Anterior cingulate activation in antipsychotic-naïve first-episode schizophrenia

Objective: Anterior cingulate (ACC) hypo-activity is commonly observed in chronically ill schizophrenia patients. However, it is unclear whether this is secondary to persistent illness and/or medication. Method: We examined eight antipsychotic-naïve first-episode patients and matched healthy controls undergoing PET scanning while performing the Stroop task. Results: Group-averaged and single-subject analyses showed ACC activation in both controls and patients, albeit in different sub-regions (paracingulate and cingulate respectively). A direct comparison revealed relative under-activity of the left paracingulate cortex in patients. Conclusion: These findings suggest that the more pervasive hypo-activation observed in chronic patients may be secondary to persistent illness and/or medication.     

Cerebellar and other neurological soft signs in antipsychotic-naïve schizophrenia

Objective: Cerebellar neurological abnormalities in schizophrenia have been associated with severe negative symptoms, cognitive deficits, and smaller cerebellar volume. This study assessed the comparative discriminant validity between Cerebellar Soft Signs (CSS) vs. other neurological soft signs (ONSS) [in discriminating between schizophrenia patients and healthy controls] as well as the relationship between the soft signs and psychopathology. Method: Antipsychotic‐naïve schizophrenia patients (n = 32) and healthy subjects (n = 32) were examined using International Co‐Operative Ataxia Rating Scale and Neurological Evaluation Scale. Results: Mean CSS scores, ONSS total score, and Sensory Integration Signs sub‐score were significantly higher in patients. Discriminant analysis revealed two CSS sub‐scores (but none of the ONSS scores) to be significant (P < 0.0001) accounting for 78% of classification. CSS total score, Posture sub‐score, and Oculomotor sub‐score had significant positive correlation with negative syndrome score. Conclusion: Findings support intrinsic cerebellar dysfunction in schizophrenia. The observations are discussed in relationship with cognitive dysmetria.     

Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia

The early course of neuropsychological dysfunction in schizophrenia and the impact of treatment on these deficits need to be better specified. A sample of 45 patients with schizophrenia underwent five neuropsychological evaluations from prior to treatment with antipsychotic treatment through a 2-year follow-up period. A comparison sample of 33 matched healthy individuals underwent neuropsychological evaluations at similar time points. At baseline, a generalized deficit across cognitive domains was evident for the schizophrenia sample. After 6 weeks of treatment, patients showed modest improvements in visual memory and visual perception, but a decline in verbal memory. Verbal memory performance returned to baseline levels by the 6-month follow-up while deficits in other neuropsychological domains persisted throughout the 2-year period. Relatively static and generalized neuropsychological dysfunction, evident from illness onset, is consistent with neurodevelopmental rather than neurodegenerative models of schizophrenia.     

Impairment of verbal memory and learning in antipsychotic-naïve patients with first-episode schizophrenia

BACKGROUND: Verbal memory deficits are of interest in schizophrenia because of the potential relationship to functional and anatomic mesial temporal lobe pathology in this disorder. The goal of this study was to characterize the nature of verbal memory impairments in antipsychotic-na?ve schizophrenic patients early in the course of illness. METHODS: Neuroleptic-na?ve patients with schizophrenia (n=62) and healthy individuals (n=67), matched on IQ, age, sex, and parental socioeconomic status, were administered the California Verbal Learning Test (CVLT). RESULTS: Schizophrenia participants performed significantly worse than healthy individuals on measures of verbal learning, short- and long-term memory, and immediate attention. Deficits in recall were related to reduced use of organizational strategies to facilitate verbal encoding and retrieval. No group differences were found in rate of forgetting or susceptibility to proactive or retroactive interference. Memory deficits had minimal relation to positive or negative symptom severity. CONCLUSIONS: Schizophrenia is characterized by significant verbal memory dysfunction early in the course of illness prior to treatment with antipsychotic medications. Deficits in consistency of learning over several trials, as well as a strong relationship between semantic organizational strategies and reduced learning capacity, implicate prefrontal dysfunction as a contributor to verbal memory deficits in schizophrenia.     

Cognitive effects of six months of treatment with quetiapine in antipsychotic-naïve first-episode schizophrenia

The aim of the study was to explore the relationships between subjective or objective symptoms and mortality in schizophrenia. 310 subjects meeting the ICD-10 criteria for schizophrenia were included in the study between 1998 and 2000. At the initial assessment the following variables were respectively assessed to evaluate subjective and objective symptoms: the Frankfurt Complaints Questionnaire (FCQ) and the Positive and Negative Syndrome Scale (PANSS). In May 2008, information about the subjects were collected in order to know if they are alive or not and if they are deceased to know the date and the causes of their death. Survival analysis was conducted using the Kaplan–Meier product-limit estimator and standardized mortality ratio (SMR) was calculated. A multivariate Cox regression was done to detect predictive factors associated with mortality. Absolute mortality rates were 10.01%, 4.46% and 5.42% for overall mortality, unnatural causes and natural causes, respectively. SMR for overall mortality was 4.73. Cox regression analyses showed that elevated scores of FCQ was significant predictor of deaths from unnatural causes. High levels of subjective symptoms, as rated by the FCQ were independent predictor of mortality by unnatural causes in schizophrenic subjects. There were several limitations: The causes of death were not determined by autopsy and secondly, the duration of the study could be insufficient to detect significant associations between clinical variables and mortality.     

Impaired temporoparietal deactivation with working memory load in antipsychotic-naïve patients with first-episode schizophrenia

Abstract

Objectives. Neuroimaging studies have shown abnormal task-related deactivations during working memory (WM) in schizophrenia patients with recent emphasis on brain regions within the default mode network. Using fMRI, we tested whether antipsychotic-naïve schizophrenia patients were impaired at deactivating brain regions that do not subserve WM. Methods. Twenty-three antipsychotic-naïve patients with first-episode schizophrenia and 35 healthy individuals underwent whole-brain 3T fMRI scans while performing a verbal N-back task including 0-back (no WM load), 1-back (low WM load), and 2-back (high WM load) conditions. Results. Contrasting the 2-back and 0-back conditions revealed that patients deactivated default mode network regions to a similar degree as controls. However, patients were impaired in deactivating large bilateral clusters centred on the superior temporal gyrus with increasing WM load. These regions activated with the no WM load condition (0-back) in both groups. Conclusions. Because 0-back activation reflects verbal attention processes, patients’ persistent activation in the 1-back and 2-back conditions may reflect an inability to shift cognitive strategy with onset of WM demands. Since patients were antipsychotic-naïve and task performance was equal to controls, we infer that this impaired temporoparietal deactivation may represent a primary dysfunction in schizophrenia.     

Novel evidence for enhanced stem cell trafficking in antipsychotic-naïve subjects during their first psychotic episode

In this study, we tested the novel hypothesis that stem cells and those factors that modulate their trafficking may be biological markers for acute psychosis. Twenty-eight subjects during their first nonaffective psychotic episode were investigated before and after antipsychotic treatment and were compared with 35 healthy controls (CG); the psychotic group (PG) was divided into “schizophrenic” (SG) and “non-schizophrenic” (NG) subgroups. We examined the number of circulating Lin^–/CD45^–/CD34⁺ and Lin^–/CD45^–/CD133⁺ very small embryonic-like stem cells (VSELs), which express markers of the neural lineage, and also the plasma levels of factors that modulate their trafficking: the C3a, C5a, and C5b-9 activated complement cascade components, stromal-derived factor 1, and sphingosine-1-phosphate (S1P). We found that the mean numbers of Lin^–/CD45^–/CD34⁺ VSELs and the plasma levels of S1P prior to treatment differ between the CG and PG and that these cells express markers of neural lineage. The number of Lin^–/CD45^–/CD133⁺ VSELs in peripheral blood differed between the SG and NG prior to treatment. Using logistic regression analysis, we found that C3a and S1P are the best predictors of risk and are potential markers for the first psychotic episode. Furthermore, in the SG, the number of circulating Lin^–/CD45^–/CD34⁺ VSELs and the S1P plasma level are the best predictors of risk and are proposed as novel markers for the first “schizophrenic” episode of psychosis.     

Startle gating in antipsychotic-naïve first episode schizophrenia patients: one ear is better than two

Prepulse inhibition (PPI) of the startle reflex to binaural prepulse stimuli is reliably reported to be reduced in patients with schizophrenia. Monaural acoustic prestimuli produce more inhibition of the eye blink reflex than binaural prestimuli in healthy people. The effect of monaural prestimulation on reflex inhibition in patients with schizophrenia is not known. In this study, inhibition of the acoustic startle response by monaural and binaural acoustic prestimuli was assessed in 20 antipsychotic-na?ve first episode schizophrenia patients and compared with 20 age and sex-matched healthy subjects. The results revealed less PPI, especially with binaural prestimuli, in patients than healthy subjects but both groups showed more PPI with monaural than binaural prestimuli. It is concluded that first episode schizophrenia patients show deficient sensorimotor gating but they are not impaired in the mechanism underlying stronger PPI with monaural than binaural prepulses.     

MRI volumetric and 31P MRS metabolic correlates of caudate nucleus in antipsychotic-naïve schizophrenia

Objective: To examine the volumetric and metabolic correlates of caudate nucleus in antipsychotic‐naïve schizophrenia patients in comparison with healthy controls. Method: Twelve antipsychotic‐naïve schizophrenia patients and 13 healthy controls underwent ³¹P magnetic resonance spectroscopy of basal ganglia. Magnetic resonance imaging volume of caudate nuclei was measured using scion image software. Results: Patients had significantly smaller caudate volume than healthy controls. Phosphocreatine (PCr)/total phosphorous and PCr/total adenosine tri‐phosphate ratios of both caudate nuclei were significantly lower in patients than controls. Significant negative correlation was found between the left caudate volume and left PCr/total phosphorus ratio in the patients. Age at onset of psychosis had i) significant negative correlation with right and left caudate volumes and ii) significant positive correlation with left PCr/total phosphorus ratio. Conclusion: The metabolic and volumetric abnormalities of caudate nucleus in antipsychotic‐naïve schizophrenia patients support neurodevelopmental etiopathogenesis.     

Differential brain glucose metabolic patterns in antipsychotic-naïve first-episode schizophrenia with and without auditory verbal hallucinations

Background

Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication.

Methods

The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences.

Results

We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error–corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal–parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < −3.3).

Limitations

The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings.

Conclusion

Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the pathophysiology of AVHs. We discuss the relevance of phenomenology-based grouping in the study of AVHs.     

Dysfunction of dorsolateral prefrontal cortex in antipsychotic-naïve schizophreniform psychosis

Reports of abnormal activation of the dorsolateral prefrontal cortex (dlPFC) are common in functional neuroimaging studies of schizophrenia, although very few have examined brain activity in patients close to the onset of illness. In this H(2)(15)O PET study, eight young male patients with first-episode schizophreniform psychosis and age-matched control subjects performed a version of the Stroop task that we have previously shown to engage the middle-frontal gyrus. At the time of testing, patients were antipsychotic-na?ve and were scanned within 1 week of initial contact with our clinical program. All patients received a later diagnosis of schizophrenia 6 months after participating in the study. Whole-brain (within-group) and region-of-interest (between-group) analyses were carried out and data underwent spatial reproducibility testing. Compared with healthy subjects, patients showed significantly greater reaction-time (RT) interference but normal RT accuracy on the Stroop task. This pattern correlated with significant under-activation of the posterior left middle-frontal gyri in the patient versus control group. These findings support an emerging model of impaired cognitive control in schizophrenia and suggest that there is significant dysfunction of the dlPFC close to the onset of illness that may coincide with, or be modulated by, the transition-to-illness phase.     

Neural oscillations in antipsychotic-naïve patients with a first psychotic episode

Objectives: In chronic schizophrenic psychoses, oscillatory abnormalities predominantly occur in prefrontal cortical regions and are associated with reduced communication across cortical areas. Nevertheless, it remains unclear whether similar alterations can be observed in patients with a first episode of psychosis (FEP), a state characterised by pathological features occurring in both late prodromal patients and initial phases of frank schizophrenic psychoses. Methods: We assessed resting-state electroencephalographic data of 31 antipsychotic-naïve FEP patients and 29 healthy controls (HC). We investigated the three-dimensional (3D) current source density (CSD) distribution and lagged phase synchronisation (LPS) of oscillations across small-scale and large-scale brain networks. We additionally investigated LPS relationships with clinical symptoms using linear mixed-effects models. Results: Compared to HC, FEP patients demonstrated abnormal CSD distributions in frontal areas of the brain; while decreased oscillations were found in the low frequencies, an increase was reported in the high frequencies (P?<?0.01). Patients also exhibited deviant LPS in the high frequencies, whose dynamics changed over increasing 3D cortico-cortical distances and increasing psychotic symptoms. Conclusions: These results indicate that in addition to prefrontal cortical abnormalities, altered synchronised neural oscillations are also present, suggesting possible disruptions in cortico-cortical communications. These findings provide new insights into the pathophysiological mechanisms of emerging schizophrenic psychoses.     

Pituitary volume in neuroleptic-naïve schizophrenia: a structural MRI study

Abnormalities in the hypothalamic–pituitary–adrenal axis (HPA) have been implicated in psychosis. To our knowledge, no prior study has measured pituitary volume in a neuroleptic-naïve schizophrenic population. Herein, we present data exploring the volumetric differences in a sample of antipsychotic-naïve patients with a DSM-IV diagnosis of schizophrenia versus appropriately matched healthy controls.

Pituitary volumes were measured in 51 patients with schizophrenia (36 males, 15 females, mean age ± S.D.: 25.2 ± 7.4 years) and 55 healthy controls (30 males, 25 females; mean age ± S.D.: 25.2 ± 6.6 years) Measurements were conducted on 1.5 mm thick T1-weighted coronal images from a 1.5T scanner by two trained raters. Patients with schizophrenia had significantly smaller pituitary volumes than healthy control subjects (mean volume ± S.D. = 0.58 ± 0.14 cm³ and 0.66 ± 0.17 cm³ respectively; ANCOVA (using intracranial volume, gender and age as covariates), F = 6.81, df = 1, 101; p = 0.01). These findings provide new evidence of a smaller pituitary volume in neuroleptic-naïve patients with schizophrenia. The observed alterations in pituitary volume are consistent with neuroendocrine studies that have reported abnormalities in the HPA axis in psychosis. Similar volume reductions have been seen in other neuropsychiatric populations and may cut across diagnostic boundaries.     

Larger putamen size in antipsychotic-naïve individuals with schizotypal personality disorder

ObjectiveTo (a) compare the size of the dorsal and ventral striatum (caudate and putamen) in a large sample of antipsychotic-naïve individuals with schizotypal personality disorder (SPD) and healthy control participants; (b) examine symptom correlates of striatal size in SPD.MethodsThe left and right caudate and putamen were hand-traced on structural MRI at five dorsal to ventral slice levels in 76 SPD and 148 healthy control participants. A Group × Region (caudate, putamen) × Slice (1–5: ventral, 2, 3, 4, dorsal) × Hemisphere (left, right) mixed-model MANOVA was conducted on size relative to whole brain.ResultsPrimary results showed that compared with the controls, the SPD group showed (a) larger bilateral putamen size overall and this enlargement was more pronounced at the most ventral and dorsal levels; in contrast, there were no between-group differences in caudate volume; (b) larger bilateral size of the striatum ventrally, averaged across the caudate and putamen. Among the SPD group, larger striatal size ventrally, particularly in the left hemisphere was associated with less severe paranoid symptoms.ConclusionsStriatal size is abnormal in SPD and resembles that of patients with schizophrenia who respond well to antipsychotic treatment. The results suggest that striatal size may be an important endophenotype to consider when developing new pharmacological treatments and when studying factors mitigating psychosis.     

Multimodal assessment of white matter microstructure in antipsychotic-naïve schizophrenia patients and confounding effects of recreational drug use

Brain Imaging and Behavior - Cerebral white matter (WM) aberrations in schizophrenia have been linked to multiple neurobiological substrates but the underlying mechanisms remain unknown. Moreover,...     

Automated MRI parcellation study of regional volume and thickness of prefrontal cortex (PFC) in antipsychotic-naïve schizophrenia

Objective: Prefrontal cortical dysfunction is considered to be critical in the pathogenesis of schizophrenia. However, structural magnetic resonance imaging (MRI) studies on the PFC have yielded inconsistent results because of various confounding factors. Method: In this study we examined the volume and thickness abnormalities of the PFC in antipsychotic‐naïve schizophrenia patients (n = 51) in comparison with age‐, sex‐, and handedness‐matched (as a group) healthy comparison subjects (n = 47) using a newly described automated MRI parcellation analysis. Results: Schizophrenia patients showed i) significant volume deficits in bilateral lateral orbitofrontal and left medial orbitofrontal cortices as well as bilateral pars triangularis; and ii) significant thickness deficit in bilateral medial orbitofrontal cortices. Negative syndrome score had a significant negative correlation with the thickness of the left medial orbitofrontal cortex. Conclusion: The study findings emphasize that prefrontal deficit in schizophrenia is differential and involves primarily the regions essential for ‘social cognition’.     

Alterations in functional network centrality in first-episode drug-naïve adolescent-onset schizophrenia

Brain Imaging and Behavior - Schizophrenia is a disorder resulting from aberrant brain networks and circuits. In the current study, we aimed to investigate specific network alterations in...