Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia, but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus.
deep brain stimulation; ventral hippocampus; MAM; auditory evoked potential; local field potential; schizophrenia
Patients with schizophrenia have well-established deficits in their ability to identify emotion from facial expression and tone of voice. In the visual modality, there is strong evidence that basic processing deficits contribute to impaired facial affect recognition in schizophrenia. However, few studies have examined the auditory modality for mechanisms underlying affective prosody identification. In this study, we explored links between different stages of auditory processing, using event-related potentials (ERPs), and affective prosody detection in schizophrenia. Thirty-six schizophrenia patients and 18 healthy control subjects received tasks of affective prosody, facial emotion identification, and tone matching, as well as two auditory oddball paradigms, one passive for mismatch negativity (MMN) and one active for P300. Patients had significantly reduced MMN and P300 amplitudes, impaired auditory and visual emotion recognition, and poorer tone matching performance, relative to healthy controls. Correlations between ERP and behavioral measures within the patient group revealed significant associations between affective prosody recognition and both MMN and P300 amplitudes. These relationships were modality specific, as MMN and P300 did not correlate with facial emotion recognition. The two ERP waves accounted for 49% of the variance in affective prosody in a regression analysis. Our results support previous suggestions of a relationship between basic auditory processing abnormalities and affective prosody dysfunction in schizophrenia, and indicate that both relatively automatic pre-attentive processes (MMN) and later attention-dependent processes (P300) are involved with accurate auditory emotion identification. These findings provide support for bottom-up (e.g., perceptually based) cognitive remediation approaches.
schizophrenia; auditory processing; affective prosody; mismatch negativity; P300
The Middle Longitudinal Fascicle (MdLF) is a long association fiber connecting the superior temporal gyrus (STG) and temporal pole with the angular gyrus through the white matter of the STG, structures which are known to play a crucial role in the pathology of schizophrenia. Functions of MdLF are thought to be related to language and thought processing in the left hemisphere, and with attention in the right hemisphere. While deficits of these functions are core clinical features of schizophrenia, no study has investigated structural abnormalities of MdLF in schizophrenia.
3T diffusion tensor data was acquired from twenty-six patients with schizophrenia and twenty-five healthy control subjects. Streamline tractography technique was used to extract MdLF. Fractional Anisotropy (FA) was compared between two groups. In addition, relationships were investigated between FA in the left MdLF and the Disorganized Thought Factor derived from the Positive and Negative Symptom Scale five factor model, and between FA in the right MdLF and the Poor Attention.
Relative to control subjects, the patients with chronic schizophrenia showed significant mean FA reductions in the bilateral MdLF. The FA of the left MdLF demonstrated a significant negative association with the Disorganized thoughts factor, and the FA of the right MdLF showed a significant negative relationship with the Poor Attention.
This study provides new evidence for structural deficits in the bilateral MdLF in patients with chronic schizophrenia. It further demonstrates contribution of these abnormalities to the core clinical features - especially to disorganization and attention deficit.
schizophrenia; DTI; FA; middle longitudinal fascicle; disorganization; attention deficit
Schizophrenia is a heterogeneous disorder that may consist of multiple etiologies and disease processes. Auditory hallucinations (AH), which are common and often disabling, represent a narrower and more basic dimension of psychosis than schizophrenia. Previous studies suggest that abnormal primary auditory cortex activity is associated with AH pathogenesis. We thus investigated functional connectivity, using a seed in primary auditory cortex, in schizophrenia patients with and without AH and healthy controls, to examine neural circuit abnormalities associated more specifically with AH than the myriad other symptoms that comprise schizophrenia.
Using resting-state fMRI (rsfMRI), we investigated functional connectivity of the primary auditory cortex, located on Heschl’s gyrus, in schizophrenia spectrum patients with AH. Participants were patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder with lifetime AH (n=27); patients with the same diagnoses but no lifetime AH (n=14); and healthy controls (n=28).
Patients with AH vulnerability showed increased left Heschl’s gyrus functional connectivity with left frontoparietal regions and decreased functional connectivity with right hippocampal formation and mediodorsal thalamus compared to patients without lifetime AH. Furthermore, among AH patients, left Heschl’s gyrus functional connectivity covaried positively with AH severity in left inferior frontal gyrus (Broca’s area), left lateral STG, right pre- and postcentral gyri, cingulate cortex, and orbitofrontal cortex. There were no differences between patients with and without lifetime AH in right Heschl’s gyrus seeded functional connectivity.
Abnormal interactions between left Heschl’s gyrus and regions involved in speech/language, memory, and the monitoring of self-generated events may contribute to AH vulnerability.
psychosis; resting-state fMRI; Broca’s area; hippocampus; mediodorsal thalamus; cingulate cortex
Antipsychotic agents; schizophrenia; metabolic screening; psychiatry
Smell identification deficits (SID) are common in adult schizophrenia, where they are associated with negative symptoms and lower intelligence. However, smell identification has not been examined in adolescents with early onset psychosis, wherein diagnosis is often obscure, and there are few prognostic predictors.
We examined smell identification, diagnosis, neuropsychological performance and symptoms in 26 well characterized adolescents with early onset psychosis, age 11–17 years.
SID existed in the sample and were more common in patients with schizophrenia and psychotic depression than in patients with psychosis NOS and bipolar disorder. As in adults, SID were significantly associated with greater negative symptoms and lower verbal IQ. However, the associations of verbal IQ (and other verbal tasks) to smell identification in this pediatric sample were explained by the relation of both of these types of variables to negative symptoms.
SID existed across this sample of youths with psychotic disorder, and were specifically related to typical characteristics of schizophrenia, such as negative symptoms and lower intelligence, but not to features of bipolar disorder, such as grandiosity. SID is a characteristic of early onset psychosis that may be useful for prognostic purposes.
Olfaction; Psychosis; Negative symptoms; Cognition; Schizophrenia and children
Characterizing working memory (WM) abnormalities represents a fundamental challenge in schizophrenia research given the impact of cognitive deficits on life outcome in patients. In prior work we demonstrated that dorsolateral prefrontal cortex (DLPFC) activation was related to successful distracter resistance during WM in healthy controls, but not in schizophrenia. Although understanding the impact of regional functional deficits is critical, functional connectivity abnormalities among nodes within WM networks may constitute a final common pathway for WM impairment. Therefore, this study tested the hypothesis that schizophrenia is associated with functional connectivity abnormalities within DLPFC networks during distraction conditions in WM. 28 patients and 24 controls completed a delayed non-verbal WM task that included transient visual distraction during the WM maintenance phase. We computed DLPFC whole-brain task-based functional connectivity (tb-fcMRI) specifically during the maintenance phase in the presence or absence of distraction. Results revealed that patients failed to modulate tb-fcMRI during distracter presentation in both cortical and sub-cortical regions. Specifically, controls demonstrated reductions in tb-fcMRI between DLPFC and the extended amygdala when distraction was present. Conversely, patients failed to demonstrate a change in coupling with the amygdala, but showed greater connectivity with medio-dorsal thalamus. While controls showed more positive coupling between DLPFC and other prefrontal cortical regions during distracter presentation, patients failed to exhibit such a modulation. Taken together, these findings support the notion that observed distracter resistance deficit involves a breakdown in coupling between DLPFC and distributed regions, encompassing both subcortical (thalamic/limbic) and control region connectivity.
Schizophrenia; DLPFC; amygdala; thalamus; fMRI; Functional connectivity; Working memory; Distraction
The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012.and this year had as its emphasis, “The Globalization of Research”. Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.
schizophrenia; genetics; gene-environment interaction; brain imaging; treatment; conference
Verbal dichotic listening performance was examined in 42 right-handed men and women with DSM-IV-defined schizotypal personality disorder (SPD) and 68 right-handed controls. As expected, both male and female control groups showed a right ear advantage on a verbal dichotic listening task. Although SPD subjects in general had lower accuracy scores than comparison subjects, only male SPD subjects showed an abnormal left ear advantage that was specifically due to deficient right ear performance. The results suggest that left hemisphere temporal lobe structures may be particularly involved in male, but not female, SPD.
schizotypal personality disorder; dichotic listening; perceptual asymmetry; neuropsychological dysfunction; gender differences
Altered brain connectivity has emerged as a central feature of schizophrenia. Low frequency oscillations and connectivity strength (CS) of resting state brain networks are altered in patients with schizophrenia (SZs). However, the relationship between these two measures has not yet been studied. Such work may be helpful in understanding the so-called “rich club” organization (i.e. high-CS nodes are more densely connected among themselves than are nodes of a lower CS in the human brain) in healthy controls (HCs) and SZs. Here we present a study of HCs and SZs examining low frequency oscillations and CS by first decomposing resting state fMRI (R-fMRI) data into independent components (ICs) using group independent component analysis (ICA) and computing the low frequency power ratio (LFPR) of each ICA time course. Weighted brain graphs consisting of ICs were built based on correlations between ICA time courses. Positive CS and negative CS of each node in the brain graphs were then examined. The correlations between LFPR and CSs as well as “rich club” coefficients of group mean brain graphs were assessed. Results demonstrate that the LFPR of some ICs were lower in SZs compared to HCs. In addition, LFPR was correlated with positive CS in HCs, but to a lesser extent in SZs. HCs showed higher normalized rich club parameter than SZs. The findings provide new insight into disordered intrinsic brain graphs in schizophrenia.
Low frequency; Connectivity strength; Rich club; R-fMRI; Schizophrenia; Brain graph
White matter alterations in schizophrenia are associated with deficits in neurocognitive performance. Recently, across task within-individual variability (WIV) has emerged as a useful construct for assessing the profile in cognitive performance in schizophrenia. However, the neural basis of WIV has not been studied in patients with schizophrenia.
Twenty-five patients with schizophrenia (SZ) and 27 healthy comparison subjects (HC) performed a computerized neurocognitive battery (CNB) and underwent diffusion tensor imaging (DTI). WIV for performance accuracy and speed on the CNB was calculated across-tasks. Voxel-wise group comparisons of white matter fractional anisotropy (FA) were performed using tract-based spatial statistics (TBSS). The relationship between accuracy and speed WIV on the CNB and white matter FA was examined within the regions that differentiated patients and healthy comparison subjects.
SZ had higher WIV for performance accuracy and speed as compared to HC. FA in SZ compared to HC was reduced in bilateral frontal, temporal and occipital white matter including a large portion of the corpus callosum. In white matter regions that differed between patients and comparison subjects, higher FA in the left cingulum bundle and left fronto-occipital fasciculus were associated with lower CNB speed WIV for HC, but not SZ. Accuracy WIV was not associated with differences in white matter FA between SZ and HC.
We provide evidence that WIV is greater in patients with SZ and that this greater within-individual variability in performance in patients is associated with disruptions of WM integrity in specific brain regions.
diffusion tensor imaging; intraindividual variability; cognition; white matter
Patients with schizophrenia may have altered pain perception, as suggested by clinical reports of pain insensitivity, and recent neuroimaging findings. Here, we examined neural responses to an aversive electrical stimulus and the immediate anticipation of such a stimulus using fMRI and a classical conditioning paradigm, which involved pairing an electrical shock with a neutral photograph. Fifteen men with schizophrenia and 13 healthy men, matched for demographic characteristics, electrical stimulation level and scan movement, were studied. The shock induced robust responses in midbrain, thalamus, cingulate gyrus, insula and somatosensory cortex in both groups. However, compared to controls, the schizophrenic patients displayed significantly lower activation of the middle insula (pFWE = 0.002, T=5.72, cluster size =24 voxels). Moreover, the lack of insula reactivity in the schizophrenia group was predicted by the magnitude of positive symptoms (r = −0.46, p=0.04). In contrast, there were no significant differences between the two groups in the magnitude of neural responses during anticipation of the shock. These findings provide support for the existence of a basic deficit in interoceptive perception in schizophrenia, which could play a role in the generation and/or maintenance of psychotic states.
Classical Conditioning; Unconditioned Response; Pain; Insula
Childhood trauma is associated with smaller gray matter volume, similar to the pattern seen in psychotic disorders. We explored the relationship between childhood abuse, psychosis, and brain volume in a group of 60 individuals with a psychotic disorder and 26 healthy control subjects. We used voxel-based morphometry (VBM) to quantify gray and white matter volume and the Childhood Trauma Questionnaire (CTQ) to measure childhood abuse. Within the psychotic disorders group, total gray matter volume was inversely correlated with the severity of childhood sexual abuse (r=−.34, p=.008), but not other types of abuse. When the 24 patients with sexual abuse were compared with demographically matched samples of 23 patients without sexual abuse and 26 control subjects, only patients with a history of sexual abuse had reduced total gray matter volume (t(48) = 2.3, p = .03; Cohen’s d = .63). Voxel-based analysis revealed a cluster in the prefrontal cortex where volume was negatively correlated with sexual abuse severity. Voxel based comparison of the three matched groups revealed a similar pattern of results, with widespread reductions in psychosis patients with sexual abuse relative to controls that were not found in psychosis patients without sexual abuse. These findings indicate that some of the variance of gray matter volume in psychotic disorders can be explained by a history of sexual abuse.
Childhood trauma; psychotic disorders; risk factors; gray matter; brain volume; Voxel-based morphometry; sexual abuse
Heterogeneity in clinical outcomes may be caused by factors working at multiple levels, e.g., between groups, between subjects, or within subjects over time. A more nuanced assessment of differences in variation among schizophrenia patients and between patients and healthy comparison subjects can clarify etiology and even facilitate the identification of patient subtypes with common neuropathology and clinical course.
We compared trajectories (mean duration 3.5 years) of cognitive impairments in a sample of 201 community-dwelling schizophrenia (SCZ) patients (aged 40–100 years) with 67 healthy comparison (HC) subjects. We employed growth mixture models to discover subclasses with more homogenous between-subject variation in cognitive trajectories. Post hoc analyses determined factors associated with class membership and class-specific correlates of cognitive trajectories.
Three latent classes were indicated: Class 1 (85% HC and 50% SCZ) exhibited relatively high and stable trajectories of cognition, Class 2 (15% HC and 40% SCZ) exhibited lower, modestly declining trajectories, and Class 3 (10% SCZ) exhibited lower, more rapidly declining trajectories. Within the patient group, membership in Classes 2–3 was associated with worse negative symptoms and living in a board and care facility.
These results bridge the gap between schizophrenia studies demonstrating cognitive decline and those demonstrating stability. Moreover, a finer-grained characterization of heterogeneity in cognitive trajectories has practical implications for interventions and for case management of patients who show accelerated cognitive decline. Such a characterization requires study designs and analyses sensitive to between- and within-patient heterogeneity in outcomes.
Late-Life Schizophrenia; Cognition; Trajectories; Heterogeneity; Growth Mixture Models
As researchers continue to understand non-clinical psychosis (NCP- brief psychotic-like experiences occurring in 5–7% of the general population; van Os et al., 2009), it is becoming evident that functioning deficits and facial emotion recognition (FER) impairment characterize this phenomenon. However, the extent to which these domains are related remains unclear. Social/role functioning and FER were assessed in 65 adolescents/young adults exhibiting Low and High-NCP. Results indicate that FER and social/role functioning deficits were present in the High-NCP group, and that the domains were associated in this group alone. Taken together, findings suggest that a core emotive deficit is tied to broader social/role dysfunction in NCP.
Social Functioning; Role Functioning; Emotion Recognition; Non-clinical Psychosis
To (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.
The 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.
Primary 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.
Striatal 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.
Schizotypal personality disorder; Putamen; Caudate; Striatum; Schizophrenia; MRI; Striatal size
Little is known about associations between the social environment and risk for psychosis within rural settings. This study sought to investigate whether such associations exist within a rural context using a prospective dataset of unusual epidemiological completeness.
Using the Cavan–Monaghan First Episode Psychosis Study database of people aged 16 years and older, both ecological analyses and multilevel modelling were applied to investigate associations between incidence of psychosis by place at onset and socio-environmental risk factors of material deprivation, social fragmentation and urban–rural classification across electoral divisions.
The primary finding was an association between more deprived social contexts and higher rates of psychotic disorder, after adjustment for age and sex [all psychoses: incidence rate ratio (IRR) = 1.12, 95% CI (1.03–1.23)].
These findings support an association between adverse socio-environmental factors and increase in risk for psychosis by place at onset within a predominantly rural environment. This study suggests that social environmental characteristics may have an impact on risk across the urban–rural gradient.
First episode psychosis; Place at onset; Rurality; Environmental factors; Social context
International studies indicate that the median prevalence of psychotic experiences in children is 7%. It has been proposed that environmental stress during pregnancy may affect the neurodevelopment of the foetus and lead to a vulnerability in the child to later stressors and psychopathology.
In this study we explore the relationship between environmental stress during pregnancy and psychotic experiences in children in the general population at 12 years.
We analysed a birth cohort of 5038 children from the Avon Longitudinal Study of Parents and Children. Environmental stress was measured as life event exposure. Data on life events were collected on women during their pregnancy, whilst psychotic experiences in the offspring were assessed at age 12.
There was a weak association between maternal exposure to life events and psychotic experiences at twelve years (crude OR 1.10 95% CI 1.02–1.18) per quartile of life event score. This association was not reduced after adjustment for socio-economic status, family history of schizophrenia, maternal education or birth weight but after adjustment for maternal anxiety and depression and smoking in early pregnancy there was no longer any evidence for an association (OR 1.01 95% CI 0.93–1.10).
This study provides some evidence to suggest that stressful life events may affect child psychotic experiences through effects on maternal psychopathology, and possibly physiology, during pregnancy.
HPA, hypothalamic–pituitary–adrenal axis; Psychosis; Schizophrenia; Life events; HPA axis; Perinatal psychiatry; Child psychiatry; ALSPAC
Schizophrenia is associated with atopy and increased inflammatory markers. We report a population-based longitudinal study of the associations between childhood atopic disorders, subsequent serum inflammatory markers, interleukin 6 (IL-6) and C-reactive protein (CRP), and the risk of psychotic experiences (PEs).
PEs were assessed at age 13 years (n = 6785). Presence of clinician-diagnosed atopic disorders (asthma and eczema) was determined from parent-completed questionnaires at age 10 years (n = 7814). Serum IL-6 and CRP were measured at age 9 years (n = 5076). Logistic regression examined the association between (1) atopy and PEs, (2) inflammatory markers and PEs, and (3) mediating effects of inflammatory markers on the atopy–PEs association. Linear regression examined the association between atopy and inflammatory markers. Age, gender, social class, ethnicity and body mass index were included as potential confounders.
At age 10 years, about 14% of the sample was reported to have asthma, 12% eczema, and 7% both asthma and eczema. Compared with children with no atopy, risk of PEs at age 13 years was increased for all of these groups; adjusted odds ratios (95% CI) were, respectively, 1.39 (1.10–1.77), 1.33 (1.04–1.69), and 1.44 (1.06–1.94). Atopy was associated with increased serum IL-6 and CRP; however, this did not mediate association between atopy and PEs. Inflammatory markers were not associated with later PEs.
Childhood atopic disorders increase the risk of psychotic experiences in adolescence. Follow-up of these individuals will be useful to determine the effect of atopy and inflammation on different trajectories of early-life PEs.
PEs, psychotic experiences; IL-6, interleukin 6; CRP, C-reactive protein; OR, odds ratio, 95%; CI, 95% confidence interval; Atopic disorders; Asthma; Eczema; Childhood; Adolescence; Psychotic experiences; Psychotic symptoms; Schizophrenia; Inflammatory markers; IL-6; CRP; Cytokine; Immunity; Birth cohort; Prospective study; ALSPAC
Poor insight in schizophrenia has been theorised to reflect a cognitive deficit that is secondary to brain abnormalities, localized in the brain regions that are implicated in higher order cognitive functions, including working memory (WM). This study investigated WM-related neural substrates of preserved and poor insight in schizophrenia.
Forty stable schizophrenia outpatients, 20 with preserved and 20 with poor insight (usable data obtained from 18 preserved and 14 poor insight patients), and 20 healthy participants underwent functional magnetic resonance imaging (fMRI) during a parametric ‘n-back’ task. The three groups were preselected to match on age, education and predicted IQ, and the two patient groups to have distinct insight levels. Performance and fMRI data were analysed to determine how groups of patients with preserved and poor insight differed from each other, and from healthy participants.
Poor insight patients showed lower performance accuracy, relative to healthy participants (p = 0.01) and preserved insight patients (p = 0.08); the two patient groups were comparable on symptoms and medication. Preserved insight patients, relative to poor insight patients, showed greater activity most consistently in the precuneus and cerebellum (both bilateral) during WM; they also showed greater activity than healthy participants in the inferior–superior frontal gyrus and cerebellum (bilateral). Group differences in brain activity did not co-vary significantly with performance accuracy.
The precuneus and cerebellum function contribute to preserved insight in schizophrenia. Preserved insight as well as normal-range WM capacity in schizophrenia sub-groups may be achieved via compensatory neural activity in the frontal cortex and cerebellum.
Psychosis; fMRI; Working memory capacity; Cerebellum; Precuneus; Frontal cortex