Article: I. GANEV, K. STOYNOV, K. KOSTADINOV, T. DONCHEV (BULGARIA)

Custom Equipment for Registration of Oculomotor Biomarkers in Schizophrenic Patients

Soft neurological signs can be found in many patients with schizophrenia. Dysfunction of smoothpursuit
eye movements is a well-studied phenomenon in such patients. These dysfunctions are very
discrete and can be detected using purposeful assessment. More accurate measurement is possible
with the use of specialized equipment.

Introduction

The theme of schizophrenia and the schizophreniа spectrum disorders in general is vast and thoroughly investigated by many authors. However, there are major uncertainties in etiological and pathophysiological aspect which often leads to difficulties and limitations in the early diagnosis and treatment of these disorders. This puts researchers in the obligation to continue the pursuit of new approaches that would enrich the current theoretical knowledge and above all – to serve the practical needs of the modern psychiatric research.

An interesting study approach towards the endophenotypes provides limited behavioral or biological markers as a gene expression of certain disorder rather than the clinical phenotype (1). This could be useful in the study of schizophrenia, having in mind the genetic, clinical and neurobiological heterogeneity of the disorders. Endophenotypes are measurable components, invisible to the bare eye, located between the visible manifestations of the disorder and the genotype and appear to be an important concept in the study of the complex neuropsychiatric disorders (1).An endophenotype may have neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive or neuropsychological nature (2). The use of measurable parameters of neuropsychiatric functioning may be more useful in research than studying behavioral phenomena. The classification of psychiatric disorders based on manifest phenotypes (syndromal behavior) may not be optimal for the precise genetic study of these diseases which have complex genetic foundations (1). There is a dynamic interaction between genetic, environmental and epigenetic factors, together forming a cumulative propensity for the development of schizophrenia. Many of these endophenotypes are addressed in detailed reviews, noting the common strategies for schizophrenic discriminators, sensory and motor gating, oculomotor function, working memory and abnormalities of glial cells (1).Dysfunction of the smooth pursuit of objects has long been connected with schizophrenia (3). This type of dysfunction is described for the first time in 1908 by Diefendorf and Dodge (4). Their work was rediscovered in 1970s by Holzman and colleagues (5). Generally, eye movements can be classified into two types – first that are saccadic, brief and extremely fast and the others are smooth-pursuit movements which are slow and controlled. Smooth-pursuit eye movements occur only when the subject tracks an object, moving with constant speed (6). Their initiation and sustainability incorporates the integration of the functions of frontal oculomotor fields of the prefrontal cortex, visual and vestibular neuronal circuits, the thalamus and the cerebellum and also the muscles and neuronal circuits directly involved in eye movements (1).

Soft neurological signs can be established in a significant percentage of patients with schizophrenia and their mentally healthy relatives (7).They include disorders of stereognosis, graphesthesia and coordination of movements and balance, proprioception and in the carrying out a series of successive movements. These neurological signs have no localizing value and rather reflect impaired connections between individual brain structures than specific dysfunctions within a given structure. From a functional point of view it can be said that they are the manifestations of dysfunction in motor and sensory integration, in each of them individually and also in the coordination between them. Soft neurological dysfunctions are very discrete and can be detected mainly with the aid of a standardized and purposeful assessment. More accurate and objective measurement is possible with the aid of specialized equipment that is able to register motor function and/or coordination. Such equipment is most commonly used for qualitative and quantitative measurement of dysfunctions in the eye movements which represent the best studied phenomenon in schizophrenia. There is an established specific pathology in saccadic and smooth-pursuit eye movements, which is considered a direct manifestation of the basic schizophrenic process in the brain. It occurs both in patients and in their clinically healthy relatives and does not depend on the presence or absence of psychotic production. On clinical level there have been described other disorders of the eye movements as well, for example - avoiding eye contact or gazing stare for a prolonged time period. Slowed or accelerated rates of blinking, and series of fast blinking have also been observed (8). Unaffected relatives i. e. obligate carriers also exhibit other neurophysiological abnormalities apart from abnormalities in smooth-pursuit of moving objects - impaired prepulse inhibition conditioning of blinking, dysfunctions in working memory and etc. It is clear that individuals can inherit the characteristics described, without being psychotic, which is probably due to the fact that schizophrenia manifests itself only when a critical threshold of inherited endophenotype abnormalities is passed (9).

Genetically transmitted disease process in the brain (shizotaxy) leads to basic deficits in brain and mental function and psychotic production (schizophrenia) is a secondary manifestation of decompensation of schizotaxic process due to abnormal adaptation to endogenous and/or exogenous stress (10). The concept of schizotaxy reflects the hypothesis of Paul Meehl, that schizophrenic process is a consequence of neurodegenerative deficit (caused by a genetic defect in the nerve cells), which is manifested by neurological disorganization (schizotaxy), personality disorganization (schizotypy) and psychotic disorganization (schizophrenia). An objective manifestation of schizotaxy, personally described by Paul Meehl (1990) is the impaired coordination of eye movements, registered by Harvard psychologist Philip Holzman (1973) in schizophrenic patients and their relatives (11).

Deficits in smooth-pursuit eye movement (SPEM) have been studied as a endophenotype in the search for genes of schizophrenia. Patients show an increased incidence of saccadic movements during pursuit as well as other eye movement errors as compared to controls. Siblings show intermediate results, i.e. - between patients and controls on most measurements (12). Hurrying forward during the smooth-pursuit movements at a constant object speed significantly correlated between patients and siblings, emphasizing the need to take into account the correlations within the family in the statistical analysis of the differences between groups. It has been found that subtle deficits in smooth-pursuit movements and antisaccades are observed in clinically unaffected siblings of schizophrenic patients; these deficits can be useful markers of genetic predisposition to schizophrenia (12). The observation of an endophenotype not only among patients but also in their unaffected relatives is an important criterion for its validity. Several studies have demonstrated impairments in smooth-pursuit eye movements and antisaccades in schizophrenic patients and their relatives confirm this hypothesis. Disturbed slow tracking eye movements observed in approximately 50-80% of patients with schizophrenia and in 30-40% of their first degree relatives, as compared to about 8% of the healthy individuals. Disturbances of the smooth-pursuit eye movements showed concordance in monozygotic twins discordant for schizophrenia and are associated with a dysfunction of the frontal cortex in patients and their relatives. There is data for deficits in the locus of chromosome 6p (12).

Schizophrenic patients show increased errors in antisaccades probably associated with prefrontal dysfunction. Several studies have shown this deficit in relatives of schizophrenic patients, especially from families with multiple cases of schizophrenia. There is evidence indicating that there is no significant mental impairments among these relatives i.e. there is no disorder or there is a family history of schizophrenia (12).

Materials and Methods

In the present study the studied individuals were divided into two groups. The first consists of 64 patients diagnosed with schizophrenia, men and women between 18 and 70 years of age. The second group is a control group - consisting of 60 healthy subjects, men and women within the same age range. All participants signed informed consent prior their volunteer participation in the study. Patient rights, safety, privacy and dignity have been respected by throughout the study in accordance with the WHO guidelines and the Declaration of Helsinki. No animal experiment has been performed for this study.

The research in the specific eye movement biomarkers for schizophrenia and their recognition requires a precise investigation, which for our team is facilitated by a specially developed for the purpose device, equipped with modules for the registration of horizontal and vertical eye movements based on the dipole nature of the eyeball and the ability for electrooculographic recording these movements. The generated raw data are graphic in nature. For the purpose of the study custom software was also developed. The possibility of converting graphic information into numerical data allows its statistical processing and drawing conclusions and their analysis. The patient is in a seated steady position, facing against horizontal light bar mounted on a tripod. On the light bar periodically passes a light signal with a constant speed from the one end to the other. The patient follows the stimulus only with his eyes without moving other parts of the body. The discharged electric signals led by the temporal electrodes reflect the horizontal movements of the eye bulbs. The information is saved on the memory hard disk and the developed software allows its precise graphical analysis.

Results

Fig. 1 shows the results graphically represented by percent proportions among the schizophrenic patients group.

Fig. 1: Distribution of the results among the patient group 1. Patients with registered abnormalities of eye movements are depicted with orange color. 2. Patients which don’t show abnormalities of eye movements are depicted with green color.

It is evident that in the group of schizophrenic patients 78.1% of all individuals showed disturbances of smooth-pursuit eye movements. In 21.9% of the group no eye movement dysfunction was found.

Percent proportions are in the control group are represented in Fig. 2.

Fig. 2: Distribution of the results the control group 1. In blue color is the part of the studied individuals with registered eye movement dysfunctions. 2. In red color is the part of the studied individuals with registered eye movement dysfunctions.

81.7% of the studied individuals in this group have no evidence of impaired smooth-pursuit eye movements. Such have been registered in 18.3% of the controls.

Discussion

At this stage, considering the initial data, there is a significant difference in the proportions between the two studied groups. These results are similar to those found in previous studies. This suggests that the used equipment is reliable and that patients and studied individuals are well-chosen for the purpose of the current study. The relationship between the registered dysfunctions in smooth-pursuit eye movements and schizophrenia is evident. There is also a clear low level of the oculomotor dysfunction in studied healthy controls. The relatively small percentage of studied individuals in the control group with dysfunction in the smooth-pursuit eye movements can be explained by the presence of family history and genetic inheritance.

Conclusion

The present study, carried out with the specifically designed equipment, marks the beginning of a series of studies planned by our team. The encouraging initial results give us a good reason to continue further investigation. One of the goals is to expand the number of the studied individuals in the described in groups which will result in better reliability of our results.

New groups of individuals are being added to study, not only of schizophrenic patients, but also patients with other disorders of the schizophrenic spectrum and also other mental disorders with the purpose of seeking general and determining the nosologically specific eye movement biomarkers, including not only smooth-pursuit eye movements but also blinking patterns.

References: Ref@mci-forum.com

Authors:

Iordan Ganev MD, Psychiatrist.

CV:

Studies: 2002 Graduation in Human Medicine at Medical University, Sofia, Bulgaria;

2010 Board certified in Psychiatry

Occupation: Assistant professor since 2016,

2013-Present PhD doctorate in Clinic of psychiatry

Adress of the author:

Military Medical Academy

Clinic of psychiatry

3 Sveti Georgi Sofiiski Str.