Temporolimbic volume reductions in schizophrenia

BACKGROUND: Neuroanatomic studies of schizophrenia have reported temporolimbic abnormalities. Most magnetic resonance imaging studies have evaluated small samples of primarily men with chronic schizophrenia. Our goal was to evaluate sex differences in segmented temporal lobe subregions with reliable parcellation methods, relating volume with clinical and neurocognitive parameters. METHODS: Magnetic resonance imaging was performed in 100 patients with schizophrenia (58 men, 42 women; 39 neuroleptic naive, 61 previously treated) and 110 healthy controls (51 men, 59 women). Gray and white matter volumes of temporolimbic (hippocampus and amygdala) and neocortical regions (superior temporal gyrus and temporal pole) were examined. Symptoms, functioning, and neurocognition were assessed concurrently. RESULTS: Hippocampal gray matter volume was reduced in men (7%) and women (8.5%) with schizophrenia. In the amygdala, however, decreased volume was evident for men (8%) whereas women (10.5%) had increased volume. Magnetic resonance imaging of the temporal pole showed decreased gray matter in men (10%) and women (8.5%). For the superior temporal gyrus, the decrease exceeded that of whole-brain only in men (11.5%). Volumes were largely uncorrelated with clinical measures, but higher hippocampal volumes were associated with better memory performance for all groups. Cortical volumes were associated with better memory performance in healthy women. CONCLUSIONS: Schizophrenia is associated with reduced gray matter volume in temporolimbic structures. In men, reduction was manifested in all regions, whereas women showed decreased hippocampal volumes but increased amygdala volumes. The abnormalities are evident in patients with first-episode schizophrenia and correlate more strongly with cognitive performance than with symptom severity.     

Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia

BACKGROUND: Converging neuroanatomic, neurophysiological, and neurobehavioral evidence implicate prefrontal subregions in schizophrenia. Neuroanatomic studies with magnetic resonance (MR) imaging enable regional volume parcellation. Inconsistent reports may relate to variable methods and small samples. We attempted to resolve volume differences within sectors of the prefrontal lobe in a large sample, relating volumes to clinical and neurocognitive features. METHODS: Magnetic resonance imaging was performed in 70 patients with schizophrenia (40 men and 30 women; 29 neuroleptic naive and 41 previously treated) and 81 healthy controls (34 men and 47 women). Gray and white matter volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were quantified. Symptoms, functioning, and neurocognition were assessed concurrently. RESULTS: Reduced prefrontal gray matter volume was observed in patients. The reduction was evident for the dorsolateral area in men (9%) and women (11%), for the dorsomedial area only in men (9%), and for orbital regions only in women (23% and 10% for lateral and medial, respectively). The reduction of orbital volume in women was associated with poorer premorbid functioning, more severe negative symptoms, and depression. Volume of dorsal cortex was positively associated with better performance on abstraction and attention tasks across all groups. CONCLUSIONS: Schizophrenia is associated with reduced gray matter volume in prefrontal cortex, which affects men and women in the dorsolateral sector. The effects are moderated by sex for dorsomedial and orbital regions and are related to symptom severity and cognitive function. This is not a by-product of treatment, since the differences are evident in neuroleptic-naive patients.     

Gender differences in the relationship of homelessness to symptom severity, substance abuse, and neuroleptic noncompliance in schizophrenia

This study examined gender differences in the relationship of homelessness in schizophrenia to symptom severity, risk behaviors, and prognostic features. Four hundred subjects with schizophrenia were studied: 100 homeless men, 100 homeless women, 100 never homeless men, and 100 never homeless women. Assessments included derivation of five symptom factors by using the Positive and Negative Syndrome Scale (PANSS). Homelessness for the entire sample was associated with greater severity of positive, activation, and autistic preoccupation symptoms, younger age at first hospitalization, and substance abuse (SA). For men only, homelessness was associated with neuroleptic noncompliance (NN). When NN and SA were statistically controlled, symptom severity was not different between the homeless and never homeless. Women, independent of residential status, had more severe negative, activation, and autistic preoccupation symptoms that were not associated with prognostic features or risk behaviors. For both men and women, SA was associated with homelessness, but independent of residence, SA was less severe in women. Additionally, SA was less severe in homeless women than never homeless men. Thus, symptom severity in homeless individuals with schizophrenia appears as an interaction of symptom profiles and risk behaviors that are gender specific. Although cross-sectional analyses cannot distinguish cause from effect, these findings suggest gender-specific routes to homelessness among indigent urban adults with schizophrenia.     

Sexually dimorphic changes in the amygdala in relation to delusional beliefs in first episode psychosis

BACKGROUND: Few attempts have been made to examine the relationship between amygdala abnormalities and specific symptoms in psychosis. The present study explored the relationship between amygdala morphology and mood congruent and mood incongruent delusional beliefs. METHODS: Amygdala volumes were measured in 43 patients presenting with delusional beliefs in the context of their first episode of psychosis and 43 healthy volunteers matched for age and gender. RESULTS: Left-greater-than-right-asymmetry of the amygdala varied as a function of gender and mood congruence of delusional beliefs, due to asymmetrical enlargement of the left amygdala in women presenting with predominantly mood incongruent delusions. However, there was no difference in amygdala volumes across groups. CONCLUSIONS: Amygdala abnormalities in women may be associated with aberrant emotional processing that could contribute to the development of mood incongruent delusional beliefs. Sexually dimorphic changes in the amygdala may contribute to differential phenotypic illness expression in men and women.     

Influence of ZNF804a on Brain Structure Volumes and Symptom Severity in Individuals With Schizophrenia

CONTEXT The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. OBJECTIVE To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. DESIGN Case-control analysis of covariance. SETTING University-based research hospital. PARTICIPANTS Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. MAIN OUTCOME MEASURES Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. RESULTS The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F =?3.98, P?=?.02; F =?4.95, P?=?.007; and F =?3.08, P?=?.05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F =?3.93, P?=?.02) and frontal WM volumes (F =?7.16, P?<?.001) and on psychotic symptom severity (F =?6.07, P?=?.003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F =?4.61, P?=?.03), replicating a previously reported association. CONCLUSIONS A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia.     

Reduced gray matter volume in schizophrenia.

BACKGROUND: There is emerging evidence that gray matter (GM) is reduced in patients with schizophrenia. Information on the extent of global differences in the 3 principal supertentorial compartments is necessary for interpretation of regional effects. The relation of GM reduction to clinical status and neurocognition also requires examination. METHODS: Magnetic resonance imaging, neurocognitive measures, and clinical assessment of symptoms and functioning were obtained for 130 patients (51 neuroleptic naive, 79 previously treated) and 130 healthy controls (75 men, 55 women in each group). RESULTS: Overall GM volume was reduced in patients compared with controls. This was evident in men (6% reduction) and women (2% reduction) and was already evident at the first presentation of neuroleptic-naive patients. The reduction sustained correction for age and total intracranial volume. Compartmental volumes did not correlate with the severity of positive (r, -0.08 to 0.23) or negative (r, -0.01 to -0.07) symptoms, but GM volume was associated with better premorbid functioning in women (r, 0.36-0.51). Small but significant correlations (r, 0.19-0.44) were observed between GM volume and performance in 6 neurocognitive domains. These correlations varied by diagnosis, most higher in patients, and were moderated by sex. CONCLUSIONS: Gray matter volume reduction in schizophrenia is already evident in men and women at first presentation. While this reduction is not correlated with symptom severity, it is associated with cognitive performance. Since GM development accelerates in the later part of gestation, while white matter growth is primarily postnatal, the results may support the hypothesis that neurodevelopmental processes relate to GM deficit.     

Amygdala Connectivity Differs Among Chronic,Early Course,and Individuals at Risk for Developing Schizophrenia

Alterations in circuits involving the amygdala have been repeatedly implicated in schizophrenia neuropathology, given their role in stress, affective salience processing, and psychosis onset. Disturbances in amygdala whole-brain functional connectivity associated with schizophrenia have yet to be fully characterized despite their importance in psychosis. Moreover, it remains unknown if there are functional alterations in amygdala circuits across illness phases. To evaluate this possibility, we compared whole-brain amygdala connectivity in healthy comparison subjects (HCS), individuals at high risk (HR) for schizophrenia, individuals in the early course of schizophrenia (EC-SCZ), and patients with chronic schizophrenia (C-SCZ). We computed whole-brain resting-state connectivity using functional magnetic resonance imaging at 3T via anatomically defined individual-specific amygdala seeds. We identified significant alterations in amygdala connectivity with orbitofrontal cortex (OFC), driven by reductions in EC-SCZ and C-SCZ (effect sizes of 1.0 and 0.97, respectively), but not in HR for schizophrenia, relative to HCS. Reduced amygdala-OFC coupling was associated with schizophrenia symptom severity (r = .32, P < .015). Conversely, we identified a robust increase in amygdala connectivity with a brainstem region around noradrenergic arousal nuclei, particularly for HR individuals relative to HCS (effect size = 1.54), but not as prominently for other clinical groups. These results suggest that deficits in amygdala-OFC coupling could emerge during the initial episode of schizophrenia (EC-SCZ) and may present as an enduring feature of the illness (C-SCZ) in association with symptom severity but are not present in individuals with elevated risk for developing schizophrenia. Instead, in HR individuals, there appears to be increased connectivity in a circuit implicated in stress response.Key words: schizophrenia, prefrontal cortex, amygdala, connectivity, first episode, risk for schizophrenia     

Kinematic analysis of facial behaviour in patients with schizophrenia under emotional stimulation by films with “Mr. Bean”

In schizophrenic patients, motor functioning is substantially disturbed. Kinematic analysis is useful in examining this motor dysfunction. Using kinematic analysis, we aimed to investigate facial movement in schizophrenic patients responding to humorous film stimuli (“Mr. Bean”). Ultrasound markers were attached to pre-defined facial points while subjects watched a funny film sketch. The study included 21 schizophrenic in-patients (13 men, 8 women; mean (S.D.) age: 32.1 (10.4) years) and 30 healthy individuals (12 men, 18 women; mean (S.D.) age: 35.7 (11.0) years). Unmedicated schizophrenic patients showed an abnormally high initial velocity of laughing (IV), while patients treated with typical neuroleptics demonstrated an abnormally low IV. There was a significant positive correlation between severity of negative symptoms and IV. Kinematical analysis of facial movement using IV could help to distinguish subclinical Parkinsonian syndromes induced by typical neuroleptics from negative symptoms of schizophrenia.     

The amygdala and schizophrenia: a volumetric magnetic resonance imaging study in first-episode, neuroleptic-naive patients.

BACKGROUND: The attempts to evaluate amygdaloid volumes using magnetic resonance imaging (MRI) in patients with schizophrenia have yielded highly divergent results. METHODS: Volumes of the amygdala were measured in 22 healthy participants and 18 neuroleptic-naive patients with first-episode schizophrenia, while controlling for intracranial area, gender, age, and handedness. RESULTS: Persons with schizophrenia presented significantly lower amygdaloid volumes bilaterally. No significant correlations were found between the amygdaloid volumes and either the duration of the disease or the symptom severity. CONCLUSIONS:Amygdaloid volume anomalies are already present in the early phases of schizophrenia.     

Hippocampal and amygdalar volume changes in elderly patients with Alzheimer's disease and schizophrenia

Patients with Alzheimer's disease (AD) and schizophrenia display cognitive, behavioural disturbances and morphological abnormalities. Although these latter reflect progressive neurodegeneration in AD, their significance in schizophrenia is still unclear. We explored the patterns of hippocampal and amygdalar atrophy in those patients and their associations with clinical parameters. Structural magnetic resonance imaging was performed in 20 elderly schizophrenia patients, 20 AD and 19 healthy older controls. Hippocampal and amygdalar volumes were obtained by manual segmentation with a standardized protocol and compared among groups. In both schizophrenia and AD patients, left hippocampal and amygdalar volumes were significantly smaller. The hippocampus/amygdala ratio was significantly lower in schizophrenia compared to both AD cases [2.4 bilaterally, 95% C.I. 2.2 to 2.7] and healthy controls bilaterally [2.5, 95% C.I. 2.3 to 2.9 in left and 2.7, 95% C.I. 2.4 to 3.1 in right hemisphere]. In schizophrenia patients, a significant positive correlation was found between age at disease onset and the right hippocampus/amygdala volume ratio (Spearman rho=0.56). Negative symptoms correlated with higher right/left amygdala volume ratio (Spearman's rho=0.43). Our data show that unlike AD, the hippocampus/amygdala ratio is abnormally low and correlates with the age at onset in schizophrenia, being a neurodevelopmental signature of the disease.     

Cerebellar posterior superior vermis and cognitive cluster scores in drug-naive patients with first-episode schizophrenia

Previously, we performed an MRI study that revealed smaller volumes of the subregions of the cerebellar vermis in men and women with chronic schizophrenia. An issue that arose from that study was whether similar structural changes in the cerebellum are found in patients with first-episode schizophrenia. In the present study, MRI scans were acquired from 14 drug-naive patients with first-episode schizophrenia and 16 healthy subjects, and used to measure the volumes of their cerebellar subregions. Positive symptom, negative symptom and cognitive cluster scores were attained using the Positive and Negative Syndrome Scale. Patients with first-episode schizophrenia had reduced volumes of the anterior vermis and posterior superior vermis compared with healthy subjects. We confirmed that there was a volume reduction of the cerebellar vermis in drug-naive patients with first-episode schizophrenia. Smaller volumes of the posterior superior vermis were associated with worse cognitive cluster scores in patients with first-episode schizophrenia.     

Cerebellar dysfunction in neuroleptic naive schizophrenia patients: clinical, cognitive, and neuroanatomic correlates of cerebellar neurologic signs.

BACKGROUND: There is increasing evidence that, aside from motor coordination, the cerebellum also plays an important role in cognition and psychiatric disorders. Our previous studies support the hypothesis that cerebellar dysfunction may disrupt the cortico-cerebellar-thalamic-cortical circuit and, in turn, lead to cognitive dysmetria in schizophrenia. The goal of this study was to investigate cerebellar dysfunction in schizophrenia by examining the clinical, cognitive, and neuroanatomic correlates of cerebellar neurologic signs in schizophrenia patients. METHODS: We compared the prevalence of cerebellar neurologic signs in 155 neuroleptic-naive schizophrenia patients against 155 age- and gender-matched healthy control subjects. Differences in clinical characteristics, standardized neuropsychologic performance, and magnetic resonance imaging brain volumes between patients with and without cerebellar signs were also examined. RESULTS: Patients had significantly higher rates of cerebellar signs than control subjects, with coordination of gait and stance being the most common abnormalities. Patients with lifetime alcohol abuse or dependence were no more likely than those without alcoholism to have cerebellar signs. Presence of cerebellar signs in patients was associated with poorer premorbid adjustment, more severe negative symptoms, poorer cognitive performance, and smaller cerebellar tissue volumes. CONCLUSIONS: These findings lend further support for cerebellar dysfunction in schizophrenia.     

Hippocampal and amygdalar volume changes in elderly patients with Alzheimer's disease and schizophrenia

Patients with Alzheimer's disease (AD) and schizophrenia display cognitive, behavioural disturbances and morphological abnormalities. Although these latter reflect progressive neurodegeneration in AD, their significance in schizophrenia is still unclear. We explored the patterns of hippocampal and amygdalar atrophy in those patients and their associations with clinical parameters. Structural magnetic resonance imaging was performed in 20 elderly schizophrenia patients, 20 AD and 19 healthy older controls. Hippocampal and amygdalar volumes were obtained by manual segmentation with a standardized protocol and compared among groups. In both schizophrenia and AD patients, left hippocampal and amygdalar volumes were significantly smaller. The hippocampus/amygdala ratio was significantly lower in schizophrenia compared to both AD cases [2.4 bilaterally, 95% C.I. 2.2 to 2.7] and healthy controls bilaterally [2.5, 95% C.I. 2.3 to 2.9 in left and 2.7, 95% C.I. 2.4 to 3.1 in right hemisphere]. In schizophrenia patients, a significant positive correlation was found between age at disease onset and the right hippocampus/amygdala volume ratio (Spearman rho = 0.56). Negative symptoms correlated with higher right/left amygdala volume ratio (Spearman's rho = 0.43). Our data show that unlike AD, the hippocampus/amygdala ratio is abnormally low and correlates with the age at onset in schizophrenia, being a neurodevelopmental signature of the disease.     

Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology.

The hippocampus and amygdala are believed to be involved in the pathology of schizophrenia. In this study, we attempted to replicate the reported bilateral volume reduction of the hippocampus and amygdala and to study the relationship of the volumes of these structures to the symptoms of schizophrenia. The hippocampus-amygdala complex (HAC) was manually traced on 3-mm coronal T(1)-weighted MRIs, resampled into 1-mm coronal slices, from 20 male patients with schizophrenia and 20 age-matched male controls. The complex was divided into three parts: anterior one-third representing the amygdala and middle and posterior thirds representing the anterior and posterior halves of the hippocampus. Positive and negative symptoms and severity of hallucinations and thought disorder (conceptual disorganization) were quantified using the Brief Psychiatric Rating Scale (BPRS). None of the above structures, controlled for brain volume, differed significantly in patients compared with normal controls. When the relationship between volumes and symptoms was examined, the left HAC was found to inversely correlate with thought disorder and negative symptoms. Specifically, significant inverse correlations were found between (i) left amygdala and thought disorder, (ii) left hippocampus and negative symptoms, and (iii) left anterior and posterior hippocampus volumes and positive and negative symptoms, respectively. Our findings further support the role of the HAC in the pathophysiology of schizophrenia and suggest unique associations between individual structures and specific symptoms of the illness.     

Reversed cerebellar asymmetry in men with first-episode schizophrenia.

BACKGROUND: Abnormalities in cerebellar structure and function have been implicated in the pathophysiology of schizophrenia. In this study, we investigated whether patients experiencing first-episode schizophrenia differed from healthy comparison subjects in regional cerebellar volumes or cerebellar asymmetry. METHODS: Volumes of four cerebellar regions (right, left; anterior, posterior) were measured from contiguous coronal magnetic resonance (MR) images in 69 (37 men, 32 women) patients experiencing first-episode schizophrenia and in 49 (27 men, 22 women) healthy comparison subjects. Patients were rated on the Scale for the Assessment of Negative Symptoms and the Schedule for Affective Disorders and Schizophrenia-Psychosis/Disorganization before the initiation of antipsychotic medication and at the time of the MR imaging exam. RESULTS: Patients and healthy comparison subjects did not differ in regional cerebellar volumes, but male patients demonstrated significantly reversed anterior and posterior asymmetry compared with healthy male subjects. Among male patients, greater reversals in a composite measure of cerebellar asymmetry (i.e., torque) correlated significantly with increased negative symptoms before the initiation of antipsychotic medication. CONCLUSIONS: These findings implicate an aberrant neurodevelopmental process involving the metencephalon in the pathophysiology of schizophrenia and are consistent with prior studies implicating abnormal asymmetry in schizophrenia at the neocortical level.     

Gender differences in the clinical expression of schizophrenia.

Gender differences have been reported for a variety of clinical measures in patients with schizophrenia. Clinical characterization may be helpful in identifying symptom clusters which can then be linked to underlying brain function. In this study 74 men and 33 women meeting DSM-IIIR criteria for schizophrenia were studied off medication and rated on measures of symptom type and severity, as well as premorbid and current function. Men were more severely impaired in ratings of negative symptoms, while positive symptoms were not significantly different. There were also differences in premorbid and current functioning, with women manifesting better social functioning than men.     

Gender differences in the incidence of definite schizophrenia and atypical psychosis--focus on negative symptoms of schizophrenia.

In a catchment area study of 101 first inceptions of schizophrenia, mania and atypical psychoses, women were significantly more likely to have atypical psychosis and men were more likely to have definite schizophrenia. Negative symptoms such as affective flattening and poverty of speech were already present in many cases, and were significantly increased in patients with definite schizophrenia (geometric mean 5.6) compared with those with atypical psychosis (geometric mean 3.2) and mania (geometric mean 1.5). Negative symptoms were also twice as severe in men (geometric mean 5.5) than women (geometric mean 2.6). There was a significant increase in negative symptom severity with longer illness and greater depression, but the diagnosis and the sex effects were not caused by these factors. We suggest that our findings are further support for the hypothesis that men have a greater biological vulnerability to negative symptoms and consequent social disability in the face of psychosis, particularly a schizophrenic psychosis, and that this may be one explanation for the apparently greater risk of definite schizophrenia and its poorer prognosis in men.     

Structural evidence for involvement of a left amygdala-orbitofrontal network in subclinical anxiety

Functional neuroimaging implicates hyperactivity of amygdala-orbitofrontal circuitry as a common neurobiological mechanism underlying the development of anxiety. Less is known about anxiety-related structural differences in this network. In this study, a sample of healthy adults with no history of anxiety disorders completed a 3T MRI scan and self-report mood inventories. Post-processing quantitative MRI image analysis included segmentation and volume estimation of subcortical structures, which were regressed on anxiety inventory scores, with depression scores used to establish discriminant validity. We then used a quantitative vertex-based post-processing method to correlate (1) anxiety scores and (2) left amygdala volumes with cortical thickness across the whole cortical mantle. Left amygdala volumes predicted anxiety, with decreased amygdala volume associated with higher anxiety on both state and trait anxiety measures. A negative correlation between left amygdala volume and cortical thickness overlapped with a positive correlation between anxiety and cortical thickness in left lateral orbitofrontal cortex. These results suggest a structural anxiety network that corresponds with a large body of evidence from functional neuroimaging. Such findings raise the possibility that structural abnormalities may result in a greater vulnerability to anxiety or conversely that elevated anxiety symptoms may result in focal structural changes.     

An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia.

BACKGROUND: Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia. The specificity of this finding to schizophrenia remains to be determined. The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated. METHODS: Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging. Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups. Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained. RESULTS: Hippocampal volumes were significantly smaller in the schizophrenic group than in both bipolar and normal comparison subjects. Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects. CONCLUSIONS: The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders.