The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia

Neural oscillations and their synchronization may represent a versatile signal to realize flexible communication within and between cortical areas. By now, there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neural responses, such as perceptual grouping, attention-dependent stimulus selection, subsystem integration, working memory, and consciousness, are associated with synchronized oscillatory activity in the theta-, alpha-, beta-, and gamma-band, suggesting a functional mechanism of neural oscillations in cortical networks. In addition to their role in normal brain functioning, there is increasing evidence that altered oscillatory activity may be associated with certain neuropsychiatric disorders, such as schizophrenia, that involve dysfunctional cognition and behavior. In the following article, we aim to summarize the evidence on the role of neural oscillations during normal brain functioning and their relationship to cognitive processes. In the second part, we review research that has examined oscillatory activity during cognitive and behavioral tasks in schizophrenia. These studies suggest that schizophrenia involves abnormal oscillations and synchrony that are related to cognitive dysfunctions and some of the symptoms of the disorder. Perspectives for future research will be discussed in relationship to methodological issues, the utility of neural oscillations as a biomarker, and the neurodevelopmental hypothesis of schizophrenia.     

Neural synchrony in schizophrenia: from networks to new treatments

Evidence is accumulating that brain regions communicate with each other in the temporal domain, relying on coincidence of neural activity to detect phasic relationships among neurons and neural assemblies. This coordination between neural populations has been described as "self-organizing," an "emergent property" of neural networks arising from the temporal synchrony between synaptic transmission and firing of distinct neuronal populations. Evidence is also accumulating that communication and coordination failures between different brain regions may account for a wide range of problems in schizophrenia, from psychosis to cognitive dysfunction. We review the knowledge about the functional neuroanatomy and neurochemistry of neural oscillations and oscillation abnormalities in schizophrenia. Based on this, we argue that we can begin to use oscillations, across frequencies, to do translational studies to understand the neural basis of schizophrenia.     

The prevalence of prodromal features of schizophrenia in adolescence: a preliminary survey

In most cases of schizophrenia the onset of frank psychosis is preceded by a period of prodromal features. This period has been relatively neglected by researchers and is potentially important in promoting early intervention. The prevalence of DSM-III-R schizophrenia prodrome symptoms was assessed as part (n= 657) of a large (n= 2525) questionnaire-based survey of high school students. Individual symptoms were highly prevalent and the prevalence of DSM-III-R prodromes ranged from 10–15% to 50%. Despite methodological weaknesses, the data suggest that DSM-III-R prodromal features are extremely prevalent among older adolescents and unlikely to be specific for subsequent schizophrenia. Clinically these features cannot be regarded as sufficient evidence of early schizophrenia and more accurate predictors of incipient schizophrenia need to be defined.     

Sparse deep neural networks on imaging genetics for schizophrenia case–control classification

Deep learning methods hold strong promise for identifying biomarkers for clinical application. However, current approaches for psychiatric classification or prediction do not allow direct interpretation of original features. In the present study, we introduce a sparse deep neural network (DNN) approach to identify sparse and interpretable features for schizophrenia (SZ) case–control classification. An L ₀‐norm regularization is implemented on the input layer of the network for sparse feature selection, which can later be interpreted based on importance weights. We applied the proposed approach on a large multi‐study cohort with gray matter volume (GMV) and single nucleotide polymorphism (SNP) data for SZ classification. A total of 634 individuals served as training samples, and the classification model was evaluated for generalizability on three independent datasets of different scanning protocols (N = 394, 255, and 160, respectively). We examined the classification power of pure GMV features, as well as combined GMV and SNP features. Empirical experiments demonstrated that sparse DNN slightly outperformed independent component analysis + support vector machine (ICA + SVM) framework, and more effectively fused GMV and SNP features for SZ discrimination, with an average error rate of 28.98% on external data. The importance weights suggested that the DNN model prioritized to select frontal and superior temporal gyrus for SZ classification with high sparsity, with parietal regions further included with lower sparsity, echoing previous literature. The results validate the application of the proposed approach to SZ classification, and promise extended utility on other data modalities and traits which ultimately may result in clinically useful tools.     

Cytokines and schizophrenia: Microglia hypothesis of schizophrenia

The etiology of schizophrenia remains unclear, while there has been a growing amount of evidence for the neuroinflammation and immunogenetics, which are characterized by an increased serum concentration of several pro-inflammatory cytokines. Despite the fact that microglia comprise only <10% of the total brain cells, microglia respond rapidly to even minor pathological changes in the brain and may contribute directly to the neuronal degeneration by producing various pro-inflammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia has recently been reported to be closely associatedwith microglial activation. Previous studies have shown the inhibitory effects of some typical/atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both of which have recently been known to cause a decrease in neurogenesis as well as white matter abnormalities in the brains of patients with schizophrenia. The microglia hypothesis of schizophrenia may shed new light on the therapeutic strategy for schizophrenia.     

The neurodevelopmental hypothesis of schizophrenia: convergent clues from epidemiology and neuropathology

The neurodevelopmental hypothesis of schizophrenia suggests that the disruption of early brain development increases the risk of later developing schizophrenia. This hypothesis focuses attention on critical periods of early brain development. From an epidemiologic perspective, various prenatal and perinatal risk factors have been linked to schizophrenia, including exposures related to infection, nutrition, and obstetric complications. From a genetic perspective, candidate genes have also been linked to altered brain development. In recent decades evidence from neuropathology has provided support for the neurodevelopmental hypothesis. Animal models involving early life exposures have been linked to changes in these same brain systems, providing convergent evidence for this long-standing hypothesis.     

Synthetic PET: Analyzing large-scale properties of neural networks

Synthetic PET is introduced as a new computational technique for connecting neural network studies based on animal data and image studies of human brain function. Synthetic PET comparisons are taken from a computational model of interacting neural networks in, for example, the monkey brain by integrating synaptic activity in each subnetwork as different simulated tasks are performed. Given a pair of tasks, comparative synaptic activity levels for each modeled neural region are then painted into the homologous regions of a three-dimensional model of the human brain corresponding to the Talairach atlas. The resulting comparison then offers predictions of relative changes of neuronal activity as obtained from PET comparisons of humans performing a similar pair of tasks. Where neurophysiological data and individual arrays of neural networks give us a very fine-grained view of the behavior of just a few neurons within nonhumans, PET measures provide a more global view of brain function. Synthetic PET allows us to integrate human and monkey studies in the construction of more complete models of the neural mechanisms used by both species in similar tasks. The technique is demonstrated in a saccade generation task. The method readily generalizes to other forms of brain imaging. © 1995 Wiley-Liss, Inc.     

The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia

The neurodevelopmental hypothesis of schizophrenia is becoming an important feature of research in the field. However, its major drawback is that it lacks any biochemical basis which might draw the diverse observations together. It is suggested that the membrane phospholipid hypothesis can provide such a biochemical basis and that the neurodevelopmental phospholipid concept offers a powerful paradigm to guide future research.     

Interactional synchrony and negative symptoms: An outcome study of body-oriented psychotherapy for schizophrenia

Objective: We sought to assess the efficacy of a manualized body-oriented psychotherapy (BPT) intervention for schizophrenia, by focusing on improvement of negative symptoms and on changes in interactional synchrony. We also explored aspects of a phenomenological theory of schizophrenia, which states that negative symptoms should be understood within an encompassing disturbance of subjectivity and intersubjectivity. Method: Sixteen persons with schizophrenia participated in 10 weeks of BPT. General psychiatric symptomatology and negative symptoms were assessed before and after therapy. Interactional synchrony was assessed via cross-correlations of movements between patient and interviewer in interviews conducted before and after therapy. Results: Psychiatric symptomatology and negative symptoms significantly improved with a medium effect size. We also demonstrated a significant increase in interactional synchrony with a strong effect size. Post hoc analyses showed a significant increase only with open-ended interviews conducted by the same interviewer. Furthermore, we explored the correlation between negative symptoms and interactional synchrony, finding a large inverse relationship. Conclusions: BPT for schizophrenia may effectively reduce patients’ negative symptoms and psychiatric symptomatology. Moreover, it may yield some recovery of pre-reflective social relations. Further evidence of the specific relation between negative symptoms and interactional synchrony would support a phenomenologically informed holistic view of schizophrenia.     

fMRI evidence of aberrant neural adaptation for objects in schizophrenia and bipolar disorder

Functional magnetic resonance imaging (fMRI) adaptation (also known as fMRI repetition suppression) has been widely used to characterize stimulus selectivity in vivo, a fundamental feature of neuronal processing in the brain. We investigated whether SZ patients and BD patients show aberrant fMRI adaptation for object perception. About 52 SZ patients, 55 BD patients, and 53 community controls completed an object discrimination task with three conditions: the same object presented twice, two exemplars from the same category, and two exemplars from different categories. We also administered two functional localizer tasks. A region of interest analysis was employed to evaluate a priori hypotheses about the lateral occipital complex (LOC) and early visual cortex (EVC). An exploratory whole brain analysis was also conducted. In the LOC and EVC, controls showed the expected reduced fMRI responses to repeated presentation of the same objects compared with different objects (i.e., fMRI adaptation for objects, p < .001). SZ patients showed an adaptation effect that was significantly smaller compared with controls. BD patients showed a lack of fMRI adaptation. The whole brain analyses showed enhanced fMRI responses to repeated presentation of the same objects only in BD patients in several brain regions including anterior cingulate cortex. This study was the first to employ fMRI adaptation for objects in SZ and BD. The current findings provide empirical evidence of aberrant fMRI adaptation in the visual cortex in SZ and BD, but in distinctly different ways.     

The role of cortical inhibition in the pathophysiology and treatment of schizophrenia

Dysfunctional cortical inhibition (CI) has been suggested as a mechanism through which symptoms of schizophrenia (SCZ) are mediated. Cortical inhibition refers to a neurophysiological process in which gamma-aminobutyric acid (GABA) inhibitory interneurons selectively attenuate the activity of other neurons (e.g., pyramidal neurons) in the cortex. Here we review the neuroanatomic and neurophysiological evidence suggesting CI deficits among persons with SCZ. We also review genetic studies that have linked CI deficits to a polymorphism in the alpha(7)-nicotinic cholinergic receptor, thereby positing that a specific genetic mechanism underlies SCZ-related GABA interneuron dysfunction. We will conclude by reviewing the role of CI as a mechanism mediating the therapeutic action of antipsychotic medications.     

Abnormal cortical folding in high-risk individuals: a predictor of the development of schizophrenia?

BACKGROUND: A number of studies have found localized differences in the appearance and extent of cortical folding between the brains of schizophrenic patients and healthy control subjects. This study aimed to determine whether, within individuals at genetic high risk for schizophrenia, there are pre-existing differences in gyral folding between those who subsequently develop the disease and those who remain unaffected. METHODS: Assessment was conducted on baseline magnetic resonance imaging scans of 30 young adults grouped into 14 who remained unaffected and 16 who subsequently developed schizophrenia. The gyrification index (GI), the ratio of the inner and outer cortical surface contours, was measured bilaterally on every second 1.88-mm image slice in four specifically defined lobar regions. Independent t tests and volume and genetic liability correlations were conducted for each region, followed by a post hoc examination. RESULTS: Right prefrontal lobe GI values were significantly increased in individuals who subsequently developed schizophrenia. Post hoc examination suggested that the areas of greatest increase lay anteriorly and laterally in Brodmann areas 9 and 10. Correlations with volume and analysis of covariance suggested some overlap between GI and volume measures. CONCLUSIONS: Differences in frontal lobe GI might reflect disturbed or abnormal connectivity predictive of subsequent schizophrenia.     

The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia.

Since the discovery that the therapeutic efficacy of antipsychotic drugs was significantly correlated to their ability to block dopamine D2 receptors, abnormal dopamine transmission in the forebrain has been postulated to underlie psychosis in schizophrenia. In the past 15 years, an impressive amount of clinical and basic research aimed at the study of schizophrenia has indicated that prefrontal and temporal cortical abnormalities may be more important in the etiology of many of the symptoms of schizophrenia, including psychosis. However, the cortical systems that appear to have structural and/or metabolic abnormalities in schizophrenia patients potently regulate forebrain dopamine transmission through a number of mechanisms. In turn, dopamine modulates excitatory transmission mediated by frontal and temporal cortical projections to the basal ganglia and other regions. The present review summarizes the multiple interactions between forebrain DA systems and frontal and temporal corticostriatal transmission. It then examines the role of these interactions in normal behaviors and the psychopathology of schizophrenia.     

Gender- and age-dependent differences in latent inhibition following pre-weaning non-handling : implications for a neurodevelopmental animal model of schizophrenia

Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its prior nonreinforced pre-exposure, and is considered to index the capacity of an organism to ignore irrelevant stimuli. LI disruption has received increasing attention as an animal model of the widely described attentional deficit of schizophrenia, consisting of an inability to ignore irrelevant stimuli. The present experiments investigated the effects of infantile manipulations on the development of LI. Male and female rats handled or nonhandled in infancy (days 1–22), were tested at 3 and 16 months. Young handled animals had lower emotional reactivity than nonhandled, and this difference persisted in females at 16 months. At 3 months, LI, poorer conditioning of stimulus pre-exposed as compared to nonpre-exposed rats, was obtained in handled and nonhandled females, as well as in handled males, but was absent in nonhandled males. This pattern changed at 16 months : both nonhandled males and females failed to show LI. These gender- and age-dependent effects of pre-weaning manipulations on LI loss may provide an animal parallel to the susceptibility of young adult males to schizophrenia and the attenuation of gender differences in long-term outcome schizophrenia.     

The Italian guidelines for early intervention in schizophrenia: development and conclusions

Aim: The effectiveness of early intervention in schizophrenia is still under discussion. The guidelines described in the present paper were aimed at contributing to the current debate by providing Italian practitioners, families, patients and health managers with evidence‐based information on early intervention. They also examined the diagnostic tools that are currently available for assessing different stages of psychotic disorders. Methods: A multidisciplinary panel of experts (the Guidelines Development Group) used a set of key‐questions to develop an explicit search strategy to conduct a systematic review of the literature published from January 2000 to June 2006. Trained personnel then selected papers from those yielded by the literature search. The Guidelines Development Group's final recommendations were scaled according to the Italian National Guidelines System grading system. Results: The evidence available up to the time of the literature search does not allow for recommendation of early intervention targeting prodromal or at‐risk patients to prevent progression from the prodromal phase to acute, full‐blown psychosis, nor to improve prognosis. Conversely, identification and timely treatment of first‐episode psychotic patients through specific early intervention programmes are highly recommended. Conclusions: The Italian Guidelines on early intervention in schizophrenia are based on a comprehensive assessment of an updated, large‐scale body of literature. They draw specific, evidence‐based conclusions to assist clinicians and stakeholders in the planning and implementation of appropriate intervention programmes. Further research is needed to ascertain the effectiveness of early intervention in delaying or preventing the conversion to psychosis and improving prognosis in prodromal or at‐risk patients. Further investigation is also required for first‐episode and critical period patients.     

Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia

Clinical studies report associations between cannabis use during adolescence and later onset of schizophrenia. We examined the causal relationship between developmental cannabinoid administration and long-term behavioral and molecular alterations in mice. Mice were administered either WIN 55,212-2 (WIN), a cannabinoid receptor 1 (CB1) agonist or vehicle (Veh) during adolescence (postnatal day 30–35) or early adulthood (postnatal day 63–70). Behavioral testing was conducted after postnatal day 120 followed by biochemical assays. Adolescent cannabinoid treatment (ACU) leads to deficits in prepulse inhibition and fear conditioning in adulthood. Metabotropic glutamate receptors type 5 (mGluR5), a receptor critically involved in fear conditioning and endocannabinoid (eCB) signaling, is significantly reduced in the ACU mouse hippocampus. Next, we examined expression profiles of genes involved in eCB synthesis (diacylglycerol lipase (DGL)) and uptake (monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH)) in the experimental mice. We find evidence of increased MGL and FAAH in ACU mice, reflecting increases in eCB uptake and degradation. These data suggest that administration of cannabinoids during adolescence leads to a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations in sensorimotor gating and hippocampal-dependent learning and memory deficits. Further, these deficits are associated with a reduction in hippocampal mGluR5 and a sustained change in eCB turnover, suggesting reduced eCB signaling in the ACU hippocampus. These data suggest that significant cannabis use during adolescence may be a contributory causal factor in the development of certain features of schizophrenia and may offer mGluR5 as a potential therapeutic target.     

Characteristic distribution of alpha 2 wave in electroencephalograms of schizophrenic patients during discriminative tasks: support for the hypofrontality hypothesis of schizophrenia.

In a preliminary study, we noticed that alpha 2 activity in the frontal regions was suppressed less in schizophrenic patients than in other patients during the discriminative tasks. This was confirmed with 37 schizophrenic and 16 nonschizophrenic patients under the treatment of neuroleptics, 15 nonmedicated schizophrenic patients and 32 normal controls. The EEGs in eye-closed resting and during the auditory and visual discriminative tasks were recorded. Alpha 2 power values of the frontal, central, parietal, occipital and temporal regions in every subject group were processed by cluster analysis. During the discriminative tasks, the frontal regions were the most isolated cluster in schizophrenic patients and, in the normal and medicated nonschizophrenic groups, the frontal regions were incorporated in a different cluster. The same result was obtained by different statistical analyses of F-alpha 2 power ratio. The relative abundance of alpha 2 power value shifts from the occipital to the frontal regions during the discriminative tasks in schizophrenic patients. The weakened suppression of alpha 2 waves in the frontal regions by the discriminative tasks in schizophrenic patients supports the hypofrontal hypothesis of schizophrenia.     

Craniofacial dysmorphogenesis in fetally irradiated nonhuman primates: implications for the neurodevelopmental hypothesis of schizophrenia.

BACKGROUND: Craniofacial abnormalities arising from gestational disturbances have been documented in some schizophrenic patients. Reduction of thalamic neurons, a key feature of the neuropathology of schizophrenia, could also have a prenatal origin via disruption of thalamic neurogenesis. This study investigates whether craniofacial dysmorphology and thalamic neuron loss might be associated manifestations of a disruption in embryonic development. METHODS: Thalamic neurons were deleted by exposing fetal macaques to x-rays during thalamic genesis (E33-42). Another group of macaques was irradiated after thalamic genesis (E70-81). Body, head, and facial measurements were obtained from the early irradiated (EX), late irradiated (LX), and control animals at adulthood. RESULTS: Head width, distance between outer eye edges, and ear width were smaller in EX macaques compared with control animals. The LX macaques exhibited only reduced ear width compared with control animals. CONCLUSIONS: These findings indicate that certain features of thalamic neuropathology and craniofacial dysmorphogenesis observed in schizophrenic patients may have a common etiology.     

Decreased efficiency of task-positive and task-negative networks during working memory in schizophrenia

Working memory (WM) is one of the most impaired cognitive processes in schizophrenia. Functional magnetic resonance imaging (fMRI) studies in this area have typically found a reduction in information processing efficiency but have focused on the dorsolateral prefrontal cortex. In the current study using the Sternberg Item Recognition Test, we consider networks of regions supporting WM and measure the activation of functionally connected neural networks over different WM load conditions. We used constrained principal component analysis with a finite impulse response basis set to compare the estimated hemodynamic response associated with different WM load condition for 15 healthy control subjects and 15 schizophrenia patients. Three components emerged, reflecting activated (task-positive) and deactivated (task-negative or default-mode) neural networks. Two of the components (with both task-positive and task-negative aspects) were load dependent, were involved in encoding and delay phases (one exclusively encoding and the other both encoding and delay), and both showed evidence for decreased efficiency in patients. The results suggest that WM capacity is reached sooner for schizophrenia patients as the overt levels of WM load increase, to the point that further increases in overt memory load do not increase fMRI activation, and lead to performance impairments. These results are consistent with an account holding that patients show reduced efficiency in task-positive and task-negative networks during WM and also partially support the shifted inverted-U-shaped curve theory of the relationship between WM load and fMRI activation in schizophrenia.