Homepage of Matthijs Vink

Matthijs Vink, PhD.

Department of Psychiatry

University Medical Centre Utrecht

Rudolf Magnus Institute of Neuroscience

The Netherlands

phone: +31 88 755 9251

email: m.vink@umcutrecht.nl

PhD thesis - June 1 2005

On Inhibition: Studies in Schizophrenia [ download ]

Summary

The research presented in this thesis examined inhibitory control in healthy subjects, schizophrenia patients, and unaffected siblings of such patients. A division was made between inhibitory control over incoming information; perceptual inhibition (chapters 2-4) and inhibitory control over outgoing information; motor inhibition (chapters 5,6). The main finding of these studies is that patients show impairments in both aspects of inhibitory control. Siblings, who were only tested on motor inhibition, displayed functional brain abnormalities similar to those of patients, despite normal behavioural performance. In the sections that follow, I will provide an overview of the main findings and conclusions of each of the studies.

2. Perceptual inhibition

The research described in chapters 2-4 concerns perceptual inhibition in healthy controls and  schizophrenia patients. Schizophrenia patients are thought to be impaired in filtering out irrelevant information, which can cause an ‘information overload’. This ‘information overload’ may underlie several clinical symptoms, such as thought disorder or hallucinations. To measure the ability to filter out irrelevant information, we developed a spatial negative priming task. In this task, subjects have to press the button that corresponds to the location of the larger (i.e. target stimulus) of two simultaneously presented dots. It has been consistently shown that

in healthy controls, presenting relevant information (e.g. a target stimulus) in a location which was previously irrelevant (e.g. occupied by a distracter stimulus) causes a slowing in responding to that relevant information.Schizophrenia patients typically do not display such a response slowing. This possibly indicates that schizophrenia patients fail in successfully inhibiting irrelevant information. However, alternative theories have proposed that this response slowing is caused either by a perceptual conflict due to a difference between the target timulus and previous distracter stimulus ( perceptual mismatching ), or by a perceptual advantage for the accompanying distracter stimulus being presented in a new location (distracter novelty advantage). Furthermore, patients may show a reduced negative priming effect as a result of reduced perceptual speed. That is, if the information is presented very briefly, patients may not adequately process this information, resulting in a reduced negative priming effect. In the studies described below, we will address the question whether the negative priming effect is caused by perceptual inhibition or is better explained by alternative perceptual processes. The first step (see chapter 2) in studying perceptual inhibition deficits in schizophrenia was to determine what is actually being measured with a negative priming task. To this end, we developed a spatial negative priming task. This task was designed so that the influence of alternative theories other than inhibition on response slowing could be tested. Chapter 2 describes a study with healthy subjects to address the question if the spatial negative priming effect is due to inhibition of the distracter, or is better explained by (a) perceptual mismatching, or (b) a novelty advantage for the distracter. The results show that a spatial negative priming effect was present in absence of perceptual mismatching and distracter novelty advantage, although the latter mechanism added to the spatial negative priming effect. We therefore concluded that perceptual inhibition plays a crucial role in the observed spatial negative priming effect in healthy controls. The next step (see chapter 3) was to administer the task to schizophrenia patients. The goal of this study was to determine the influence of the above-mentioned perceptual confounds on the negative priming effect in schizophrenia. In addition, we assessed the effect of distracter salience, that is, does it matter if the distracter stimulus is larger or smaller than the target stimulus. The main finding was that, when controlled for reduced perceptual speed and perceptual mismatching, schizophrenia patients show a reduced spatial negative priming effect compared to matched healthy controls. Varying the salience of the distracter stimulus did not affect the size of the negative priming effect in schizophrenia, whereas in controls the size of the effect was significantly reduced when the distracter stimulus was larger (i.e. more salient). These data provide evidence for a reduced ability to distinguish relevant from irrelevant information in schizophrenia patients. Such deficits probably underlie clinical symptoms of attentional dysfunction, although further studies in larger samples are necessary to demonstrate such relationships. In chapter 4, a functional magnetic resonance imaging (fMRI) study with healthy subjects is described. This study was done to investigate the neural mechanisms underlying the negative priming effect. In the task, subjects had to respond to a target stimulus which was presented in either a location previously occupied by a distracter (negative priming condition) or a new location (control condition). As expected, responses were slowed in the negative priming inhibition compared to the control condition. To study the brain processes underlying this response slowing, we first determined which areas of the brain were involved in performing the task. In turn, the mean brain activation for both conditions within these selected areas was compared. We found decreased activation in the superior parietal lobe (SPL), but increased activation in the motor areas (supplementary motor area (SMA), putamen) during spatial negative priming compared to the control condition. These findings (chapter 4) are consistent with the notion that visual selective attention also involves the active inhibition of distracter stimuli. The consequences of such active inhibition become apparent as responding to stimuli presented in previous distracter locations is slowed. The inhibitory mechanism constitutes a normal part of attention as it serves to bias selective attention based on a priori knowledge. This allows the brain to respond more efficiently to changes within the environment, thereby requiring less activation, especially in the superior parietal lobe. When such a change occurs within a previous distracter location, additional processing in premotor areas is required to respond to that location. So, whereas the brain is set to perform tasks as efficient as possible by using prior knowledge to bias the processing of incoming information, all information remains available, be it after some delay, to maintain a high degree of cognitive flexibility.

3. Motor inhibition

Schizophrenia has been associated with poor response (or motor) inhibition. For example, patients make more errors during inhibition of strongly automated eye-movements, word reading during the Stroop task, and motor responses. Impaired inhibitory control in schizophrenia has been linked to thought disorder, auditory hallucinations, and delusions. In chapter 5, an fMRI study is described which was performed to examine what exactly happens when subjects have to inhibit a strongly automated response (i.e. during a so-called stop-trial). We found that in healthy volunteers, the striatum was activated when a response had to be blocked. Moreover, success of inhibiting responses was strongly correlated with magnitude of activity in this region. We also found that the striatum was more active when subjects anticipated stop cues within a series of motor cues, compared to a series when no stop-cues occurred. Finally, the level of activation within the striatum increased as the likelihood of a stop cue increased. These findings indicate that the striatum plays an important role in inhibitory motor control. Not only is the striatum required to inhibit responses, but it is also involved in the preparation of responses in anticipation of inhibition. In chapter 6, the same task was administered to both schizophrenia patients and unaffected siblings of such patients. The aim of this study was to investigate whether impaired inhibitory control is associated with abnormal striatal activation in schizophrenia. We used our motor inhibition task (chapter 5) to visualize brain activation during, as well as prior to, response blocking (i.e. anticipation-related activity). Given indications that schizophrenia patients perform poorly in tasks that require inhibition of prepotent responses, we expected to find decreased activation in the striatum in these patients. Furthermore, if patients fail to anticipate the occurrence of stop cues, then activation in the striatum should not increase with increasing stop-cue likelihood. An important question is whether any abnormality is associated with the illness itself, or with the risk for that illness. To address this issue, we included a second group, consisting of unaffected siblings of schizophrenia patients. If abnormal activation of the striatum is related to a (genetic) risk of developing schizophrenia, then striatal activation should be abnormal in siblings as well. The main finding of the experiments described in chapter 6 is that a striatal dysfunction was found both in schizophrenia patients and in unaffected first-degree relatives. This striatal dysfunction was apparent during a task in which the likelihood of having to inhibit a motor response increased. In healthy controls, striatal activation increased proportionally to the likelihood of having to inhibit a response. In contrast, in both schizophrenia patients and siblings, striatal activation was unaffected by this likelihood. In addition the level of striatal activation was reduced in the patients as compared to the controls. Behaviourally, only controls and siblings became more cautious in responding, and consequently became more accurate in inhibiting their response as the likelihood of having to inhibit the response increased. Thus, despite a normal behavioural response in the first-degree relatives, we found their striatal activation to be abnormal. This latter finding suggests that functional brain measures may be a more sensitive marker of (genetic) risk factors for the development of schizophrenia than are behavioural measures. The question arises what the abnormal striatal function in siblings of schizophrenia patients signifies if performance is normal. We argue that it may well mean that there could be two mechanisms at play in schizophrenia, with regard to inhibitory control. The primary mechanism concerns a predisposition to abnormal function of striatum with regard to expectation, and this is supported by the presented data. The secondary mechanism would involve compensation for the striatal malfunction. Many systems in the brain consist of multiple parallel and overlapping circuits which can serve as back-up systems. It may well be that the striatal abnormality is compensated by other brain systems in siblings. The fact that schizophrenia patients exhibit poor performance would indeed indicate that compensatory mechanisms are no longer available as a consequence of the illness or, alternatively, of medication. In conclusion, these results (chapter 6) indicate that striatal abnormalities are present in schizophrenia patients and in unaffected siblings. Striatal hypoactivity was associated with behavioural deficits in patients only while siblings showed normal behaviour, suggesting some form of intact cerebral compensating mechanism. Striatal abnormalities may be related to a (genetic) risk factor for the development of schizophrenia.