Matthew T. Avila

Effects of Nicotine on Leading Saccades during Smooth Pursuit Eye Movements in Smokers and Nonsmokers with Schizophrenia

Several studies have shown that schizophrenic patients and their biological relatives generate a greater number of leading saccades during smooth pursuit eye movement (SPEM) tasks. This abnormality may reflect a failure of cortical and/or cerebellar areas to coordinate saccadic and pursuit eye movements during visual tracking. The pharmacology of this phenomenon is not known. Here, we sought to replicate and extend the findings of Olincy et al (1998), who found that nicotine transiently reduced the number of leading saccades during SPEMs. A total of 27 subjects with schizophrenia (17 males; 14 smokers), and 25 healthy comparison subjects (nine males; 14 smokers) completed an eye-tracking task after receiving a 1.0 mg nasal spray of nicotine and during drug-free conditions. Results confirm that nicotine reduces the number of leading saccadic eye movements during visual tracking in schizophrenic patients. Baseline impairments and the beneficial effects of nicotine were not restricted to patient smokers, as nonsmoker patients exhibited the greatest number of leading saccades in the no drug condition and exhibited the most pronounced improvements after nicotine administration. Improvement in patient nonsmokers was not a function of previous smoking history. No effect of nicotine was observed in control nonsmokers. In contrast to the previous study, nicotine appeared to improve performance in control smokers. Overall, the study results support a functional role of nACh receptors in improving eye-tracking performance, and are consistent with the hypothesis, articulated by several investigators, that nACh receptor system abnormalities are responsible for a number of schizophrenia-related neurophysiological deficits.

Specific motion processing pathway deficit during eye tracking in schizophrenia: A performance-matched functional magnetic resonance imaging study

BACKGROUND The neural mechanisms underlying smooth pursuit eye movement (SPEM) abnormalities in schizophrenia are not well understood. Previous evidence suggests that a deficit in the processing of internal representations of object motion (extraretinal motion) contributes to SPEM deficits in patients. Functional magnetic resonance imaging (fMRI) activation was compared between patients and control subjects to determine whether schizophrenia patients exhibit abnormal cerebral activation in regions associated with extraretinal motion processing during SPEM. METHODS Patients and control subjects were selected based on matched performance in the closed-loop gain. Despite similar performance on closed-loop pursuit gain, patients showed consistent deficits in extraretinal motion based on predictive pursuit. In the magnet, subjects were tested using a traditional smooth-pursuit task that elicits closed-loop response. RESULTS Patients had reduced pursuit-related activation in several known extraretinal motion processing areas including frontal and supplemental eye fields, medial superior temporal cortex, and anterior cingulate. Patients also showed increased activation in medial occipitotemporal cortex. CONCLUSIONS These results provide functional anatomic evidence supporting reduced function in the extraretinal motion processing pathway in schizophrenia. Increased activation in medial occipitotemporal cortex suggests an increased dependence on immediate retinal motion information, which may be used to compensate for reduced extraretinal signaling during sustained visual tracking.

Components of the smooth pursuit function in deficit and nondeficit schizophrenia

The diagnosis of schizophrenia likely encompasses a heterogeneous group of disorders, complicating the search for its causes. Studies of deficit schizophrenia represent an attempt to reduce this heterogeneity by identifying biologically distinct subgroups. Supplementing clinical phenotypes with biological markers of risk (e.g., eye-tracking and sensory-gating deficits) have also been used to reduce disease heterogeneity. In this study, we examined smooth pursuit eye movements in healthy controls (n = 37), and deficit (n = 18) and nondeficit (n = 32) patients with schizophrenia to determine what aspects of abnormal smooth pursuit are associated with the two patient groups, and which, if any, specifically mark the deficit phenotype. A small sample of relatives of deficit (n = 12) and nondeficit (n = 35) patients was also examined. Positive symptoms were equally present in deficit and nondeficit patients. Subtle, psychotic-like positive traits were also equally present in the relatives of both deficit and nondeficit probands, whereas negative symptoms were significantly more prevalent among the relatives of deficit probands. Deficits in predictive pursuit were present in both patient groups and both groups of relatives. Deficit patients showed significantly lower initiation acceleration. A similar pattern of results was seen in our pilot sample of relatives of deficit patients. These findings suggest that predictive smooth pursuit abnormality is associated with positive symptoms in schizophrenia, and that initiation abnormalities may be associated with the deficit syndrome.

Tardive dyskinesia in children treated with atypical antipsychotic medications

Recent years have witnessed increased antipsychotic treatment of children despite limited long‐term safety data in children. In this study, motor side effects associated with the use of antipsychotic drugs in children were examined in a sample of pediatric psychiatric patients. Child and adolescent psychiatric patients receiving antipsychotics (most were on atypicals) for 6 months or longer (n = 118) were compared with antipsychotic‐naïve patients (n = 80) with similar age, sex ratio, and diagnoses. Only 19% of patients on antipsychotics had ever experienced psychotic symptoms. Eleven children (9%) on antipsychotics exhibited dyskinesia, when compared with 0 in the naïve group (P = 0.003, Fishers exact test). Nine of 62 African–American children (15%) on antipsychotics exhibited dyskinesia, when compared with only 4% (2 of 52) of European–American children (P = 0.003, Fishers exact test). Children treated with antipsychotic drugs might experience a significant risk of dyskinesia even when treated only with atypical antipsychotics. Ethnicity might also be a risk factor for dyskinesia in children. Side‐effect profile of the atypical antipsychotic drugs in children may be much different than that in adults.

Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia

A previous study has shown an association between the *2236T > C allele polymorphism of the dihydropyrimidinase‐related protein 2 (DRP‐2) gene and schizophrenia in a Japanese sample [Nakata et al. ( 2003 ); Biological Psychiatry 53:571–576]. DRP‐2 is an important molecule in guiding neuronal development and its gene is located in 8p21, a chromosomal region that was previously shown to have significant linkage to schizophrenia and to several deficit symptoms of schizophrenia. We compared the frequency of the DRP‐2 *2236T > C polymorphism between subjects with (n = 117) and without (n = 72) schizophrenia, and then further evaluated whether the association was specific for the deficit (n = 24) and nondeficit (n = 93) forms of schizophrenia. In both Caucasians and African‐Americans, the C allele occurred more frequently in schizophrenia cases than controls, with this difference achieving statistical significance in Caucasians (C allele frequency: 42.0% in cases vs. 25.0% in controls, P = 0.014) but not African Americans (52.6% in cases vs. 50.0% in controls, P = 0.93). In Caucasians, the frequency of the C allele was significantly higher in both the deficit (allele frequency 53.3%, P = 0.009) and nondeficit (39.2%, P =0.050) forms of schizophrenia compared to controls (allele frequency 25.0%). We conclude that the DRP‐2 *2236 C allele may mark another polymorphism in DRP‐2, or in a nearby gene, that may influence susceptibility to schizophrenia.

Ethnicity and the course of tardive dyskinesia in outpatients presenting to the motor disorders clinic at the Maryland psychiatric research center.

Background: Although newly emergent tardive dyskinesia (TD) is less of a concern, about one-fourth to one-third of patients on or previously on chronic first-generation antipsychotic agents have TD. The long-term course and outcome, as well as their predictors, are unknown. Earlier studies identify ethnicity as one of the risk factors for the development of TD, and case reports have noted a preponderance of African-American males in cohorts of patients with tardive dystonia. The current study examines the anatomic distribution and course of TD in a cohort of schizophrenia patients of European and African descent with TD who were referred to the Motor Disorders Clinic (MDC). Methods: We evaluated data collected on 1149 TD patients who were given a focused neurologic examination for movement disorders. Movements were evaluated with the MPRC Scale for Involuntary Movements (IMS). All patients met RDC-TD criteria for diagnosis of persistent TD. One to 10-year follow-up data on 528 patients were evaluated to examine the course of TD following recommendations made to referring primary clinicians. Suggested interventions to referring primary clinicians included dose reduction of first-generation antipsychotic medication, or switching to a second-generation antipsychotic. Results: Initial evaluation included 701 European American (EA) patients and 448 African-American (AA) patients. AA patients had a significantly higher proportion of males [χ2(1) = 7.50, P < 0.05]. EA subjects had a higher mean age than AA patients 42.8 ± 11.2 and 39.8 ± 10.4, respectively [F(1,1147) = 22.27, P < 0.05]. Mean neuroleptic exposure (chlorpromazine equivalents) was similar in both groups after controlling for differences in age. Follow-up data analyzed in 528 patients (329 EA and 199AA) showed a significant ethnicity by TD interaction [F(1,504) = 4.26, P < 0.05]. Examination of body distribution of dyskinetic movements showed an effect of ethnicity. Subsequent analyses suggest EA patients experienced more improvement in TD over the course of follow up [F(1,319) = 22.39, P < 0.05] compared with AAs [F(1,189) = 1.58, P > 0.05]. These findings were unchanged when age, change in antipsychotic drug dose, and duration of follow-up were covaried. Conclusion: Reports from earlier studies note ethnicity (African descent) as a risk factor in the development of TD. Our study findings suggest ethnicity might be an important factor in predicting a poor course of TD.

Response to unexpected target changes during sustained visual tracking in schizophrenic patients

Background: Evidence supports an association between liability to schizophrenia and smooth-pursuit eye movement (SPEM) abnormalities. Knowledge of the biological mechanisms of SPEM abnormalities may provide critical insights into the etiology of schizophrenia. SPEM is elicited by sensory motor information from the movement of the object’s image on the retina (retinal motion signal) and subsequent extraretinal motion signals. Previous studies suggest that a deficit in predictive responses to extraretinal motion signals may underlie the SPEM phenotype in schizophrenia. Data suggest that at-risk individuals for schizophrenia depend less on extraretinal and more on retinal motion signals to maintain pursuit than healthy individuals. Methods: We designed a pursuit task that employs unexpected changes in target direction during smooth pursuit. The unpredictable task is unique in that performance is expected to be better if the subject’s response is biased towards retinal motion. Results: The study included 23 schizophrenia patients and 22 normal controls. Results showed that schizophrenia patients showed significantly superior performance (i.e. higher smooth pursuit gain) for a brief period after an unexpected change in target direction compared with healthy subjects. Conclusion: Findings of superior performance by schizophrenic patients are interesting because they circumvent confounds of generalized deficits. These results provide further evidence of specific deficit in the predictive pursuit mechanism and over-reliance on retinal error signals to maintain pursuit in schizophrenia.

Deficits on the Continuous Performance Test within the schizophrenia spectrum and the mediating effects of family history of schizophrenia.

Individuals with schizophrenia spectrum personality disorders (SSPD) and schizophrenia show similar cognitive impairments. The authors examined the contributions of SSPD symptoms and familial risk for schizophrenia to impairments on the Continuous Performance Test--Identical Pairs Version. Participants included 103 schizophrenia patients, 66 first-degree relatives (29 SSPD), and 103 community controls (26 SSPD) screened for family history of psychosis. Patients and SSPD relatives performed significantly worse than non-SSPD relatives and SSPD and non-SSPD community controls. No differences in performance were observed among non-SSPD relatives and SSPD and non-SSPD community controls. Results suggest a continuum in which risk for schizophrenia-related cognitive impairments is highest among patients and SSPD relatives, intermediate among non-SSPD relatives, and lowest among SSPD and non-SSPD community controls. Results suggest that SSPD in the absence of a family history of psychosis may be a phenocopy.

Current progress in schizophrenia research. Eye movement abnormalities in schizophrenia: what is the nature of the deficit?

The presence of smooth pursuit eye movement (SPEM) abnormalities among patients with schizophrenia and their relatives has been consistently reported in the schizophrenia literature. Interest in these abnormalities is twofold. First, familial aggregation of SPEM deficits suggests that they may be useful in searching for genes related to schizophrenia by providing a neurophysiological marker of genetic vulnerability—one that can be used to identify the phenotype independent of the presence or absence of overt clinical signs and symptoms (Arolt et al., 1996). Second, localization and description of the smooth pursuit deficit in schizophrenia is likely to provide insight into the pathological changes in neuronal functioning that characterize individuals who carry the genetic liability for schizophrenia. However, to use the presence of SPEM abnormalities to search for genes and to study pathophysiology, we need to understand what is the specific nature of the deficit. SPEM is a complex behavioral response served by a widely distributed neuronal network including the occipital cortex, the medial and medial superior temporal and posterior parietal regions of the cortex, the frontal eye fields, the cerebellum, the basal ganglia, and the brain stem areas. This is shown in Figure 1. SPEMs are generated in response to the movement of a target image on the retina (i.e., retinal motion). This initial response, in combination with saccadic eye movements, allows us to capture the image of a moving object onto the fovea, where visual acuity is greatest. This phase of the response is often referred to as initiation and is primarily based on the processing of retinal motion by the medial temporal region of the cortex (Lisberger and Movshon, 1999). When the eyes have reached and are moving with the target, there is limited retinal motion; the brain uses internal representations of the motor command and previous retinal motion information (i.e., extraretinal signals) to help maintain pursuit (Barnes and Asselman, 1992). This component of the response is referred to as predictive pursuit, and is thought to involve neurons in medial superior temporal and posterior parietal regions of the cortex and in the cerebellum (Assad and Maunsell, 1995; Komatsu and Wurtz, 1989; Suh et al., 2000). Several studies of SPEM performance in schizophrenia have found that patients exhibit decreased eye acceleration during initiation (Clementz et al., 1995). Because the initiation of pursuit is based primarily on retinal motion signals, these findings suggest that SPEM abnormalities in schizophrenia reflect a deficit in retinal motion processing. This would appear consistent with psychophysical studies of motion perception, which report higher perceptual thresholds for velocity discrimination in patients with schizophrenia and their relatives (Chen et al., 1999). Alternatively, it has been shown that healthy subjects improve during initiation when targets are repeated—presumably by predicting target motion based on the motor and sensory memory of previous targets (Barnes et al., 2000). This raises the possibility that abnormal initiation in schizophrenia is related to a deficit in extraretinal signal processing. Additionally, recent studies by Turano et al. have shown that both retinal and extraretinal signals can play a role in the perception of motion (Turano and Massof, 2001), providing an alternative explanation for the findings of previous psychophysical studies of motion perception in schizophrenia. Target masking, a procedure in which the target is briefly extinguished or masked along its trajectory, has been used to study the extraretinal component of the SPEM response. During target masking, the 1 Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Box 21247, Baltimore, Maryland 21228. Send reprint requests to Dr. Thaker. Supported by NIH Grants MH49826 and MH40279. 0022-3018/02/1907–479 Vol. 190, No. 7 THE JOURNAL OF NERVOUS AND MENTAL DISEASE Printed in U.S.A. Copyright

A comparison of symptom provocation procedures in psychiatry and other areas of medicine : Implications for their ethical use in research

BACKGROUND Symptom provocation is used to study a wide variety of medical disorders. In contrast to other areas of medicine, the application of these procedures to the study of mental disease has generated significant scientific, political, and public debate. Purported differences include an overabundance of these procedures in psychiatry and a lack of diagnostic and therapeutic utility. Accurate appraisal of these research designs is needed to address scientific merit and ethical concerns. This article provides a general review of challenge studies in several areas of medical research, compares purposes and methods to those used in psychiatry, and ascertains whether fundamental differences exist. METHODS In total, 655 challenge studies were identified using MEDLINE and PsychInfo Boolean key word searches. Information was collected from each study including the year of publication, whether subjects were healthy or patient volunteers, the disease being studied, and the study purpose (e.g., to study pathophysiology, test treatment efficacy, or diagnosis of a disorder). RESULTS Differences in study design, purpose, and frequency of studies across time were similar for medical and psychiatric diseases. CONCLUSIONS Given extensive similarity in purpose and procedures, why are psychiatric challenge studies being subjected to public criticism and special review and approval procedures? Several relevant issues are addressed including risk, scientific merit, and clinical application.