Eye movements and the perceptual span in disordered reading: A comparison of schizophrenia and dyslexia.

Increasing evidence of a common neurodevelopmental etiology between schizophrenia and developmental dyslexia suggests that neurocognitive functions, such as reading, may be similarly disrupted. However, direct comparisons of reading performance in these disorders have yet to be conducted. To address this gap in the literature, we employed a gaze-contingent moving window paradigm to examine sentence-level reading fluency and perceptual span (breadth of parafoveal processing) in adults with schizophrenia (dataset from Whitford et al., 2013) and psychiatrically healthy adults with dyslexia (newly collected dataset). We found that the schizophrenia and dyslexia groups exhibited similar reductions in sentence-level reading fluency (e.g., slower reading rates, more regressions) compared to matched controls. Similar reductions were also found for standardized language/reading and executive functioning measures. However, despite these reductions, the dyslexia group exhibited a larger perceptual span (greater parafoveal processing) than the schizophrenia group, potentially reflecting a disruption in normal foveal-parafoveal processing dynamics. Taken together, our findings suggest that reading and reading-related functions are largely similarly disrupted in schizophrenia and dyslexia, providing additional support for a common neurodevelopmental etiology.

Reading deficits in schizophrenia and their relationship to developmental dyslexia: A review.

Although schizophrenia and developmental dyslexia are considered distinct disorders in terms of clinical presentation and functional outcome, they both involve disruption in the processes that support skilled reading, including language, auditory perception, visual perception, oculomotor control, and executive function. Further, recent work has proposed a common neurodevelopmental basis for the two disorders, as suggested by genetic and pathophysiological overlap. Thus, these lines of research suggest that reading may be similarly impacted in schizophrenia and dyslexia. In this review, we survey research on reading abilities in individuals with schizophrenia, and review the potential mechanisms underlying reading deficits in schizophrenia that may be shared with those implicated in dyslexia. Elucidating the relationship between reading impairment in schizophrenia and dyslexia could allow for a better understanding of the pathophysiological underpinnings of schizophrenia, and could facilitate remediation of cognitive deficits that impact day-to-day functioning.

Differential Associations between Cortical Thickness and Striatal Dopamine in Treatment-Naïve Adults with ADHD vs. Healthy Controls.

Alterations in catecholamine signaling and cortical morphology have both been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, possible links between the two remain unstudied. Here, we report exploratory analyses of cortical thickness and its relation to striatal dopamine transmission in treatment-naïve adults with ADHD and matched healthy controls. All participants had one magnetic resonance imaging (MRI) and two [11C]raclopride positron emission tomography scans. Associations between frontal cortical thickness and the magnitude of d-amphetamine-induced [11C]raclopride binding changes were observed that were divergent in the two groups. In the healthy controls, a thicker cortex was associated with less dopamine release; in the ADHD participants the converse was seen. The same divergence was seen for baseline D2/3 receptor availability. In healthy volunteers, lower D2/3 receptor availability was associated with a thicker cortex, while in the ADHD group lower baseline D2/3 receptor availability was associated with a thinner cortex. Individual differences in cortical thickness in these regions correlated with ADHD symptom severity. Together, these findings add to the evidence of associations between dopamine transmission and cortical morphology, and suggest that these relationships are altered in treatment-naïve adults with ADHD.

Perisaccadic perception of visual space in people with schizophrenia.

Corollary discharge signals are found in the nervous systems of many animals, where they serve a large variety of functions related to the integration of sensory and motor signals. In humans, an important corollary discharge signal is generated by oculomotor structures and communicated to sensory systems in concert with the execution of each saccade. This signal is thought to serve a number of purposes related to the maintenance of accurate visual perception. The properties of the oculomotor corollary discharge can be probed by asking subjects to localize stimuli that are flashed briefly around the time of a saccade. The results of such experiments typically reveal large errors in localization. Here, we have exploited these well-known psychophysical effects to assess the potential dysfunction of corollary discharge signals in people with schizophrenia. In a standard perisaccadic localization task, we found that, compared with controls, patients with schizophrenia exhibited larger errors in localizing visual stimuli. The pattern of errors could be modeled as an overdamped corollary discharge signal that encodes instantaneous eye position. The dynamics of this signal predicted symptom severity among patients, suggesting a possible mechanistic basis for widely observed behavioral manifestations of schizophrenia.

Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD.

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.

Reading impairments in schizophrenia relate to individual differences in phonological processing and oculomotor control: evidence from a gaze-contingent moving window paradigm.

Language and oculomotor disturbances are 2 of the best replicated findings in schizophrenia. However, few studies have examined skilled reading in schizophrenia (e.g., Arnott, Sali, Copland, 2011; Hayes & O'Grady, 2003; Revheim et al., 2006; E. O. Roberts et al., 2012), and none have examined the contribution of cognitive and motor processes that underlie reading performance. Thus, to evaluate the relationship of linguistic processes and oculomotor control to skilled reading in schizophrenia, 20 individuals with schizophrenia and 16 demographically matched controls were tested using a moving window paradigm (McConkie & Rayner, 1975). Linguistic skills supporting reading (phonological awareness) were assessed with the Comprehensive Test of Phonological Processing (R. K. Wagner, Torgesen, & Rashotte, 1999). Eye movements were assessed during reading tasks and during nonlinguistic tasks tapping basic oculomotor control (prosaccades, smooth pursuit) and executive functions (predictive saccades, antisaccades). Compared with controls, schizophrenia patients exhibited robust oculomotor markers of reading difficulty (e.g., reduced forward saccade amplitude) and were less affected by reductions in window size, indicative of reduced perceptual span. Reduced perceptual span in schizophrenia was associated with deficits in phonological processing and reduced saccade amplitudes. Executive functioning (antisaccade errors) was not related to perceptual span but was related to reading comprehension. These findings suggest that deficits in language, oculomotor control, and cognitive control contribute to skilled reading deficits in schizophrenia. Given that both language and oculomotor dysfunction precede illness onset, reading may provide a sensitive window onto cognitive dysfunction in schizophrenia vulnerability and be an important target for cognitive remediation.

Effects of methylphenidate on basic and higher-order oculomotor functions.

Eye movements are sensitive indicators of pharmacological effects on sensorimotor and cognitive processing. Methylphenidate (MPH) is one of the most prescribed medications in psychiatry. It is increasingly used as a cognitive enhancer by healthy individuals. However, little is known of its effect on healthy cognition. Here we used oculomotor tests to evaluate the effects of MPH on basic oculomotor and executive functions. Twenty-nine males were given 20mg of MPH orally in a double-blind placebo-controlled crossover design. Participants performed visually-guided saccades, sinusoidal smooth pursuit, predictive saccades and antisaccades one hour post-capsule administration. Heart rate and blood pressure were assessed prior to capsule administration, and again before and after task performance. Visually-guided saccade latency decreased with MPH (p<0.004). Smooth pursuit gain increased on MPH (p<0.001) and number of saccades during pursuit decreased (p<0.001). Proportion of predictive saccades increased on MPH (p<0.004), specifically in conditions with predictable timing. Peak velocity of predictive saccades increased with MPH (p<0.01). Antisaccade errors and latency were unaffected. Physiological variables were also unaffected. The effects on visually-guided saccade latency and peak velocity are consistent with MPH effects on dopamine in basal ganglia. The improvements in predictive saccade conditions and smooth pursuit suggest effects on timing functions.

Limbic response to psychosocial stress in schizotypy: a functional magnetic resonance imaging study.

Psychological stress causes dopamine release in the striatum and is thought to play a role in susceptibility to psychotic illness. Previous work suggests that an elevated dopaminergic response to stress may index vulnerability to psychosis in certain individuals. With functional magnetic resonance imaging, we measured stress-induced changes in brain activity in healthy individuals at elevated risk of developing psychosis. Participants were 15 controls and 25 psychometric schizotypes: 12 with positive symptom schizotypy (perceptual aberrations) and 13 with negative symptom schizotypy (physical anhedonia), as determined by questionnaires (Chapman et al., 1976; Chapman and Chapman, 1978). In the scanner, participants performed the Montreal Imaging Stress Task and a matched sensory-motor control task. Measures of self-reported stress and salivary cortisol levels were taken throughout the experiment. All three groups showed significant increases in self-reported stress and significant fMRI signal change in the striatal, limbic and cortical regions. However, the Physical Anhedonia group showed greater stress-induced striatal and limbic deactivation than the other two groups. Deactivation in the striatum was significantly correlated with Physical Anhedonia score across all subjects. Our findings suggest the presence of abnormalities in striatal response to stress in negative symptom schizotypy.

Effect of D-amphetamine on inhibition and motor planning as a function of baseline performance.

RATIONALE: Baseline performance has been reported to predict dopamine (DA) effects on working memory, following an inverted-U pattern. This pattern may hold true for other executive functions that are DA-sensitive. OBJECTIVES: The objective of this study is to investigate the effect of D: -amphetamine, an indirect DA agonist, on two other putatively DA-sensitive executive functions, inhibition and motor planning, as a function of baseline performance. METHODS: Participants with no prior stimulant exposure participated in a double-blind crossover study of a single dose of 0.3 mg/kg, p.o. of D: -amphetamine and placebo. Participants were divided into high and low groups, based on their performance on the antisaccade and predictive saccade tasks on the baseline day. Executive functions, mood states, heart rate and blood pressure were assessed before (T0) and after drug administration, at 1.5 (T1), 2.5 (T2) and 3.5 h (T3) post-drug. RESULTS: Antisaccade errors decreased with D: -amphetamine irrespective of baseline performance (p = 0.025). For antisaccade latency, participants who generated short-latency antisaccades at baseline had longer latencies on D: -amphetamine than placebo, while those with long-latency antisaccades at baseline had shorter latencies on D: -amphetamine than placebo (drug x group, p = 0.04). D: -amphetamine did not affect motor planning. Ratings of mood improved on D: -amphetamine (p < 0.001). Magnitude of D: -amphetamine-induced changes in elation was related to baseline reaction time variability. CONCLUSIONS: D: -amphetamine reduced antisaccade error rates in healthy controls, replicating and extending findings with DA agonists in clinical populations. D: -amphetamine had baseline-dependent effects on antisaccade latency, consistent with an inverted-U relationship between performance and DA activity.

Smooth pursuit in schizophrenia: a meta-analytic review of research since 1993.

Abnormal smooth pursuit eye-tracking is one of the most replicated deficits in the psychophysiological literature in schizophrenia [Levy, D. L., Holzman, P. S., Matthysse, S., & Mendell, N. R. (1993). Eye tracking dysfunction and schizophrenia: A critical perspective. Schizophrenia Bulletin, 19, 461-505]. We used meta-analytic procedures to quantify patient-control differences in eye-tracking and to evaluate potential moderators of effect size including patient and target characteristics and characteristics of the control population (matched or not). The magnitude of patient-control differences in pursuit depended on the measure. Global measures had large effect sizes. Among specific measures, maintenance gain and leading saccades yielded large effect sizes, with gain also yielding the narrowest confidence interval. Effect sizes associated with specific measures of smooth pursuit vs. specific measures of intrusive saccades did not clearly implicate one system over the other. Patient demographics and target characteristics generally had little influence on effect sizes. However, studies that failed to sex-match patients and controls tended to have smaller effect sizes for maintenance gain and catch-up saccade rate. Average effect sizes and confidence limits for global measures of pursuit and for maintenance gain place these measures alongside the very strongest neurocognitive measures in the literature [Heinrichs, R. W. (2004). Meta-analysis, and the science of schizophrenia: Variant evidence or evidence of variants? Neuroscience and Biobehavioral Reviews, 28, 379-394] for distinguishing between patients with schizophrenia and controls.

Stress-induced dopamine release in humans at risk of psychosis: a [11C]raclopride PET study.

Drugs that increase dopamine levels in the brain can cause psychotic symptoms in healthy individuals and worsen them in schizophrenic patients. Psychological stress also increases dopamine release and is thought to play a role in susceptibility to psychotic illness. We hypothesized that healthy individuals at elevated risk of developing psychosis would show greater striatal dopamine release than controls in response to stress. Using positron emission tomography and [(11)C]raclopride, we measured changes in synaptic dopamine concentrations in 10 controls and 16 psychometric schizotypes; 9 with perceptual aberrations (PerAb, ie positive schizotypy) and 7 with physical anhedonia (PhysAn, ie negative schizotypy). [(11)C]Raclopride binding potential was measured during a psychological stress task and a sensory-motor control. All three groups showed significant increases in self-reported stress and cortisol levels between the stress and control conditions. However, only the PhysAn group showed significant stress-induced dopamine release. Dopamine release in the entire sample was significantly negatively correlated with smooth pursuit gain, an endophenotype linked to frontal lobe function. Our findings suggest the presence of abnormalities in the dopamine response to stress in negative symptom schizotypy, and provide indirect evidence of a link to frontal function.

Schizotypy, attention deficit hyperactivity disorder, and dopamine genes.

Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of Schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.

Smooth pursuit eye movement and schizotypy in the community.

Deficits in smooth pursuit eye movements are well documented in schizophrenia and schizotypic psychopathology. The status of eye tracking dysfunction (ETD) as an endophenotype for schizophrenia liability is relatively robust. However, the relation of ETD to schizophrenia-related deviance in the general population has not been confirmed. This study examined smooth pursuit eye tracking and schizotypal personality features in the general population. Smooth pursuit eye movement and schizotypal features were measured in 300 adult community subjects. The sample included both sexes, subjects with a wide age and educational range, and subjects with no prior history of psychosis. Primary outcome measures were peak gain (eye velocity/target velocity), catch-up saccade rate, and schizotypal feature scores. Total schizotypal features were significantly associated with decreased peak gain and were associated at the trend level with increased catch-up saccade rate. These associations were essentially unchanged after controlling for age, sex, and intellectual level effects. These data confirm a hypothesized association between schizotypal features and poorer eye tracking performance (principally, peak gain) in the general population as well as support the conceptualization of ETD as an endophenotype for schizophrenia liability.

Transcranial magnetic stimulation of frontal oculomotor regions during smooth pursuit.

Both the frontal eye fields (FEFs) and supplementary eye fields (SEFs) are known to be involved in smooth pursuit eye movements. It has been shown recently that stimulation of the smooth-pursuit area of the FEF [frontal pursuit area (FPA)] in monkey increases the pursuit response to unexpected changes in target motion during pursuit. In the current study, we applied transcranial magnetic stimulation (TMS) to the FPA and SEF in humans during sinusoidal pursuit to assess its effects on the pursuit response to predictable, rather than unexpected, changes in target motion. For the FPA, we found that TMS applied immediately before the target reversed direction increased eye velocity in the new direction, whereas TMS applied in mid-cycle, immediately before the target began to slow, decreased eye velocity. For the SEF, TMS applied at target reversal increased eye velocity in the new direction but had no effect on eye velocity when applied at mid-cycle. TMS of the control region (leg region of the somatosensory cortex) did not affect eye velocity at either point. Previous stimulation studies of FPA during pursuit have suggested that this region is involved in controlling the gain of the transformation of visual signals into pursuit motor commands. The current results suggest that the gain of the transformation of predictive signals into motor commands is also controlled by the FPA. The effect of stimulation of the SEF is distinct from that of the FPA and suggests that its role in sinusoidal pursuit is primarily at the target direction reversal.

Antisaccade and smooth pursuit performance in positive- and negative-symptom schizotypy.

Schizophrenic patients have well-documented abnormalities in smooth pursuit eye movements and antisaccade performance. In populations at risk for schizophrenia, smooth pursuit abnormalities are also well documented. Antisaccade deficits have been replicated in high-risk populations as well, but the findings are more variable and the reasons for the variability are not clear. Some evidence suggests that antisaccade deficits increase in high-risk populations in relation to the presence of positive symptoms. Whether antisaccade deficits increase in relation to negative symptoms in high-risk populations is relatively uninvestigated. We evaluated antisaccade and pursuit performance in "psychometric schizotypes" who had elevated scores on either the Perceptual Aberration Scale (PerAb; i.e., positive symptoms) or the Physical Anhedonia Scale (PhysAnh; i.e., negative symptoms) but not both, and in normal controls. We used the standard version of the antisaccade task, for which results in positive-symptom schizotypes have previously been reported, and investigated performance on a gap and overlap version. We replicated the finding that a significantly larger percentage of positive-symptom schizotypes than controls have elevated antisaccade error rates on the standard antisaccade task (P=0.03); the percentage of negative-symptom schizotypes with elevated antisaccade error rates did not differ from that of control subjects. Neither schizotypal group was impaired on the gap or overlap versions of the task. On the pursuit task, a higher percentage of positive- and negative-symptom schizotypes were classified as having deviant performance than control subjects (both Ps<0.04). These findings suggest that antisaccade deficits may be better at identifying high-risk subjects with positive symptoms. Pursuit deficits identified both positive- and negative-symptom schizotypes, but was better at identifying the latter.

Executive functions and methylphenidate response in subtypes of attention-deficit/hyperactivity disorder.

BACKGROUND: Oculomotor tasks are a well-established means of studying executive functions and frontal-striatal functioning in both nonhuman primates and humans. Attention-deficit/hyperactivity disorder (ADHD) is thought to implicate frontal-striatal circuitry. We used oculomotor tests to investigate executive functions and methylphenidate response in two subtypes of ADHD. METHODS: Subjects were boys, aged 11.5-14 years, with ADHD-combined (n = 10), ADHD-inattentive (n = 12), and control subjects (n = 10). Executive functions assessed were motor planning (tapped with predictive saccades), response inhibition (antisaccades), and task switching (saccades-antisaccades mixed). RESULTS: The ADHD-combined boys were impaired relative to control subjects in motor planning (p < .003) and response inhibition (p < .007) but not in task switching (p > .92). They were also significantly impaired relative to ADHD-inattentive boys, making fewer predictive saccades (p < .03) and having more subjects with antisaccade performance in the impaired range (p < .04). Methylphenidate significantly improved motor planning and response inhibition in both subtypes. CONCLUSIONS: ADHD-combined but not ADHD-inattentive boys showed impairments on motor planning and response inhibition. These deficits might be mediated by brain structures implicated specifically in the hyperactive/impulsive symptoms. Methylphenidate improved oculomotor performance in both subtypes; thus, it was effective even when initial performance was not impaired.

Nicotine and behavioral markers of risk for schizophrenia: a double-blind, placebo-controlled, cross-over study.

We investigated the effect of nicotine on three behavioral markers of risk for schizophrenia: sustained attention (using the Continuous Performance Task (CPT)), antisaccade performance, and smooth pursuit. Smooth pursuit was investigated in two conditions, one in which attention was enhanced (monitoring target changes) and one in which attention was not enhanced (no monitoring). Patients with schizophrenia (n = 15) and controls (n = 14) were given a 14-mg nicotine patch in a double-blind, placebo-controlled, crossover design and plasma nicotine concentrations were monitored. Nicotine concentrations were similar in both groups. A Group x Drug interaction (p <.02) on CPT hits indicated that nicotine improved sustained attention in patients but not in controls. Nicotine significantly decreased antisaccade errors (p <.01) in both groups. A Drug x Monitoring condition interaction (p <.01) on pursuit gain indicated that nicotine significantly increased pursuit gain in the no-monitoring condition in patients and controls equally, but did not improve pursuit in the monitoring condition. Thus, improvement in pursuit may have been mediated via an effect on attention rather than by an effect on oculomotor function per se. In patients, the magnitude of improvement in attention on nicotine was correlated with the improvement on eye movement tasks. Thus, nicotine improves performance on both attention and oculomotor markers of risk for schizophrenia, possibly via common mechanisms.