Regional thinning of the cerebral cortex in schizophrenia: effects of diagnosis, age and antipsychotic medication

Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies in schizophrenia. Uncertainty remains regarding cause, mechanism and progression of the alterations. It has been suggested that antipsychotic medication reduces total gray matter volumes, but results are inconsistent. In the present study differences in regional cortical thickness between 96 patients with a DSM-IV diagnosis of schizophrenia (n=81) or schizoaffective disorder (n=15) and 107 healthy subjects (mean age 42 years, range 17-57 years) were investigated using MRI and computer image analysis. Cortical thickness was estimated as the shortest distance between the gray/white matter border and the pial surface at numerous points across the entire cortical mantle. The influence of age and antipsychotic medication on variation in global and regional cortical thickness was explored. Thinner cortex among patients than controls was found in prefrontal and temporal regions of both hemispheres, while parietal and occipital regions were relatively spared. Some hemispheric specificity was noted, as regions of the prefrontal cortex were more affected in the right hemisphere, and regions of the temporal cortex in the left hemisphere. No significant interaction effect of age and diagnostic group on variation in cortical thickness was demonstrated. Among patients, dose or type of antipsychotic medication did not affect variation in cortical thickness. The results from this hitherto largest study on the topic show that prefrontal and temporal cortical thinning in patients with schizophrenia compared to controls is as pronounced in older as in younger subjects. The lack of significant influence from antipsychotic medication supports that regional cortical thinning is an inherent feature of the neurobiological disease process in schizophrenia.     

Age-related cortical thinning in schizophrenia

Although the effects of aging on the neural correlates of schizophrenia have been researched for many years, no clear conclusion has been reached. While some studies have demonstrated progressive age-related gray matter reductions in schizophrenia, other studies have not found evidence of progression. Moreover, it remains unclear whether the influence of aging on global or regional cortical thickness differs between schizophrenia patients and healthy controls. This study aimed to confirm previous reports of reduced cortical thickness in schizophrenia, and to investigate the effects of age on global and regional cortical thickness. Eighty-three patients with schizophrenia (six first-episode patients and 77 chronic patients; age range=18-55 years) and 90 age-, gender- and education-matched healthy controls (age range=19-56 years) underwent structural magnetic resonance imaging (MRI) using a 3-Tesla scanner. Surface-based analysis was applied to assess cortical thickness in the whole brain. The patient group exhibited both global and regional cortical thinning in regions including the prefrontal and temporal cortices. The correlation between age and cortical thickness showed a similar pattern in patients and controls, both globally and regionally. These results suggest that the reduction of cortical thickness in schizophrenia might not be progressive over the course of the illness, indicating that pathological processes occur in a relatively limited period of time around the onset of illness.     

Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia

BACKGROUND: Two brain regions often implicated in schizophrenia are the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF). It has been hypothesized that the pathophysiology of the disorder might involve an alteration of functional interactions between medial temporal and prefrontal areas. METHODS: We used neuroimaging data acquired during a working memory challenge and a sensorimotor control task in 22 medication-free schizophrenic patients and 22 performance-, age-, and sex-matched healthy subjects to investigate "functional connectivity" between HF and DLPFC in schizophrenia. The HF blood flow, measured with positron emission tomography, was assessed within a probabilistic template. Brain areas whose activity was positively or negatively coupled to HF were identified using voxelwise analysis of covariance throughout the entire brain and analyzed using a random effects model. RESULTS: During working memory, patients showed reduced activation of the right DLPFC and left cerebellum. In both groups, inverse correlations were observed between the HF and the contralateral DLPFC and inferior parietal lobule. While these did not differ between diagnostic groups during the control task, the working memory challenge revealed a specific abnormality in DLPFC-HF functional connectivity-while the right DLPFC was significantly coupled to the left HF in both groups during the control task, this correlation was not seen in healthy subjects during working memory but persisted undiminished in patients, resulting in a significant task-by-group interaction. CONCLUSIONS: Our results suggest a regionally specific alteration of HF-DLPFC functional connectivity in schizophrenia that manifests as an unmodulated persistence of an HF-DLPFC linkage during working memory activation. Thus, a mechanism by which HF dysfunction may manifest in schizophrenia is by inappropriate reciprocal modulatory interaction with the DLPFC.     

Magnetic resonance imaging abnormalities in lenticular nuclei and cerebral cortex in schizophrenia

Neuropathologic and brain imaging studies have produced evidence of brain abnormalities in schizophrenic patients, often within the cerebrum's limbic lobe, and, less frequently, within basal ganglia. In the present study we used magnetic resonance imaging morphometric techniques to estimate volumes of specific cerebral structures in schizophrenic patients and age- and sex-matched normal controls. Estimates of the volume of mesial temporal lobe structures were reduced and estimates of the volume of the lenticular nucleus were increased in the schizophrenic patients. There was also evidence of reduced cranial volume in some schizophrenics. The magnitude of the lenticular abnormality, but not the temporal lobe abnormality, was associated with age at first psychiatric contact; earlier onset was associated with larger lenticular nuclei. The possible relevance of these results to neurodevelopmental hypotheses about the pathogenesis of schizophrenia is discussed.     

Regionally diverse cortical pathology in schizophrenia: clues to the etiology of the disease

Perhaps the most surprising revelation that has emerged from recent pathologic studies of schizophrenia is the marked cortical regional heterogeneity of the disease. Areal specific alterations of many parameters have been reported (e.g., neuronal density, density of gamma-aminobutyric acid [GABA]-immunoreactive cells, and concentration of synapse-associated proteins and messenger ribonucleic acid [mRNA]s). In the past 5 years, as a flood of seemingly contradictory findings have been published, divergent findings often have been regarded as further evidence of the irreplicability and futility of postmortem studies. Although some discrepancies in findings may be due to methodological differences or to the study of different cohorts of patients, a growing number of laboratories are examining the same parameter(s) in multiple cortical areas in a single brain cohort and finding regionally specific abnormalities. These findings provide compelling evidence that cortical pathology in schizophrenia is nonuniform and complex. A major challenge in contemporary schizophrenia research is to make sense of the patterning of whole brain pathology in schizophrenia, as the mosaic of neuropathologic alterations may provide clues to the disease etiology.     

Regional cerebral cortical thinning in bipolar disorder

OBJECTIVE: This study was conducted to explore differences in cortical thickness between subjects with bipolar disorder and healthy comparison subjects using cortical surface-based analysis. METHODS: Brain magnetic resonance images were acquired from 25 subjects with bipolar disorder and 21 healthy comparison subjects. Cortical surface-based analysis was conducted using the Freesurfer application. Group differences in cortical thickness, defined by the distance from gray/white boundary to the pial surface, were assessed using statistical difference maps. RESULTS: Subjects with bipolar disorder exhibited significantly decreased cortical thickness in left cingulate cortex, left middle frontal cortex, left middle occipital cortex, right medial frontal cortex, right angular cortex, right fusiform cortex and bilateral postcentral cortices, relative to healthy comparison subjects (all p < 0.001). Duration of illness in bipolar subjects was inversely correlated with the cortical thickness of the left middle frontal cortex. CONCLUSIONS: Cortical thinning was present in multiple prefrontal cortices in bipolar disorder. There was also cortical thinning in sensory and sensory association cortices, which has not been reported in previous studies using region-of-interest or voxel-based morphometry methods. Cortical thinning observed in the current study may be related to impairment of emotional, cognitive, and sensory processing in bipolar disorder but longitudinal studies will be necessary to test this hypothesis.     

Regionally distinct processing of rewards and punishments by the primate ventromedial prefrontal cortex

The ventromedial prefrontal cortex (vmPFC) is thought to be related to emotional experience and to the processing of stimulus and action values. However, little is known about how single vmPFC neurons process the prediction and reception of rewards and punishments. We recorded from monkey vmPFC neurons in an experimental situation with alternating blocks, one in which rewards were delivered and one in which punishments were delivered. Many vmPFC neurons changed their activity between blocks. Importantly, neurons in ventral vmPFC were persistently more active in the appetitive "reward" block, whereas neurons in dorsal vmPFC were persistently more active in the aversive "punishment" block. Furthermore, within ventral vmPFC, posterior neurons phasically encoded probability of reward, whereas anterior neurons tonically encoded possibility of reward. We found multiple distinct nonlinear valuation mechanisms within the primate prefrontal cortex. Our findings suggest that different subregions of vmPFC contribute differentially to the processing of valence. By conveying such multidimensional and nonlinear signals, the vmPFC may enable flexible control of decisions and emotions to adapt to complex environments.     

Retrosplenial cortex connectivity in schizophrenia

In this paper, we build on our previous analysis [Bluhm, R.L., Miller, J., Lanius, R.A., Osuch, E.A., Boksman, K., Neufeld, R.W.J., et al., 2007 Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophrenia Bulletin 33, 1004–1012] of resting state connectivity in schizophrenia by examining alterations in connectivity of the retrosplenial cortex. We have previously demonstrated altered connectivity of the posterior cingulate/precuneus, particularly with other regions of the “default network” (which includes the medial prefrontal cortex and bilateral lateral parietal cortex). It was hypothesized that the retrosplenial cortex would show aberrant patterns of connectivity with regions of the default network and regions associated with memory. Patients with schizophrenia (N = 17) and healthy controls (N = 17) underwent a 5.5-min resting functional magnetic resonance imaging scan. Lower correlations were observed in patients with schizophrenia than in healthy controls between the retrosplenial cortex and both the temporal lobe and regions of the default network. In patients with schizophrenia, activity in the retrosplenial cortex correlated negatively with activity in bilateral anterior cingulate gyrus/medial prefrontal cortex (BA 32/10), despite the fact that these regions, as part of the default network, were expected to show positive correlations in activity. Connectivity of the retrosplenial cortex was greater in patients with more positive symptoms with areas previously associated with hallucinations, particularly the left superior temporal gyrus. These results suggest that spontaneous activity in the retrosplenial cortex during rest is altered in patients with schizophrenia. These alterations may help to explain alterations in self-oriented processing in this patient population.     

Optical coherence tomography reveals retinal thinning in schizophrenia spectrum disorders

Background

Schizophrenia spectrum disorders (SSDs) are presumed to be associated with retinal thinning. However, evidence is lacking as to whether these retinal alterations reflect a disease-specific process or are rather a consequence of comorbid diseases or concomitant microvascular impairment.

Methods

The study included 126 eyes of 65 patients with SSDs and 143 eyes of 72 healthy controls. We examined macula and optic disc measures by optical coherence tomography (OCT) and OCT angiography (OCT-A). Additive mixed models were used to assess the impact of SSDs on retinal thickness and perfusion and to explore the association of retinal and clinical disease-related parameters by controlling for several ocular and systemic covariates (age, sex, spherical equivalent, intraocular pressure, body mass index, diabetes, hypertension, smoking status, and OCT signal strength).

Results

OCT revealed significantly lower parafoveal macular, macular ganglion cell–inner plexiform layer (GCIPL), and macular retinal nerve fiber layer (RNFL) thickness and thinner mean and superior peripapillary RNFL in SSDs. In contrast, the applied OCT-A investigations, which included macular and peripapillary perfusion density, macular vessel density, and size of the foveal avascular zone, did not reveal any significant between-group differences. Finally, a longer duration of illness and higher chlorpromazine equivalent doses were associated with lower parafoveal macular and macular RNFL thickness.

Conclusions

This study strengthens the evidence for disease-related retinal thinning in SSDs.

     

Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence

To evaluate dorsolateral prefrontal cortex (DLPFC) physiology and function simultaneously, 20 medication-free patients with chronic schizophrenia and 25 normal controls underwent three separate xenon Xe 133 inhalation procedures for determination of regional cerebral blood flow (rCBF): first at rest, then while performing an automated version of the Wisconsin Card Sort (WCS), a DLPFC-specific cognitive test, and while performing a simple number-matching (NM) test. During rest, patients had significantly reduced relative, but not absolute, rCBF to DLPFC. During NM, no specific region differentiated patients from controls. During WCS, however, both absolute and relative rCBF to DLPFC significantly distinguished patients from controls. While controls showed a clear increase in DLPFC rCBF, patients did not. The changes were regionally specific, involving only DLPFC. Furthermore, in patients, DLPFC rCBF correlated positively with WCS cognitive performance, suggesting that the better DLPFC was able to function, the better patients could perform. Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.     

Decreased entorhinal cortex volumes in schizophrenia

BACKGROUND: The entorhinal cortex is located in the medial temporal lobe and is involved in memory and learning. Previous MRI studies reported conflicting findings in schizophrenia, showing normal or reduced entorhinal size. OBJECTIVES: To explore entorhinal cortex volumes in a large sample of patients with schizophrenia recruited from the geographically defined catchment area of South Verona (i.e. 100,000 inhabitants). We also investigated the size of hippocampus as part of the medial temporal lobe. METHODS: 70 patients with schizophrenia and 77 normal controls underwent a session of MRI (TR=2060 ms, TE=3.9 ms, slice thickness=1.25 mm). Entorhinal and hippocampal volumes were explored using the Brains2 software. RESULTS: A significant group effect was found for total entorhinal cortex but not for hippocampus, with patients suffering from schizophrenia having smaller entorhinal volumes compared to normal subjects (F=6.24, p=0.01), particularly on the right side (F=9.76, p=0.002). Also, the laterality index for entorhinal cortex was higher in normal individuals than in patients with schizophrenia (F=5.45, p=0.02). CONCLUSIONS: Consistent with some of the previous reports, our study confirmed the presence of abnormally decreased entorhinal volumes, particularly on the right side, in a large number of patients with schizophrenia and also found altered asymmetry. This may play a major role in the psychopathology and cognitive disturbances of the disease. Future longitudinal MRI studies including high-risk subjects and drug-free, first-episode patients are crucial to further understand whether entorhinal cortex shrinkage is already present at the onset of the illness or appears as a consequence of the illness.     

Gyrification in the cerebral cortex of primates

The degree of cortical folding in primates has been analyzed using a gyrification index (GI). Correlation analyses of the GI with body weight, brain weight and neopallial volume show that the human data fit the general trend of the nonhuman anthropoids. Bigger primate brains exhibit a higher degree of fissurization, but a taxonomic difference that is independent of brain weight between prosimians and anthropoids has also been observed. In these regressions, anthropoids differed from prosimians by having a larger increase in gyrification for every unit increase in body or brain weight or neopallial volume. A stepwise regression also shows a prosimian-anthropoid difference. The best predictor for convolutedness in anthropoids is neocortical volume, while in prosimians it is brain weight. The GI in catarrhines is correlated with total sulcal length but not number of sulci. This result suggests paleontological studies of total sulcal length can give direct information on the evolution of cortical folding in primates.     

Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia

The cytoarchitecture of the entorhinal cortex was examined in the brains of six patients with a diagnosis of schizophrenia and in 16 controls. All six brains of schizophrenic patients showed abnormalities of the rostral and intermediate portions of the entorhinal cortex. The abnormalities included aberrant invaginations of the surface, disruption of cortical layers, heterotopic displacement of neurons, and paucity of neurons in superficial layers. These changes suggest disturbed development. Because the entorhinal cortex is pivotal for neural systems that mediate corticohippocampal interactions, early disruption of its structure could lead to important neuropsychological changes during development and in adult life and could contribute to the symptomatology of schizophrenia.     

Morphometric assessment of the heteromodal association cortex in schizophrenia

OBJECTIVE: The heteromodal association cortex has been hypothesized to be selectively involved in the pathophysiology of schizophrenia. To test this hypothesis, the authors measured prefrontal, inferior parietal, and superior temporal gyrus volumes and examined the pattern of connections among these regions. METHOD: Forty-four patients with schizophrenia or schizoaffective disorder and 34 healthy comparison subjects were included in the study. A spoiled gradient recall acquisition in the steady-state three-dimensional magnetic resonance imaging sequence was used for morphometric assessment of the heteromodal association cortex. RESULTS: Patients with schizophrenia had significantly smaller inferior prefrontal region volumes and significant reversal of the normal asymmetry of the inferior parietal cortex. No significant group differences were found in superior temporal gyrus volume. The groups differed significantly in the correlation between inferior prefrontal region volumes and angular gyrus volumes. CONCLUSIONS: The results suggest that patients with schizophrenia may be characterized by selective abnormalities of the heteromodal regions involved in the neuroanatomy of language.