Low olfactory bulb volume in first-degree relatives of patients with schizophrenia

OBJECTIVE: There is a substantial genetic contribution to schizophrenia but no way to readily identify individuals at risk. Biological abnormalities reflecting greater genetic vulnerability may be discovered by examining healthy family members of patients with schizophrenia. There is evidence that olfactory impairments are common in patients. The authors previously reported that patients have abnormal olfactory bulbs, assessed by magnetic resonance imaging (MRI). This study examined olfactory bulbs in patients' relatives to determine whether low bulb volume represents an endophenotypic marker of genetic vulnerability. METHOD: Olfactory psychophysical measures and MRI scans of olfactory bulbs were acquired from 19 healthy first-degree relatives, 20 healthy comparison subjects with similar age and gender distributions, and the 11 patient probands of these relatives. Olfactory bulb volumes were measured by using a reliable region-of-interest procedure. RESULTS: The patients had impaired ability to detect odors and had lower olfactory bulb volumes than the comparison subjects. Although the family members had normal olfactory ability, they exhibited low right bulb volume. The patients had smaller left, but not right, olfactory bulbs than their own healthy relatives. CONCLUSIONS: The findings in family members suggest that structural abnormalities of the olfactory system in schizophrenia may partly reflect preexisting genetic vulnerability to illness. Preliminary analyses suggest that right olfactory bulb volume may serve as an endophenotypic marker of genetic vulnerability, while left bulb volume may reflect overt disease among individuals who share genetic vulnerability. Bulb abnormalities in patients are consistent with reports of cellular abnormalities affecting peripheral olfactory receptor neurons.     

Physiologic impairment of olfactory stimulus processing in schizophrenia.

BACKGROUND: Behavioral studies of olfaction have demonstrated impairments in the ability to detect and identify odors in patients with schizophrenia. These deficits appear to be independent of either symptom severity or other cognitive impairment. Only limited efforts have been made to investigate the neurophysiologic substrate of these olfactory abnormalities. This article reports the first examination of olfactory electrophysiologic responses in patients with schizophrenia. METHODS: Olfactory event-related potential responses to three different concentrations of hydrogen sulfide were recorded in a sample of 21 patients and 20 healthy control subjects. Odors were presented via an olfactometer to ensure there was no associated trigeminal nerve stimulation. RESULTS: Patients exhibited abnormalities in the amplitudes of the N1 and P2 components of the olfactory evoked potential, and delayed latency of the P2. The N1 abnormality, which denotes primary olfactory cortex activity, was related to impaired odor detection threshold sensitivity; the P2 abnormality was related to impaired odor identification. CONCLUSIONS: These data indicate the presence of a primary physiologic impairment in the olfactory cortex underlying behavioral olfactory deficits seen in patients with schizophrenia. This is consistent with postmortem and in vitro studies suggesting abnormalities in olfactory receptor neurons. Understanding the nature of these physiologic olfactory impairments could offer clues to the basic neuropathology of this disorder.     

Associations between olfactory identification and verbal memory in patients with schizophrenia, first-degree relatives, and non-psychiatric controls

OBJECTIVE: Olfactory identification deficits and verbal memory impairments may represent trait markers for schizophrenia. The aims of this study were to: (1) assess olfactory identification in patients, first-degree relatives, and non-psychiatric controls, (2) determine differences in verbal memory functioning in these three groups, and (3) study correlations between olfactory identification and three specific verbal memory domains. METHOD: A total of 106 participants-41 patients with schizophrenia or related disorders, 27 relatives, and 38 controls-were assessed with the University of Pennsylvania Smell Identification Test (UPSIT) and the Wechsler Memory Scale-Third Edition. Linear mixed models, accounting for clustering within families and relevant covariates, were used to compare scores across groups and to examine associations between olfactory identification ability and the three verbal memory domains. RESULTS: A group effect was apparent for all four measures, and relatives scored midway between patients and controls on all three memory domains. UPSIT scores were significantly correlated with all three forms of verbal memory. Age, verbal working memory, and auditory recognition delayed memory were independently predictive of UPSIT scores. CONCLUSIONS: Impairments in olfactory identification and verbal memory appear to represent two correlated risk markers for schizophrenia, and frontal-temporal deficits likely account for both impairments.     

The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia

Specifying the complex genetic architecture of the "fuzzy" clinical phenotype of schizophrenia is an imposing problem. Utilizing metabolic, neurocognitive, and neurophysiological "intermediate" endophenotypic measures offers significant advantages from a statistical genetics standpoint. Endophenotypic measures are amenable to quantitative genetic analyses, conferring upon them a major methodological advantage compared with largely qualitative diagnoses using the Diagnostic and Statistical Manual of Mental Health, 4th Edition (DSM-IV). Endophenotypic deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients, and clinically unaffected relatives of schizophrenia patients. Neurophysiological measures, such as P50 event-related suppression and the prepulse inhibition (PPI) of the startle response, are endophenotypes that can be conceptualized as being impaired because of a single genetic abnormality in the functional cascade of DNA to RNA to protein. The "endophenotype approach" is also being used to understand other medical disorders, such as colon cancer, hemochromatosis, and hypertension, where there is interplay between genetically conferred vulnerability and nongenetic stressors. The power and utility of utilizing endophenotypes to understand the genetics of schizophrenia is discussed in detail in this article.     

Neurocognitive endophenotypes for bipolar disorder

Objectives:  Neurocognitive deficits have been proposed as vulnerability markers or endophenotypes for the development of bipolar I disorder (BD I). However, few research studies have examined whether neurocognitive deficits also exist in first-degree relatives of individuals with BD I.
Methods:  This prospective study examined neurocognitive function in individuals with BD I, their first-degree relatives and a normal control group using a comprehensive battery of neurocognitive tests.
Results:  Results indicated that individuals with bipolar disorder and their unaffected relatives demonstrated neuropsychological deficits in comparison to the normal control group in the domains of visuospatial/constructional abilities, executive function, visual learning and memory, and motor speed. In general, the unaffected relatives demonstrated an intermediate level of performance in comparison to the normal control and bipolar group. After adjustment for mood symptoms, significant differences were present for the visuospatial/constructional, executive function, and motor domains. Individuals with bipolar disorder also demonstrated a differential right versus left hemisphere deficit with respect to neurocognitive tasks.
Conclusions:  Results suggest that deficits on specific neuropsychological tests, most notably Digit Symbol, Block Design and Judgment of Line Orientation, may be indicative of cognitive endophenotypes for bipolar disorder. Replication studies are needed to further identify these deficits as endophenotypes for BD I.     

Are brain structural abnormalities useful as endophenotypes in schizophrenia?

Endophenotypes, which represent intermediate phenotypes on the causal pathway from the genotype to the phenotype, can help unravel the molecular etiopathology of complex psychiatric disorders such as schizophrenia. Several candidate endophenotypic markers have been proposed in schizophrenia, including neurocognitive and neurophysiological impairments. Over the past three decades, there has been an impressive body of literature in support of brain structural alterations in schizophrenia, but few studies have critically examined whether these abnormalities can be considered useful endophenotypic markers. We critically reviewed the extant literature on the neuroanatomy of schizophrenia in this paper to evaluate their candidacy as endophenotypes. Structural brain changes are robustly associated with schizophrenia, are state independent and may cut across the diagnostic boundaries of major psychotic illnesses. Brain morphometric measures are heritable, co-segregate with the broadly defined neurocognitive and behavioural phenotypes within the first degree relatives of schizophrenia patients and are present in unaffected family members more frequently than in the general population. Taken together, brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders.     

Dementia of frontal type and the focal lobar atrophies

Endophenotypes, which represent intermediate phenotypes on the causal pathway from the genotype to the phenotype, can help unravel the molecular etiopathology of complex psychiatric disorders such as schizophrenia. Several candidate endophenotypic markers have been proposed in schizophrenia, including neurocognitive and neurophysiological impairments. Over the past three decades, there has been an impressive body of literature in support of brain structural alterations in schizophrenia, but few studies have critically examined whether these abnormalities can be considered useful endophenotypic markers. We critically reviewed the extant literature on the neuroanatomy of schizophrenia in this paper to evaluate their candidacy as endophenotypes. Structural brain changes are robustly associated with schizophrenia, are state independent and may cut across the diagnostic boundaries of major psychotic illnesses. Brain morphometric measures are heritable, co-segregate with the broadly defined neurocognitive and behavioural phenotypes within the first degree relatives of schizophrenia patients and are present in unaffected family members more frequently than in the general population. Taken together, brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders.     

Neurobiology of emotion and high risk for schizophrenia: role of the amygdala and the X-chromosome

Abnormalities in emotion processing and in structure of the amygdala have consistently been documented in schizophrenia. A major question is whether amygdala abnormalities reflect a genetic vulnerability for the disease. In the present paper, we reviewed Magnetic Resonance Imaging (MRI) studies that reported amygdala measures in several high-risk populations: subjects from the general population with subclinical schizophrenia symptoms and relatives of schizophrenia patients. In addition, we reviewed the evidence regarding Klinefelter syndrome (characterised by an additional X-chromosome), which has also been related to an increased risk for schizophrenia. Overall, the evidence points to structural abnormalities of the amygdala in individuals at increased risk for schizophrenia. Although the genetic basis of amygdala deficits remains unclear, abnormalities (of genes) on the X-chromosome might play a role as suggested by the evidence from individuals with sex chromosome aneuploidies. We propose that amygdala abnormalities are an endophenotype in schizophrenia and may account for subtle emotional processing deficits that have been described in these high-risk groups.     

Scent of a disorder: Olfactory functioning in schizophrenia

The use of olfactory probes to assess frontal and temporal-limbic system functioning in patients with schizophrenia has garnered increasing interest among basic and clinical investigators. Deficits in odor identification, detection threshold sensitivity, discrimination, and memory have been reported and are thought to represent a centrally mediated deficit in the processing of this information. These impairments are seen in affected probands, first-degree family members, and those at risk for developing the illness, suggesting a genetic vulnerability or predisposition to chemosensory abnormalities. The observed deficits are not explained by gender, medication use, cognitive impairment, or smoking status, and support the hypothesis of primary dysfunction in the olfactory system. Along this same line, structural abnormalities in the peripheral and central olfactory brain regions, as well as disruptions of the basic physiology of this system, have been described. The study of olfactory processing in schizophrenia has already advanced the knowledge of the neural substrate for this disorder. Because the olfactory system continuously regenerates throughout life, it allows for a unique view of an ongoing neurodevelopmental process.     

The face and its emotion: right N170 deficits in structural processing and early emotional discrimination in schizophrenic patients and relatives

Previous studies have reported facial emotion recognition impairments in schizophrenic patients, as well as abnormalities in the N170 component of the event-related potential. Current research on schizophrenia highlights the importance of complexly-inherited brain-based deficits. In order to examine the N170 markers of face structural and emotional processing, DSM-IV diagnosed schizophrenia probands (n=13), unaffected first-degree relatives from multiplex families (n=13), and control subjects (n=13) matched by age, gender and educational level, performed a categorization task which involved words and faces with positive and negative valence. The N170 component, while present in relatives and control subjects, was reduced in patients, not only for faces, but also for face-word differences, suggesting a deficit in structural processing of stimuli. Control subjects showed N170 modulation according to the valence of facial stimuli. However, this discrimination effect was found to be reduced both in patients and relatives. This is the first report showing N170 valence deficits in relatives. Our results suggest a generalized deficit affecting the structural encoding of faces in patients, as well as the emotion discrimination both in patients and relatives. Finally, these findings lend support to the notion that cortical markers of facial discrimination can be validly considered as vulnerability markers.     

Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures

In an effort to reveal susceptibility genes, schizophrenia research has turned to the endophenotype strategy. Endophenotypes are characteristics that reflect the actions of genes predisposing an individual to a disorder, even in the absence of diagnosable pathology. Individual endophenotypes are presumably determined by fewer genes than the more complex phenotype of schizophrenia and would, therefore, reduce the complexity of genetic analyses. Unfortunately, despite there being rational criteria to define a viable endophenotype, the term is sometimes applied indiscriminately to characteristics that are deviant in affected individuals. Schizophrenia patients exhibit deficits in several neurophysiological measures of information processing that have been proposed as candidate endophenotypes. Successful processing of sensory inputs requires the ability to inhibit intrinsic responses to redundant stimuli and, reciprocally, to facilitate responses to less frequent salient stimuli. There is evidence to suggest that both these processes are "impaired" in schizophrenia. Measures of inhibitory failure include prepulse inhibition of the startle reflex, P50 auditory evoked potential suppression, and antisaccade eye movements. Measures of impaired deviance detection include mismatch negativity and the P300 event-related potential. The purpose of this review is to systematically evaluate the endophenotype candidacy of these key neurophysiological abilities. For each candidate, we describe typical experimental procedures, the current understanding of the underlying neurobiology, the nature of the abnormality in schizophrenia, the reliability, stability and heritability of the measure, and any reported gene associations. We conclude with a discussion of the few studies thus far that have employed a multivariate approach with these candidates.     

Information Processing and Attentional Dysfunctions as Vulnerability Indicators in Schizophrenia Spectrum Disorders

Summary: The schizotypal personality disorder is believed to be part of the schizophrenic spectrum of disorders including schizophrenic patients as well as some of their seemingly unaffected relatives with discreet symptoms. Spectrum-individuals are characterised by a genetic vulnerability for schizophrenia. The vulnerability is connected with neurocognitive deficits independent of clinical state. Some cognitive dysfunctions are unspecific and probably related to non-genetic brain damage. A consistent finding has, however, been poor performance in tasks involving information processing and attention. The findings point to the existence of specific sensory-perceptual deficits or a general attentional dysfunction. Identification of cognitive disturbances characteristic not only of schizophrenics, but also of schizotypal disordered and their relatives in the boundaries of schizophrenia, is relevant in order better to understand the pathogenetic mechanisms and treatment of schizophrenia. In the present review clinical data are analysed based on models of vulnerability and information processing with reference to a characterisation of the neurointegrative deficits that form the core abnormalities of the spectrum.     

Information processing and attentional dysfunctions as vulnerability indicators in schizophrenia spectrum disorders.

The schizotypal personality disorder is believed to be part of the schizophrenic spectrum of disorders including schizophrenic patients as well as some of their seemingly unaffected relatives with discreet symptoms. Spectrum-individuals are characterised by a genetic vulnerability for schizophrenia. The vulnerability is connected with neurocognitive deficits independent of clinical state. Some cognitive dysfunctions are unspecific and probably related to non-genetic brain damage. A consistent finding has, however, been poor performance in tasks involving information processing and attention. The findings point to the existence of specific sensory-perceptual deficits or a general attentional dysfunction. Identification of cognitive disturbances characteristic not only of schizophrenics, but also of schizotypal disordered and their relatives in the boundaries of schizophrenia, is relevant in order better to understand the pathogenetic mechanisms and treatment of schizophrenia. In the present review clinical data are analysed based on models of vulnerability and information processing with reference to a characterisation of the neuro-integrative deficits that form the core abnormalities of the spectrum.     

Critical evaluation of cognitive dysfunctions as endophenotypes of schizophrenia

OBJECTIVE: Cognitive dysfunctions are potential endophenotypes of schizophrenia. The aim of this study was to investigate whether recent evidence indeed suggests that cognitive dysfunctions are potent indicators of specific genetic traits that represent susceptibility for schizophrenia. METHOD: Studies including large, well-defined samples and controlled cognitive assessment have been reviewed. RESULTS: Evidence suggests that schizophrenia patients and their unaffected biological relatives are impaired in several cognitive domains, including working memory, executive functions, sustained attention, verbal episodic memory, processing of visual and auditory stimuli, and smooth pursuit eye movements. However, these impairments are present only in a limited proportion of subjects, showing low specificity and sensitivity and high variability. Linkage with specific genes is weak. CONCLUSION: Although some results are promising, at present cognitive dysfunctions cannot be considered as highly sensitive and specific endophenotypes of schizophrenia.     

Unirhinal olfactory identification deficits in young male patients with schizophrenia and related disorders: association with impaired memory function

We have observed discreet subgroups of male patients with psychotic disorders who have unirhinal olfactory identification deficits (microsmia). The purpose of this study was to examine the relationship between left or right nostril microsmia and performance on literalised neuropsychological tests sensitive to lesions in brain areas implicated in the pathogenesis of schizophrenia. Sixty-six male patients diagnosed with schizophrenia or related disorders were assessed with a battery of neuropsychological tests, sensitive to literalised and regional (temporal and frontal lobe) dysfunction. The University of Pennsylvania Smell Identification Test (UPSIT) was administered unirhinally and resultant scores were used to classify patients into olfactory subgroups. Neuropsychological test scores were compared amongst subgroups. A mixed design MANOVA was performed on cognitive domains with olfactory status (right microsmic; RM, n=8, left microsmic; LM, n=20, and normosmic schizophrenic controls; NSzC, n=38) as the between subject factor while hemisphere (left versus right) and domain (executive/fluency versus memory) were within-subject factors. A three-way (olfactory subgroup by hemisphere by region) interaction was observed. Non-verbal memory impairment was observed in the right and left microsmic subgroups. Verbal memory deficits were demonstrated in patients with left nostril microsmia.These results indicate that unirhinal olfactory performance may provide a meaningful manner by which to subtype patients with schizophrenia. Moreover, the data suggest that olfactory deficits in patients with schizophrenia are associated with dysfunction of temporal lobe, rather than frontal lobe abnormalities. The data are consistent with reports linking the right temporal lobe integrity to adequate olfactory processing.     

Olfaction, "olfiction," and the schizophrenia-spectrum: an updated meta-analysis on identification and acuity

Olfaction deficits in individuals with schizophrenia are well documented. A meta-analysis conducted nearly a dozen years ago on the topic revealed a deficit of a full standard deviation in magnitude compared to nonpatient controls. Recent efforts have been attempted to determine whether deficits in olfactory identification and acuity reflect a vulnerability marker of schizophrenia-spectrum pathology. To address this issue, the present study conducted a meta-analysis of 16 studies of individuals with schizotypy, defined in terms of a) "ultra-high risk" status, b) having an affected biological family member, or c) having extreme scores on a schizotypy questionnaire. We also conducted an updated meta-analysis of 40 studies of olfactory functioning in schizophrenia. Consistent with the prior meta-analysis, patients with schizophrenia showed impairments in olfaction identification on a full standard deviation in magnitude (d = -.99). Individuals with schizotypy showed much more subtle (d = -.24) differences in olfaction, though the effect sizes were higher for studies examining individuals at "ultra-high risk" (d = -.67) versus studies examining individuals with psychometrically-defined (d = -.14) schizotypy. Differences in olfactory acuity, relative to their respective control groups, were small for both the schizophrenia (d = -.45) and schizotypy (d = -.38) studies but were similar in magnitude. The present findings argue against the notion that deficits in olfaction identification are a vulnerability marker of schizophrenia. Suggestions for future research are recommended.     

Investigation of unirhinal olfactory identification in antipsychotic-free patients experiencing a first-episode schizophrenia

Although olfactory deficits have been reported in patients with schizophrenia, few studies have examined whether these deficits are lateralized or investigated their possible clinical correlates. In this study, we administered the University of Pennsylvania Smell Identification Test (UPSIT) unirhinally (one nostril at a time) to 15 patients experiencing a first-episode of schizophrenia and 17 healthy comparison subjects. Clinical and olfactory assessments were conducted on the same day in patients while they were antipsychotic drug-free. Patients performed more poorly compared to healthy volunteers in their ability to identify odors across both nostrils, but there were no group differences in right and left nostril impairment. Among patients, greater deficits in grooming and hygiene correlated significantly and more strongly with poorer ability in identifying odors presented to the left compared to the right nostril. Our findings suggest that deficits in grooming and hygiene, including poor body odor, observed in patients experiencing a first-episode of schizophrenia are associated with an impairment in left nostril, and possibly left hemisphere, olfactory processing.     

Decrements in volume of anterior ventromedial temporal lobe and olfactory dysfunction in schizophrenia

CONTEXT: Patients with schizophrenia exhibit olfactory deficits, but it is unclear whether these represent a specific abnormality. The link between olfactory impairments and regional brain abnormalities has yet to be established. OBJECTIVES: To determine whether patients with schizophrenia exhibit volumetric deficits in the anterior ventromedial temporal lobe, the target for neuronal inputs from the olfactory bulb, and whether these are related to olfactory performance deficits. DESIGN: A cohort study of patients and healthy control subjects who underwent both 1-mm spoiled-gradient echo magnetic resonance imaging and behavioral tests of olfaction and memory. SETTING: Schizophrenia Research Center at the University of Pennsylvania, Philadelphia. PARTICIPANTS: Fifty-two patients with a DSM-IV diagnosis of schizophrenia and 38 healthy control subjects. Individuals were excluded for history of head trauma, significant substance abuse, and medical conditions affecting brain function or olfactory capacity. MAIN OUTCOME MEASURES: Gray matter volumes of the left and right temporal poles and the perirhinal and entorhinal cortexes; olfactory threshold detection sensitivity and identification test scores; composite indexes of verbal and spatial memory ability. RESULTS: Patients had reduced volumes, relative to cranial size, in left (P =.003) and right (P =.01) perirhinal and left (P =.002) and right (P =.002) entorhinal cortexes, but not in the temporal pole. Perirhinal, but not entorhinal, cortical volume decrement was associated with decreased olfactory threshold sensitivity. Neither region was associated with impaired memory performance. CONCLUSIONS: Patients with schizophrenia have reduced cortical volumes in brain regions that receive afferents directly from the olfactory bulb. Behavioral olfactory deficits are related to structural brain abnormalities in these regions.     

Reduced posterior nasal cavity volume: a gender-specific neurodevelopmental abnormality in schizophrenia

OBJECTIVE: We previously reported that men with schizophrenia had reduced volumes of the posterior nasal cavity bilaterally. Since the nasal cavities develop in conjunction with both the palate and ventral forebrain, this could represent a simple marker of embryological dysmorphogenesis contributing to schizophrenia. The current study expands on this finding by examining a larger sample of both male and female patients and unaffected 1st-degree relatives, to determine the gender distribution of this abnormality and the extent to which it may be genetically mediated. METHOD: A measurement of nasal volume and geometry was acquired by acoustic rhinometry for 85 schizophrenia patients, 25 unaffected 1st-degree relatives of schizophrenia probands and 66 healthy comparison subjects. RESULTS: Male patients had smaller posterior nasal volumes than both male control subjects and male relatives. However, female patients did not differ from either female controls or female family members. Unaffected 1st-degree relatives did not differ from same-sex control subjects. These findings persisted after covarying for height and smoking history, and were unrelated to clinical symptomatology or antipsychotic medication usage. CONCLUSION: Posterior nasal cavity volume decrement appears to be a specific developmental craniofacial abnormality that may reflect an early disruption in embryological development in males with schizophrenia. Although further study is needed, this may be a marker of a "second hit" that distinguishes genetically vulnerable men who go on to develop the illness from those who do not.     

Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia

Attentional and executive impairments have been found both in patients with schizophrenia and in their unaffected first-degree relatives, suggesting that they might be considered as familial vulnerability markers. Several studies have shown that the performance of bipolar patients does not significantly differ from that of schizophrenic patients, so that executive and attentional deficits might not be specific to schizophrenia. In the present study, we aimed to identify executive dysfunctions in schizophrenia and bipolar disorder that might be vulnerability trait markers specific to one or common to both of these diseases. We assessed cognitive performance of euthymic bipolar and schizophrenic patients, their unaffected first-degree relatives and a healthy control group, using neuropsychological tasks to test different components of executive function: the Verbal Fluency Test, the Stroop Word Colour Test, the Wisconsin Card Sorting Test and the Trail Making Test. The two groups of patients and their unaffected relatives demonstrated disproportionately increased slowness on the Stroop test in comparison to the normal healthy group. Patients with schizophrenia performed poorly on all the tests in comparison to the normal healthy subjects, while no other impairment was observed in the bipolar patients and in the relatives of schizophrenic and bipolar patients. Enhanced susceptibility to interference and reduced inhibition could be transnosographical markers for a shared familial vulnerability common to schizophrenia and bipolar disorders.