|Year : 2014 | Volume
| Issue : 3 | Page : 127-132
Study of olfactory identification and EEG in a sample of schizophrenic patients and their first-degree relatives as an endophenotype for schizophrenia
Hoda M Salama, Soliman A Tahon, Tarek K Molokhia, Nada A Mohamed
Neurology and Psychiatry Department, Faculty of Medicine, University of Alexandria, Egypt
|Date of Submission||01-Apr-2012|
|Date of Acceptance||09-Nov-2014|
|Date of Web Publication||11-Nov-2014|
Nada A Mohamed
Consultant of Neurology and Psychiatry, Lecturer at University of Alexandria
Source of Support: None, Conflict of Interest: None
Investigations of the genetic basis for mental disorders have recently focused on Endophenotypes as alternative phenotypes reflecting internal phenomena of organisms that define elements of mental disorders proximal to effects of genes.
Olfactory deficits and abnormal resting state electroencephalogram (EEG) are among endophenotypes that have been reported in patients with schizophrenia. This study assessed olfactory function and resting state EEG abnormalities in patients (first episode and chronic schizophrenic patients) and again in the healthy first degree family members of schizophrenic patients to determine genetic liability for the disorder.
The University Of Pennsylvania Smell Identification Test (UPSIT) was administered birhinally to three groups of subjects aged less than 65 years: 30 schizophrenic patients, 30 healthy first degree family members and 30 age- and sex-matched healthy volunteers. Resting EEG data were also collected from the study groups.
A high percentage of schizophrenic patients (both first episodes and chronic patients) were microsmic compared with control subject (P = 0,000*). However there was no significant statistical difference between first episode patients and family group (P = 0.915). The family group showed significantly statistical difference in UPSIT score compared to control subjects (P = 0,001*).These group differences could not be accounted for by age, sex, medication exposure, education or smoking habit.
Schizophrenic patients had no significantly statistical difference (on the augmented low frequency-delta component than did normal control subjects P = 0.167), and there was no significant difference in scores on the delta component between first episode and chronic schizophrenic patients (P = 713). In the family group no significant difference on the augmented low frequency-delta component than did normal control subjects (P = 176).
Impairment in olfactory identification ability was present from the onset of psychotic illness which suggests central causes. Olfactory identification deficit aggregates in healthy first-degree family members which may serve as a strong endophenotypic vulnerability marker.
The findings of Resting state EEG collected from the study groups suggest that there is EEG abnormalities in schizophrenia patients and their first degree healthy family members, but because small sample size the data wasn't' conclusive and needs to be repeated on larger sample size.
Keywords: EEG, first degree relatives UPSIT, first degree psychosis, schizophrenia
|How to cite this article:|
Salama HM, Tahon SA, Molokhia TK, Mohamed NA. Study of olfactory identification and EEG in a sample of schizophrenic patients and their first-degree relatives as an endophenotype for schizophrenia. Egypt J Psychiatr 2014;35:127-32
|How to cite this URL:|
Salama HM, Tahon SA, Molokhia TK, Mohamed NA. Study of olfactory identification and EEG in a sample of schizophrenic patients and their first-degree relatives as an endophenotype for schizophrenia. Egypt J Psychiatr [serial online] 2014 [cited 2021 Oct 23];35:127-32. Available from: http://new.ejpsy.eg.net/text.asp?2014/35/3/127/144327
| Introduction|| |
The complexity and heterogeneity of schizophrenia symptomatology have made it difficult to determine the pathophysiology and etiology of the disorder. Family studies offer evidence for a significant genetic contribution toward the disorder. Efforts to determine the underlying susceptibility genes schizophrenia research have turned to the endophenotype strategy (Turetsky et al., 2007a). Endophenotypes are characteristics that reflect the actions of genes predisposing the individual to a disorder, even in the absence of a diagnosable pathology. As relatively simple, well-defined, and quantifiable biobehavioral characteristics, endophenotypes are presumably determined by fewer genes than the more complex phenotype of schizophrenia. Ideally, these markers may serve as dissected components of the complex schizophrenia phenotype, thereby reducing the complexity of genetic analyses (Roalf et al., 2006).
Neuropsychological and neuroimaging studies offer strong evidence that schizophrenic patients have selective impairments in the functional domains of memory, attention, executive planning, and affect regulation (Turetsky et al., 2007b). Neuroanatomical and physiological abnormalities in the temprolimbic and frontal lobes regions that underlie these behavioral domains have also been reported (Turetsky et al., 1995). Among the sensory modalities, olfaction is most closely associated with these neuroanatomical regions and most strongly related to the affective and mnemonic functions that they subserve (Schneider et al., 2007).
Therefore, olfactory probes may be ideal tools through which we can assess the structural and functional integrity of the neural substrates underlying disease-related cognitive and emotional disturbances; perhaps more importantly, to the extent that early sensory afferents are disrupted in schizophrenia, the olfactory system - owing to its strategic anatomic location - may be especially vulnerable to this early disruption (Corcoran et al., 2005). Olfactory dysfunction may therefore be a sensitive indicator of schizophrenia pathology and may even serve as an 'early warning' sign of disease vulnerability or onset (Seckinger et al., 2004; Pause et al., 2008).
Efforts to characterize genetic vulnerability to schizophrenia are increasingly being focused on the identification of endophenotypes-neurobiological abnormalities that are evident in individuals at risk (Ugur et al., 2005).
Behavioral studies have reported olfactory impairments in odor detection and identification in unaffected first-degree relatives of schizophrenic patients; similarly, family and twin studies document odor identification deficits in healthy monozygotic twins discordant for schizophrenia and in first-degree relatives of patients with schizophrenia, suggesting that abnormalities in this simple sensory system may serve as a candidate endophenotype (Lombion-Pouthier et al., 2006). Overall, these previous reports suggest that the study of olfaction may advance our understanding of the neurodevelopmental origins of schizophrenia, the factors contributing toward genetic vulnerability, and the pathophysiology of disease progression (Mishkin et al., 2004).
Deficits in odor identification have been described in young patients with schizophrenia; use of neuroleptics; smoking; cognitive deficits; and severity of illness all appear to be unrelated to this abnormality (Turetsky and Moberg, 2009). Olfactory processing is mediated by limbic neuroanatomical structures that have been implicated in the pathophysiology of schizophrenia, particularly the prefrontal cortex, ventromedial temporal lobe, and diencephalon. Olfactory deficits in patients with schizophrenia may reflect disturbances of cortical or subcortical brain regions untapped by traditional neuropsychological measures (Hudry et al., 2002).
Another candidate endophenotype is the resting electroencephalogram (EEG) abnormalities seen in schizophrenic patients. Generally, the electrical activity of the brain of an individual at rest is generally stable and heritable; researchers have examined the frequency composition of the resting state EEG and identified augmented low-frequency activity in individuals with schizophrenia (Zietsch et al., 2007). Studies have reported that the frequency characteristics of the EEG of schizophrenic patients have more deltas (1-3 Hz) and theta (3.125-8 Hz) activity and less alpha (8.125-13 Hz) activity than normal comparison individuals. Schizophrenic patients had significantly higher scores on the augmented low frequency-diminished alpha component than did normal comparison individuals. There were no significant differences in the EEG frequency composition of first-episode and chronic patients. Because first-episode and chronic patients were characterized by different disorder durations and treatment histories, the similarity of their EEGs suggests that EEG abnormalities are stable characteristics of schizophrenia and are not treatment-related epiphenomena. The findings of this investigation suggest that EEG abnormalities in schizophrenia reflect aspects of brain dysfunction (Nuechterlien and Dawson, 1984). Several investigations have also shown resting state EEG abnormalities in unaffected relatives of individuals with schizophrenia. Nonetheless, to determine whether the frequency composition of resting EEG may operate as an endophenotype for schizophrenia, the current study examined the resting state brain electrical activity of schizophrenia patients, first-degree relatives of schizophrenic patients (Chen et al., 1998; Brewer et al., 2001).
| Objectives|| |
This work aims to study:
(a) The relationship between deficits in olfactory identification and duration of illness in young and elderly patients with schizophrenia.
(b) The olfactory function in healthy first-degree family members of schizophrenic patients to assess the genetic vulnerabilities for the disorder.
(c) Determine whether abnormal frequency composition of the resting state EEG in schizophrenia may operate as an endophenotype for the disease.
| Materials and methods|| |
The patient group included 30 schizophrenic patients according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) criteria, recruited from the outpatient clinic at El-Hadara University Hospital. Accordingly, the patients were divided as follows: subgroup A included 15 patients suffering from the first episode of schizophrenia and subgroup B included 15 patients with chronic schizophrenia. Family members were 30 first-degree family members who were chosen according to the following inclusion criteria:
(a) The relative must be the father, mother, offspring, or full sibling of an individual with a sole diagnosis of schizophrenia.
(b) Be currently and historically free from any axis I or II psychiatric disorder.
Control participants included 30 age-matched and sex-matched individuals who were free from any axis I or axis II disorder and had a negative family history of psychiatric illness.
The exclusion criteria were as follows:
(a) History of neurological disorder, including (head trauma with loss of consciousness)
(b) History of substance abuse or dependence
(c) Medical condition that might alter cerebral function
(d) Recent respiratory infection or any other condition that could affect olfactory performance.
Olfactory assessment procedures
Olfactory assessments were performed using the University of Pennsylvania Smell Identification Test (UPSIT).
Clinical ratings were performed on the basis of symptom severity using the Positive and Negative Syndrome Scale and The Wechsler Adult Intelligence Scale intelligence quotient test (Axelrod and Ryan, 2000).
Participants were tested in a temperature-controlled, light-attenuated and sound-attenuated room. Participants were instructed to keep their eyes closed and to minimize all hand and other body movements for the duration of the resting EEG recording; EEG was recorded from 16 scalp sites according to the international 10/20 system.
| Results|| |
No significant differences were present between the groups on primary matching variables, including age (P = 0.174), sex (P = 0.392), and handedness (P = 0.872). Compared with the family and controls groups, schizophrenic patients smoke significantly (P = 0.035) more cigarettes per day. A high percentage of schizophrenic patients (both first episodes and chronic patients) were microsmic, compared with control participants; the patients showed significant statistical differences (P = 0.000), mean = 21.03, SD = 4.605, in olfactory identification ability compared with the family group, mean 24.20 and (SD = 2.917), and control participants, mean 34.13 and (SD = 1.479), as shown in [Table 1].
There was no significant statistical difference (P = 0.687) in the UPSIT score between patients who were taking medications, mean = 20.73, SD = 4.723, and patients who were not taking medications, mean = 22.86, SD = 3.671, which suggests minimal medication effect.
In the patient group, there was no significant statistical difference (P = 0.237) in the UPSIT score between men, mean = 20.42 and SD = 3.920, and women, mean = 22.09 and SD = 5.647. There was no statistically significant difference (P = 0.457) in the patient group between smokers and nonsmokers.
Among the first-degree family members, there was a significant statistical difference (P = 0.000) in the total UPSIT score, mean 24.20 and (SD = 2.917), compared with the control participants, mean 34.13 and (SD = 1.479). These results could not be explained by the influence of sex, smoking history, or level of education. A nonsignificant correlation was observed between scores on the UPSIT and duration of illness (P = 0.885).
Analysis of the EEG activity in the slow-frequency delta band (1-7 Hz) showed no significant difference between schizophrenic patients and controls (P = 0.176). Slow EEG activity was not related to the effect of medication (P = 0.927). In the patient group, there was no significant statistical difference (P = 0.713) between first-episode schizophrenia and chronic patients. Analysis of the EEG activity in the slow-frequency delta band (1-7 Hz) showed no significant difference between the family group and the controls (P = 0.165).
| Discussion|| |
This study examined two candidate endophenotypes; the first one is olfactory identification ability, as measured by the UPSIT, and the second is slow wave delta components of the resting EEG as both are considered functional abnormalities observed in schizophrenic patients.
No significant differences were present between the three groups of participants, chronic and first-episode schizophrenic patients, their healthy first-degree family members, and control participants on primary matching variables that could be related to neuropsychological findings, including, age, sex, and handedness. Compared with the family and control groups, schizophrenic patients smoked significantly more cigarettes per day.
The first aim of this study was to assess olfactory identification across the three groups of participants. It was found that a high percentage of schizophrenic patients (first episodes and chronic patients) were microsmic, with significant statistical differences (P = 0.000), compared with family and control participants; this was consistent with previously reported studies on patients with schizophrenia that reported significant olfactory deficits in schizophrenic patients (Brewer et al., 2005a).
The crude mean for the UPSIT score in first-episode patients was 23. 53 (SD = 4.015), with significantly impaired olfactory identification ability (P = 0.000) compared with the control group, mean 34.13(SD = 1.479), but there was no significant statistical difference (P = 0.915) between first-episode patients and the family group. In general, first-episode schizophrenic patients performed better than chronic patients in UPSIT; this was consistent with other studies that showed significant deficits in olfactory identification ability in first-episode psychotic patients. These results could not be explained by the influence of sex, smoking history, or the effects of medication. Thus, impairment in olfactory identification ability was apparent from the onset of psychotic illness and remains stable over the initial course of psychosis. The deficit could not be explained by peripheral factors that might contribute toward olfactory identification ability, suggesting that it reflects central mechanisms (Brewer, 2001).
In the patient group, there was no statistically significant difference (P = 0.457) in the level of education and the total UPSIT score. Education may not have contributed toward the olfactory identification deficits observed; this was consistent with a previous study. In the patient groups, current smoking status did not appear to affect olfactory identification ability despite the difference in smoking rates between the study groups. This was consistent with previous studies of schizophrenia; smoking habits have not been shown to alter olfactory function (Nuechterlien and Dawson, 1984; Wu et al., 1993; Chen et al., 1998; Kopala et al., 1998; Brewer et al., 2001).
No relationship was found between olfactory identification ability and medication intake. There was no significant statistical difference in the UPSIT score between medicated and nonmedicated patients (P = 0.687). Olfactory deficits have been reported for patients with schizophrenia who are experiencing a first psychotic episode, neuroleptic-naive, and for chronic patients. This was consistent with previous studies that found that there was no effect of medication history on the total UPSIT score, and that olfactory deficit is an inherited and functional abnormality that was observed in schizophrenic patients.
In the present study, sex was not associated with UPSIT scores in the overall sample or in the three groups, which is consistent with several studies that have reported that sex had no significant effect on the total UPSIT score (Economou, 2003; Szeszko, 2004).
However, this was different from another study that showed a significant main effect for sex (i.e. women outperforming men), and from the existing, multiple literature on olfactory sex differences in the general population, which shows that women have consistently been reported to outperform men on the UPSIT across all ages (Compton, 2006; Good et al., 2007).
This could be explained either by:
(a) Previous studies had shown that perimenopausal women with schizophrenia disorder perform poorly on olfactory identification to a level that is comparable with similarly aged men (Doty et al., 1984). Menstrual history was not assessed in that study.
(b) This study does not include sufficient number of female participants to clearly test possible sex differences.
Another finding in our study was that there was no significant correlation, P = 0.885, between the total UPSIT scores and the duration of illness; this was different from another study that showed that olfactory deficit was greater in patients with a long duration of illness. Although longitudinal assessment of individual patients is the ideal method to demonstrate decrease over a lifespan, this is rarely possible for human studies (Kopala et al., 1995a).
First-degree family members showed a significant statistical difference (P = 0.000) in UPSIT compared with the control participants. This was consistent with other studies that found apparently greater and significant variability in UPSIT scores in relatives compared with patients and controls (Compton, 2006). In the family group, current smoking status, sex difference, and level of education had no observed effect on the total UPSIT score. This was consistent with previous studies of schizophrenia; smoking habits have not been shown to alter olfactory function (Coleman et al., 2005).
The findings from the current study show that olfactory deficits may be enduring and are not affected by exposure to antipsychotic medications (Kopala et al., 1992; Brewer et al., 2003). Moreover, an olfactory deficit occurs in healthy first-degree family members of schizophrenia patients in an attenuated form (Kopala et al., 2001). Thus, impaired olfactory functions may be one of the growing lists of endophenotypes in schizophrenia disorders.
The second aim of the study was to measure the slow wave delta components of EEG in the three groups under resting conditions and with closed eyes. As a measure for the activity in the slow-frequency band, the average log power from 1 to 7 Hz was determined. EEG activity in the resting state defines a baseline for brain activity, which allows the study of different brain regions governed by the same 'dynamic' process. Further, resting EEG has been shown to be a heritable trait across the entire frequency spectrum. Previous studies that have examined differences in resting EEG power between healthy comparison participants and chronic medicated schizophrenia patients have yielded intriguing results (Elbert et al., 1992).
On comparing the frequency of slow wave delta components among the study groups, we found increased delta wave in the patient group compared with the control group, but still, this increase was not statistically significant (P = 0.176). In previous studies, delta wave had been reported for patients with schizophrenia experiencing a first psychotic episode and, again in the current study, it was not statistically significant (P = 0.713; Sponheim et al., 1997; Winterer et al., 2000; Venables, 2009).
There was no significant statistical difference in the frequency of delta wave between medicated and nonmedicated patients (P = 0.927). This was consistent with previous studies that found that there was no effect of medication on the delta wave frequency.
The topographical distribution of EEG deviations showed that slow wave abnormality (mainly delta increase) was more or less localized to the frontal lobe, but it was not significantly different between the study groups [Figure 1]. Frontal localization of EEG abnormalities was confirmed in a number of studies and only a small number of studies found spectral EEG abnormalities to be localized to the more posterior regions of the brain distribution of EEG; others suggested that the topographic deviations represent different biological subtypes of the disorder (Clementz et al., 1994; John et al., 1994; Mientus et al., 2002).
|Figure 1: Topographic distribution of EEG deviations. EEG, electroencephalogram.|
Click here to view
In the family group, analysis of the EEG activity in the slow-frequency delta band showed no significant difference from the control group (P = 0.165), which was different from other studies that had indicated that resting state EEG frequency abnormalities are evident in schizophrenic patients and their biological relatives and that low-frequency resting state EEG abnormalities may serve as an indicator of genetic liability specific to schizophrenia (i.e. endophenotype) (Zimmermann, 2010).
| Conclusion|| |
Genetic contribution toward the etiology of schizophrenia has been reported in epidemiological studies. The precise nature and mode of inheritance of this genetic vulnerability are not clear, and individuals who are genotypically at risk for schizophrenia cannot be identified easily. One approach to this problem is to explore biological and behavioral markers that might indicate an increased genetic predisposition to the disorder, even in the absence of an overt phenotype. The identification of such 'latent traits' or 'endophenotypic' markers can aid our understanding of the disorder by clarifying the mechanisms of gene action as distinct from the clinical phenotype. This, in turn, can facilitate linkage analyses designed to identify the associated genes loci, as well as the possible development of prevention and rehabilitation strategies .
Further work should examine larger numbers of patients to confirm these findings and should assess patients over a longer follow-up period. Studies should also examine high-risk individuals before the onset of psychosis.
| Acknowledgements|| |
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