task, the symbol digit substitution test (SDST) and the continuous trail making test (CTMT). Farampator (500 mg) unequivocally improved short-term memory but appeared to impair episodic memory. Furthermore, it tended to decrease the number of switching errors in the CTMT. Drug-induced side effects (SEs) included headache, somnolence and nausea. Subjects with SEs had significantly higher plasma levels of farampator than subjects without SEs. Additional analyses revealed that in the farampator condition the group without SEs showed a significantly superior memory performance relative to the group with SEs. The positive results on short-term memory and the favorable trends in the trail making test (CTMT) are interesting in view of the development of ampakines in the treatment of Alzheimers disease and schizophrenia.

Parsing the components of the psychomotor syndrome in schizophrenia

Docx L, Morrens M, Bervoets C, Hulstijn W, Fransen E, De Hert M, Baeken C, Audenaert K, Sabbe B. Parsing the components of the psychomotor syndrome in schizophrenia.

Differentiation of cognitive and motor slowing in the Digit Symbol Test (DST): differences between depression and schizophrenia

Abstract Schizophrenia and depression have an overlap in symptomatology, namely a slowing in both motor and mental activities, denoted in depression as ‘psychomotor retardation’ and in schizophrenia as ‘psychomotor poverty’. By means of a new technique that allows the measurement of psychomotor speed and the computerized analysis of writing movements recorded during the performance of the Digit Symbol Test, it indeed proved to be possible to observe a slowing in both disorders. In addition, a different structure of slowing in the two patient groups could be identified.

Stereotypy in schizophrenia

OBJECTIVES In schizophrenia, stereotypy is observed, a symptom characterized by repetitive, functionless motor behaviour. Whereas cognitive dysfunctioning is known to remain stable throughout the illness, less is known about the course of the motor symptoms. The Zeigeversuch [Mittenecker, E., 1953. Perseveration und Persönlichkeit: 1. Teil: experimentelle Untersuchungen. Z. Exp. Angew. Psychol. 1, 5-31], which entails the generation of a random sequence of button presses, was claimed to capture stereotypy. We used a newly designed computerized version of the Zeigeversuch, the Stereotypy Test Apparatus (STA) to evaluate the evolution of STA performance through the course of the illness. METHODS To assess stereotyped and perseverative behaviour, 58 schizophrenic inpatients and 48 healthy controls performed the STA and the Wisconsin Card Sorting Test (WCST), respectively, as well as several other traditional neuropsychological tests and the Symbol Digit Substitution Test (SDST) on a writing digitizer. RESULTS The STA correlated only weakly with the WCST and SDST measures but not with the cognitive or motor slowing on the SDST, nor with the other cognitive measures. Stereotyped and perseverative idiosyncrasies both seem to increase in the course of the illness, in contrast with other cognitive dysfunctions. However, whereas perseveration is already present in the early stages of the illness, stereotyped behaviour only manifests itself in the later stages of schizophrenia. Failure of cognitive inhibition may result in an activation of prepotent stereotyped responses captured by the STA.