Cerebellar-dependent eyeblink conditioning deficits in schizophrenia spectrum disorders

Accumulating evidence suggests that abnormalities in neural circuitry and timing associated with the cerebellum may play a role in the pathophysiology of schizophrenia. Schizotypal personality disorder (SPD) may be genetically linked to schizophrenia, but individuals with SPD are freer from potential research confounds and may therefore offer insight into psychophysiological correlates of schizophrenia. The present study employed a delay eyeblink conditioning (EBC) procedure to examine cerebellar-dependent learning in schizophrenia, SPD, and healthy control subjects (n = 18 per group) who were matched for age and gender. The conditioned stimulus was a 400-ms tone that coterminated with a 50 ms unconditioned stimulus air puff. Cognitive performance on the Picture Completion, Digit Symbol Coding, Similarities, and Digit Span subscales of the Wechsler Adult Intelligence Scale--Third Edition was also investigated. The schizophrenia and SPD groups demonstrated robust EBC impairment relative to the control subjects; they had significantly fewer conditioned responses (CRs), as well as smaller CR amplitudes. Schizophrenia subjects showed cognitive impairment across subscales compared with SPD and control subjects; SPD subjects showed intermediate performance to schizophrenia and control subjects and performed significantly worse than controls on Picture Completion. Impaired EBC was significantly related to decreased processing speed in schizophrenia spectrum subjects. These findings support the role of altered cortico-cerebellar-thalamic-cortical circuitry in the pathophysiology of schizophrenia spectrum disorders.     

Apathy in schizophrenia: reduced frontal lobe volume and neuropsychological deficits

OBJECTIVE: Apathy is a common negative symptom in schizophrenia. The authors investigated neuropsychological performance and regional brain volumes in schizophrenia patients with high versus low levels of apathy. METHOD: Schizophrenia patients with low apathy levels (N=18) and high apathy levels (N=20) and 12 healthy comparison subjects completed neuropsychological testing as well as magnetic resonance imaging scanning to obtain lobar volumes after total intracranial volume was controlled. RESULTS: The high apathy group scored lower than comparison subjects on rapid visuomotor sequencing and verbal learning/recall. The high apathy group had lower performance IQ scores than the low apathy and comparison groups. Only the high apathy group showed significantly reduced bilateral frontal lobe volumes relative to comparison subjects; both schizophrenia patient groups showed bilateral temporal lobe volume reductions. CONCLUSIONS: The present findings are consistent with studies in other disorders showing frontal lobe involvement in apathy.     

Increased familiarity of intellectual deficits in early-onset schizophrenia spectrum disorders

Abstract

Objectives. Early-onset schizophrenia is considered to be neurobiologically similar to adult-onset forms, although it represents a more severe expression of the disorder. In the present study, we explored putative larger familial vulnerability of intellectual impairments in early-onset schizophrenia spectrum disorders (EOS) when compared to adult-onset (AOS) families. Methods. A sample of 340 subjects including schizophrenia spectrum disorder patients, their first degree relatives and age-matched healthy controls was assessed on intelligence quotient (IQ). We used linear regression analysis and intraclass correlation coefficients (ICC) to explore familial aggregation of IQ across age at onset groups. Results. The relationship between IQ level of patients and their first-degree relatives showed positive linear association (β = 0.43, P < 0.01). High significant familial aggregation was found for intelligence quotient in EOS families (ICC = 0.618, P < 0.01), while AOS families responded to lower estimates (ICC = 0.204, P = 0.26; between ICC comparison z = 1.993, P < 0.05). Conclusions. High aggregation of intellectual performance in the EOS group suggests larger familial vulnerability in early-onset forms of the disease when cognitive functions are considered. Within a continuum of psychopathology in schizophrenia spectrum disorders, specific genetic effects are discussed for distinct onset forms that might be in line with a neurodevelopmental model of the disease.     

Dermatoglyphic anomalies and neurocognitive deficits in sibling pairs discordant for schizophrenia spectrum disorders

The neurodevelopmental hypothesis of schizophrenia suggests that adverse genetic loading in conjunction with environmental factors early in fetal life causes a disruption of neural development, decades before the symptomatic manifestation of the disease. Neurocognitive deficits have been observed early on the course of schizophrenia, and their association with an early developmental brain lesion has been postulated. Dermatoglyphics have been analyzed in schizophrenia as markers of prenatal brain injury because of their early fetal ontogenesis and susceptibility to the same environmental factors that can also affect cerebral development. The aim of our study was to conduct a comparative examination of neurocognitive functions and dermatoglyphic variables in 89 sibling pairs discordant for schizophrenia spectrum disorders. Therefore, we investigated the association between these two markers to explore the prenatal origin of cognitive deficits in schizophrenia. The affected siblings were significantly impaired on all the cognitive variables assessed (Wisconsin Card Sorting Test, Trail Making Test and Continuous Performance Test) and had a greater number of dermatoglyphic anomalies. These results suggest the influence of intrauterine environmental factors in the siblings affected with schizophrenia. However, we did not detect a significant association between these two vulnerability markers in the schizophrenic patients, suggesting the role of genetic or late environmental factors in the origin of the neurocognitive deficits found in these patients.     

Elevated levels of cognitive-perceptual deficits in individuals with a family history of schizophrenia spectrum disorders

This study finds that the relatives of schizophrenics have elevated scores on the cognitive-perceptual factor of the schizotypal personality questionnaire (SPQ), particularly for the 'unusual perceptual experiences' and 'ideas of reference' subscales. These results support recent findings by Kremen et al. (1998) and suggest that previous failures to demonstrate elevated scores on 'positive' symptoms of schizotypy may be a function of instrumentation.     

Early signs in schizophrenia spectrum disorders

The frequency of various early signs of illness was examined in 96 first-episode patients suffering from schizophrenia, schizoaffective, or schizophreniform disorder. A factor analysis of these early signs was performed, and each of the five dimensions identified was examined for its relation to symptoms of psychosis at presentation and after 1 year of treatment. The results suggested five primary dimensions of early signs: emotional dysphoria and odd perceptual and cognitive content, impaired functioning, changes related to psychobiological or vegetative functioning, suspiciousness accompanied by difficulties in concentration, and irritability/aggression. Impaired functioning in the prepsychosis period was associated with higher negative symptoms at presentation for treatment, and higher levels of psychobiological changes were associated with lower positive symptoms of psychosis after a year of treatment. The latter findings may indicate that patients with more profound indications of affective disturbance or stress have a better prognosis.     

Illness denial in schizophrenia spectrum disorders

Impaired illness awareness or anosognosia is a common, but poorly understood feature of schizophrenia that contributes to medication nonadherence and poor treatment outcomes. Here we present a functional imaging study to measure brain activity at the moment of illness denial. To accomplish this, participants with schizophrenia (n = 18) with varying degrees of illness awareness were confronted with their illness beliefs while undergoing functional MRI. To link structure with function, we explored the relationships among impaired illness awareness and brain activity during the illness denial task with cortical thickness. Impaired illness awareness was associated with increased brain activity in the left temporoparieto‐occipital junction (TPO) and left medial prefrontal cortex (mPFC) at the moment of illness denial. Brain activity in the left mPFC appeared to be a function of participants' degree of self‐reflectiveness, while the activity in the left TPO was associated with cortical thinning in this region and more specific to illness denial. Participants with impaired illness awareness had slower response times to illness related stimuli than those with good illness awareness. Increased left hemisphere brain activity in association with illness denial is consistent with the literature in other neuropsychiatric conditions attributing anosognosia or impaired illness awareness to left hemisphere dominance. The TPO and mPFC may represent putative targets for noninvasive treatment interventions, such as transcranial magnetic or direct current stimulation. Hum Brain Mapp, 36:391–414, 2015. © 2014 Wiley Periodicals, Inc.     

Parental schizophrenia spectrum disorders in childhood-onset and adult-onset schizophrenia

OBJECTIVE: Childhood onset of "adult" psychiatric disorders may be caused, in part, by more salient genetic risk. In this study, the rates of schizophrenia spectrum disorders among parents of patients with childhood-onset and adult-onset schizophrenia and parents of community comparison subjects were compared. METHOD: To assess the presence of axis I and axis II disorders associated with schizophrenia, parents of patients with childhood-onset schizophrenia (95 parents), patients with adult-onset schizophrenia (86 parents), and community comparison subjects (123 parents) were interviewed directly by using semistructured instruments. Information on 19 additional parents (parents of childhood-onset patients, N=2; parents of adult-onset patients, N=11; parents of community comparison subjects, N=6) was obtained by using a family history interview with the same instruments. Transcribed interviews were scored by a rater blind to group membership, and the morbid risks for schizophrenia spectrum disorders in the three groups were compared. RESULTS: Parents of patients with childhood-onset schizophrenia had a significantly higher morbid risk of schizophrenia spectrum disorders (24.74%) than parents of patients with adult-onset schizophrenia (11.35%), and parents of both patient groups had a greater risk of schizophrenia spectrum disorders than did parents of comparison subjects (1.55%). CONCLUSIONS: Parents of patients with childhood-onset schizophrenia have a higher rate of schizophrenia spectrum disorders than parents of patients with adult-onset illness. This is consistent with the hypothesis that a childhood onset of schizophrenia is due, at least in part, to a greater familial diathesis for the disorder.     

Widespread cerebral gray matter volume deficits in schizophrenia.

Magnetic resonance imaging was used to investigate whether the structural brain differences commonly observed in patients with schizophrenia as compared with normal control subjects are specific to gray or white matter, and furthermore whether such abnormalities are localizable to circumscribed cortical regions. Accordingly, 22 patients meeting DSM-III-R criteria for schizophrenia and 20 healthy community volunteers, all 23 to 45 years old, received magnetic resonance imaging scans. Seven axial magnetic resonance imaging sections of 5-mm thickness were segmented into cerebrospinal fluid, gray matter, and white matter compartments and used for volumetric quantification. For the healthy control subjects, age correlated significantly with the percentage of all magnetic resonance imaging sections taken up by gray matter but not white matter. After correcting for the normal effect of age, the schizophrenic group was found to have significantly less gray matter than the control group but no difference in white matter; ventricular volume was 34% greater in the schizophrenic group. The schizophrenic group had less gray matter in all six cortical subregions analyzed; these differences attained statistical significance for all but the parietal measure. These findings have implications for studies of localized gray matter abnormalities and suggest that regional brain volume measurements need to be expressed in the context of possible widespread gray matter volume deficits in schizophrenia.     

Cognitive dimensions in first-episode schizophrenia spectrum disorders

BACKGROUND: The severity and pattern of cognitive deficits in epidemiological cohorts of patients with first-episode schizophrenia spectrum disorders still remains unclear. We aimed to characterize the basic cognitive functioning of a representative sample of patients with a first-episode schizophrenia spectrum disorders. METHOD: One hundred thirty-one patients experiencing first-episode psychosis and 28 healthy volunteers were administered a comprehensive neuropsychological evaluation. To reduce the number of cognitive test measures into meaningful cognitive dimensions, before analyzing differences between patient and healthy volunteer samples, exploratory factor analysis was carried out on data collected in patients group. The method of extraction was Principal Components Analysis with oblique rotation. RESULTS: An eight-factor model including verbal learning/memory, verbal comprehensive abilities, speed of processing/executive functioning, motor dexterity, motor speed, sustained attention, and impulsivity emerged. A significant below average performance in all cognitive dimensions, except impulsivity, was found. Patient's performance in speed of processing/executive functioning, motor dexterity and sustained attention dimensions exceeded one standard deviation below healthy comparison subjects. CONCLUSIONS: At early stages of the illness, patients display a marked impairment in several functionally relevant cognitive domains.     

The relationship between prefrontal brain volume and characteristics of memory strategy in schizophrenia spectrum disorders

The present study investigated the relationship between memory strategy use and prefrontal gray/white matter volumes of healthy control subjects, patients with schizophrenia or schizotypal disorder. Gray/white matter volumes were measured for the superior, middle, inferior, ventral medial and orbital prefrontal regions, using high-resolution magnetic resonance (MR) images that were acquired from 35 patients with schizophrenia, 25 patients with schizotypal disorder and 19 healthy subjects. Participants were also administered the Japanese Verbal Learning Test (JVLT). In control subjects, larger left inferior frontal and straight gyrus's gray matter volumes were associated with higher semantic clustering rates on the JVLT, and smaller left inferior frontal gray matter volumes were associated with higher serial clustering ratio. In schizophrenic patients, smaller left orbitofrontal gray matter volumes were associated with lower semantic clustering rates on the JVLT. In schizotypal patients, smaller left inferior frontal white matter volume was associated with smaller serial clustering rates and larger semantic clustering rate. These findings suggest that semantic organization in schizophrenic patients might depend on mobilization of a memory strategy that is mediated by orbitofrontal cortex functioning. Failure to use a semantic organization strategy might be related to reduced volume in the inferior frontal gyrus. The findings for schizotypal patients suggest a compensation mechanism to remember the words using a serial processing strategy is at work when the inferior frontal gyrus cannot mediate semantic processing.     

Parietal lobe function in developmental dyslexia

The theory that developmental dyslexia is due to malfunction of the parietal lobes was examined by administering tests sensitive to parietal function to groups of dyslexic and normal children. Dyslexic children performed poorly on two of the five tests administered. A factor analysis of the tests revealed two factors, with dyslexics performing poorly on one factor but not on the other. It was concluded that these tests tap two separate functional systems involving the parietal lobes, and that the operation of one of these systems is deficient in developmental dyslexia.     

Hippocampal volume reduction and autobiographical memory deficits in chronic schizophrenia

Although autobiographical memory (AM) deficits and hippocampal changes are frequently found in schizophrenia, their actual association remained yet to be established. AM performance and hippocampal volume were examined in 33 older, chronic schizophrenic patients and 21 healthy volunteers matched for age, gender and education. Psychopathological symptoms and additional neuropsychological parameters were assessed by using appropriate rating scales; magnetic resonance imaging (MRI) 3-T data were analyzed via an automated region-of-interest procedure. When compared with the control subjects, patients showed significantly decreased left anterior and posterior hippocampal volumes. Episodic but not semantic AM performance was significantly lower in the patients than in the healthy controls. Both episodic and semantic AM deficits were significantly correlated with volume of the left hippocampus in the patient group. In contrast, deficits in verbal memory, working memory and remote semantic memory observed in the patients did not relate to hippocampal volume. Our findings indicate that AM deficits in chronic schizophrenia are associated with hippocampal volume reductions and underline the importance of this pathology in schizophrenia.     

Symptomatic determinants of insight in schizophrenia spectrum disorders

Impaired insight in schizophrenia spectrum disorders has been linked to several psychopathologic features including positive symptoms, although not all dimensions of psychopathology have been studied and confounds from other symptoms have not been ruled out. In addition, the nature of the association between insight and specific positive symptoms, in particular delusions, remains unclear. The present investigation examined whether, in patients with schizophrenia spectrum disorders insight is associated with specific symptom dimensions including delusional severity. The factor structure was determined from scores of 151 patients rated on the Signs and Symptoms of Psychotic Illness scale. Associations of the Signs and Symptoms of Psychotic Illness insight item with the resulting components and delusions were assessed using regression-based methodology. Principal component analysis revealed 4 orthogonal symptom clusters. Correlational analyses demonstrated that only depression/anxiety and psychomotor excitation were significantly related to insight. Hierarchical regression indicated that delusions explained unique variance in insight over and above depression/anxiety and psychomotor excitation. These results suggest that depression/anxiety is associated with better insight and that psychomotor excitation and delusions are associated with poorer insight.