Reduced Attentional Engagement Contributes to Deficits in Prefrontal Inhibitory Control in Schizophrenia

doi:10.1016/j.biopsych.2007.11.009

Biological Psychiatry

Volume 63, Issue 8, 15 April 2008, Pages 776-783

https://doi.org/10.1016/j.biopsych.2007.11.009 Get rights and content

Background

Problems with the voluntary control of behavior, such as those leading to increased antisaccade errors, are accepted as evidence of prefrontal dysfunction in schizophrenia. We previously reported that speeded prosaccade responses, i.e., shorter response latencies for automatic shifts of attention to visual targets, were associated with higher antisaccade error rates in schizophrenia. This suggests that dysregulation of automatic attentional processes may contribute to disturbances in prefrontally mediated control of voluntary behavior.

Methods

Twenty-four antipsychotic-naïve schizophrenia patients and 30 healthy individuals completed three tasks: a no-gap prosaccade task in which subjects shifted gaze toward a peripheral target that appeared coincident with the disappearance of a central fixation target and separate prosaccade and antisaccade tasks in which a temporal gap or overlap of the central target offset and peripheral target onset occurred. Sixteen patients were retested after 6 weeks of antipsychotic treatment.

Results

Patients’ prosaccade latencies in the no-gap task were speeded compared with healthy individuals. While patients were not atypical in the degree to which response latencies were speeded or slowed by the gap and overlap manipulations, those patients with diminished attentional engagement on the prosaccade task (i.e., reduced overlap effect) had significantly elevated antisaccade error rates. This effect persisted in patients evaluated after antipsychotic treatment.

Conclusions

This study provides evidence that a reduced ability to engage attention may render patients more distracted by sensory inputs, thereby further compromising impaired executive control during antisaccade tasks. Thus, alterations in attentional and executive control functions can synergistically disrupt voluntary behavioral responses in schizophrenia.

Section snippets

Subjects

Twenty-four antipsychotic-naïve individuals (16 male subjects, 8 female subjects) with a DSM-IV diagnosis of schizophrenia (n = 22) or schizoaffective disorder (n = 2) according to structured clinical interviews (Structured Clinical Interview for DSM-IV [SCID]) (24) and additional clinical data reviewed at consensus diagnosis meetings participated. Thirty healthy individuals (14 male subjects, 16 female subjects) recruited from the community matched patients on age, sex, and intelligence

Prosaccade Latencies

In the no-gap prosaccade task, patients’ latencies were faster than those of healthy individuals [F_group(1,53) = 6.00, p = .02; Figure 2]. For the gap-overlap prosaccade task, analyses revealed shorter latencies in the gap than overlap condition [F_trial(1,52) = 382.13, p < .001; Figure 2]. However, there was no overall group difference [F_group(1,52) = .10, p = .76] or differential effect of gap versus overlap trials between groups [F_{group × trial}(1,52) = .02, p = .89].

Figure 3 shows

Discussion

The established inability to suppress context-inappropriate responses on antisaccade tasks in schizophrenia is widely considered to reflect prefrontal cortical dysfunction that impairs the voluntary inhibition of prepotent responses, akin to disinhibition of a visual grasp reflex. Using no-gap and gap-overlap paradigms to manipulate the balance between neurophysiological mechanisms supporting sustained visual attention and the automatic shift of attention to new visual stimuli, we report the

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We aimed to gain further insight into previously reported beneficial effects of subthalamic nucleus deep brain stimulation (STN-DBS) on visually-guided saccades by examining the effects of unilateral compared to bilateral stimulation, paradigm, and target eccentricity on saccades in individuals with Parkinson’s disease (PD).
Eleven participants with PD and STN-DBS completed the visually-guided saccade paradigms with OFF, RIGHT, LEFT, and BOTH stimulation. Rightward saccade performance was evaluated for three paradigms and two target eccentricities.
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Citation Excerpt :
In contrast, compared to the step paradigm, the overlap paradigm results in prolonged latencies due to the fixation offset occurring after target onset (Saslow, 1967), which maintains activity related to the central foveated target thus making it harder to disengage visual attention from the center. Therefore, the paradigm effect gives insight into the balance between maintaining and shifting attention and gaze (Munoz and Fecteau, 2002; Reilly et al., 2008). This balance between maintaining and shifting attention may be regulated by the top-down descending inputs to the superior colliculus from the cortex, both directly and indirectly through the basal ganglia (Helminski and Segraves, 2003; Hikosaka et al., 2000; Munoz, 2002; Pierrot-Deseilligny et al., 2002).
We examined whether previous inconsistent findings about the effect of anti-Parkinsonian medication on visually-guided saccades (VGS) were due to the use of different paradigms, which change the timing of fixation offset and target onset, or different target eccentricities.
Thirty-three participants with Parkinson’s disease (PD) completed the VGS tasks OFF and ON medication, along with 13 healthy controls. Performance on 3 paradigms (gap, step, and overlap) and 2 target eccentricities was recorded. We used mixed models to determine the effect of medication, paradigm, and target eccentricity on saccade latency, gain, and peak velocity.
First, we confirmed known paradigm effects on latency, and target eccentricity effects on gain and peak velocity in participants with PD. Second, latency was positively associated with OFF medication Movement Disorders Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score in PD. Third, medication prolonged latency for the larger target eccentricity across the 3 paradigms, while decreasing gain and peak velocity in the step paradigm across target eccentricities.
Medication adversely affected and was not therapeutically beneficial for VGS. Previous inconsistencies may have resulted from chosen target eccentricity.
The negative medication effect on VGS may be clinically significant, as many activities in daily life require oculomotor control, inhibitory control, and visually-guided shifts of attention.
Reduced task-evoked pupillary response in preparation for an executive cognitive control response among individuals across the psychosis spectrum
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Task-evoked pupillary response (TEPR) is a measure of physiological arousal modulated by cognitive demand. Healthy individuals demonstrate greater TEPR prior to correct versus error antisaccade trials and correct antisaccade versus visually guided saccade (VGS) trials. The relationship between TEPR and antisaccade performance in individuals with psychotic disorders and their relatives has not been investigated.
Probands with schizophrenia, schizoaffective disorder, psychotic bipolar disorder, their first-degree relatives, and controls from the B-SNIP study completed antisaccade and VGS tasks. TEPR prior to execution of responses on these tasks was evaluated among controls compared to probands and relatives according to diagnostic groups and neurobiologically defined subgroups (biotypes).
Controls demonstrated greater TEPR on antisaccade correct versus error versus VGS trials. TEPR was not differentiated between antisaccade correct versus error trials in bipolar or schizophrenia probands, though was greater on antisaccade compared to prosaccade trials. There was no modulation of TEPR in schizoaffective probands. Relatives of schizophrenia and schizoaffective probands and those with elevated psychosis spectrum traits failed to demonstrate differential TEPR on antisaccade correct versus error trials. No proband or relative biotypes demonstrated differential TEPR on antisaccade correct versus error trials, and only proband biotype 3 and relative biotypes 3 and 2 demonstrated greater TEPR on antisaccade versus VGS trials.
Our findings suggest that aberrant modulation of preparatory activity prior to saccade execution contributes to impaired executive cognitive control across the psychosis spectrum, including nonpsychotic relatives with elevated clinical risk. Reduced pupillary modulation under cognitive challenge may thus be a biomarker for the psychosis phenotype.
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Six weeks of lurasidone resulted in increased prosaccade saccade latency and reduced antisaccade errors, with no change in memory guided saccade accuracy. After randomization, prosaccade and antisaccade latencies increased in only the high dose group, with no change in antisaccade errors in both groups. Memory guided saccade error increased in the high dose group and remained stable in the low dose group.
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Some aspects of saccadic performance have been found to be abnormal in chronic schizophrenia. The majority of this research has, however, been performed on patients treated with long-term antipsychotic medication. Very few studies have examined saccadic performance in antipsychotic-naïve/free patients. There are also very few studies describing the relationship between saccadic performance and clinical symptoms, particularly in antipsychotic free patients. In this study, we compared pro and antisaccade performance in a large sample of antipsychotic-naïve/free schizophrenia patients (N = 45) with healthy controls (N = 57). Clinical symptoms were assessed using Scale for Assessment of Positive Symptoms (SAPS) and Negative Symptoms (SANS). In the antisaccade task, patients made significantly more errors, and their correct antisaccades had smaller amplitudes in comparison to healthy controls. Higher error rates were associated with increased severity of hallucinations. In the prosaccade task, patients had less accurate final eye positions, and made saccades with slower latency and reduced amplitude compared to the healthy controls. These observations in schizophrenia patients without the potential confounds of antipsychotic treatment suggest intrinsic link between saccadic deficits and schizophrenia pathogenesis. The relationship between antisaccade errors and hallucination severity supports the potential link between hallucinations and deficits in inhibitory control.

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Original ArticleReduced Attentional Engagement Contributes to Deficits in Prefrontal Inhibitory Control in Schizophrenia

Background

Methods

Results

Conclusions

Section snippets

Subjects

Prosaccade Latencies

Discussion

Neuron

Neuroimage

J Psychiatr Res

Biol Psychiatry

Biol Psychiatry

Prog Brain Res

Psychiatry Res

Schizophr Res

Vision Res

Schizophr Res

Biol Psychiatry

Neuroimage

Cognitive Neuroscience of Attention

Decisional role of the dorsolateral prefrontal cortex in ocular motor behaviour

Brain

Control of eye movements and spatial attention

Proc Natl Acad Sci U S A

Prefrontal neuronal activity in rhesus monkeys performing a delayed anti-saccade task

Nature

Look away: The anti-saccade task and the voluntary control of eye movement

Nat Rev Neurosci

When does the brain inform the eyes whether and where to move the eyes? An EEG study in humans

Cereb Cortex

Positron emission tomography study of voluntary saccadic eye movements and spatial working memory

J Neurophysiol

The antisaccade task as a research tool in psychopathology: A critical review

Psychophysiology

Saccadic system functioning among schizophrenia patients and their first-degree biological relatives

J Abnorm Psychol

Temporal stability of saccadic task performance in schizophrenia and bipolar patients

Psychol Med

Original Article
Reduced Attentional Engagement Contributes to Deficits in Prefrontal Inhibitory Control in Schizophrenia