Acute stress modifies oscillatory indices of affective processing: Insight on the pathophysiology of schizophrenia spectrum disorders

ObjectiveThe current study evaluated the differential impact of acute psychosocial stress exposure on oscillatory correlates of affective processing in control participants and patients with schizophrenia spectrum disorders (SCZ) to elucidate the stress-mediated pathway to psychopathology.MethodsEEG was recorded while 21 control participants and 21 patients with SCZ performed emotional framing tasks (assessing a key aspect of emotion regulation (ER)) before and after a laboratory stress challenge (Trier Social Stress Test). EEG spectral perturbations evoked in response to neutral and aversive stimuli (presented with positive or negative contextual cues) were extracted in theta (4–8 Hz) and beta (12–30 Hz) frequencies.ResultsPatients demonstrated aberrant theta and beta oscillatory activity, with impaired frontal theta-mediated framing and beta-derived motivated attention processes relative to controls. Following stress exposure, controls exhibited impaired frontal theta-mediated emotional framing, similar to the oscillatory profile observed in patients before stress.ConclusionsThe acute stress-induced oscillatory changes observed in controls were persistently present in patients, indicating an inefficiency of fronto-limbic adaptation to stress exposure.SignificanceResults provide novel insight on the electrophysiological correlates of arousal and affect regulation, which are core homogeneous symptom dimensions shared across neuropsychiatric disorders, and shed light on putative mechanisms in the translation of stress into psychopathology.     

The genetic epidemiology of schizophrenia and of schizophrenia spectrum disorders

It has been known for a long time that schizophrenia and several related psychopathological traits aggregate in families on a common genetic basis. Improved methodology of recent family, twin and adoption studies has led to a better understanding of which psychopathologically defined syndromes and personality traits are part of a schizophrenia spectrum, and to which degree individual spectrum conditions share the same genetic background with schizophrenia. The spectrum concept has been extended to include neuropsychologically, neurophysiologically and neuroradiologically measurable familial traits as subclinical endophenotypes of schizophrenia that may be more fundamental to the development of the disease than overt psychopathology. This knowledge has been useful in designing molecular genetic linkage and association studies the aim at directly identifying individual risk genes. Replicable linkage findings have emerged from genome scans that imply at least seven chromosomal regions to harbour schizophrenia susceptibility genes. They strengthen the conviction that schizophrenia is indeed a genetically complex disorder, based on a larger number of susceptibility genes with risk-increasing alleles that are common in the population and exert a limited effect on the individual level. Although demanding increased investments into sample collection, genotyping and computational technology, identification of these genetic variants will be possible and worthwhile since they may have a large effect in terms of population attributable risk. Received: 3 March 2000 / Accepted: 24 March 2000     

The Dutch Famine and schizophrenia spectrum disorders

In the Dutch Hunger Winter at the end of World War II a combination of circumstances created the conditions of a natural experiment. Unlike other famines, the Dutch famine struck at a precisely circumscribed time and place, and in a society able to document the timing and severity of the nutritional deprivation as well as the effects on fertility and health. Because the Dutch maintained comprehensive military and health records, it was possible to compare the incidence of neurodevelopmental disorders in adulthood for birth cohorts exposed versus those unexposed to prenatal famine. We have conducted several studies guided by the hypothesis that prenatal micronutrient deficiencies can cause neurodevelopmental schizophrenia or related personality disorders. In this paper we shall summarize our previous work and combine the outcome data of the different studies. Early prenatal famine was found to be specifically and robustly associated with each of three conditions: (1) congenital anomalies of the central nervous system, (2) schizophrenia, and (3) schizophrenia spectrum personality disorders. We found that the greatest increase in the risk of schizophrenia spectrum disorder – schizophrenia plus spectrum personality disorder – occurred among males born in the famine cities in December 1945 (relative risk = 2.7; 95% confidence interval = 1.5–5.1). Persons born in December 1945 were generally conceived at the absolute peak of the famine (March–April 1945). In the hope that the associations we have found may offer clues to the aetiology of schizophrenia, we are currently tracing and examining the cases of schizophrenia after prenatal exposure to famine. Accepted: 11 February 1998     

The treatment of hallucinations in schizophrenia spectrum disorders

This article reviews the treatment of hallucinations in schizophrenia. The first treatment option for hallucinations in schizophrenia is antipsychotic medication, which can induce a rapid decrease in severity. Only 8% of first-episode patients still experience mild to moderate hallucinations after continuing medication for 1 year. Olanzapine, amisulpride, ziprasidone, and quetiapine are equally effective against hallucinations, but haloperidol may be slightly inferior. If the drug of first choice provides inadequate improvement, it is probably best to switch medication after 2-4 weeks of treatment. Clozapine is the drug of choice for patients who are resistant to 2 antipsychotic agents. Blood levels should be above 350-450 μg/ml for maximal effect. For relapse prevention, medication should be continued in the same dose. Depot medication should be considered for all patients because nonadherence is high. Cognitive-behavioral therapy (CBT) can be applied as an augmentation to antipsychotic medication. The success of CBT depends on the reduction of catastrophic appraisals, thereby reducing the concurrent anxiety and distress. CBT aims at reducing the emotional distress associated with auditory hallucinations and develops new coping strategies. Transcranial magnetic stimulation (TMS) is capable of reducing the frequency and severity of auditory hallucinations. Several meta-analyses found significantly better symptom reduction for low-frequency repetitive TMS as compared with placebo. Consequently, TMS currently has the status of a potentially useful treatment method for auditory hallucinations, but only in combination with state of the art antipsychotic treatment. Electroconvulsive therapy (ECT) is considered a last resort for treatment-resistant psychosis. Although several studies showed clinical improvement, a specific reduction in hallucination severity has never been demonstrated.     

Early signs in schizophrenia spectrum disorders

The frequency of various early signs of illness was examined in 96 first-episode patients suffering from schizophrenia, schizoaffective, or schizophreniform disorder. A factor analysis of these early signs was performed, and each of the five dimensions identified was examined for its relation to symptoms of psychosis at presentation and after 1 year of treatment. The results suggested five primary dimensions of early signs: emotional dysphoria and odd perceptual and cognitive content, impaired functioning, changes related to psychobiological or vegetative functioning, suspiciousness accompanied by difficulties in concentration, and irritability/aggression. Impaired functioning in the prepsychosis period was associated with higher negative symptoms at presentation for treatment, and higher levels of psychobiological changes were associated with lower positive symptoms of psychosis after a year of treatment. The latter findings may indicate that patients with more profound indications of affective disturbance or stress have a better prognosis.     

Illness denial in schizophrenia spectrum disorders

Impaired illness awareness or anosognosia is a common, but poorly understood feature of schizophrenia that contributes to medication nonadherence and poor treatment outcomes. Here we present a functional imaging study to measure brain activity at the moment of illness denial. To accomplish this, participants with schizophrenia (n = 18) with varying degrees of illness awareness were confronted with their illness beliefs while undergoing functional MRI. To link structure with function, we explored the relationships among impaired illness awareness and brain activity during the illness denial task with cortical thickness. Impaired illness awareness was associated with increased brain activity in the left temporoparieto‐occipital junction (TPO) and left medial prefrontal cortex (mPFC) at the moment of illness denial. Brain activity in the left mPFC appeared to be a function of participants' degree of self‐reflectiveness, while the activity in the left TPO was associated with cortical thinning in this region and more specific to illness denial. Participants with impaired illness awareness had slower response times to illness related stimuli than those with good illness awareness. Increased left hemisphere brain activity in association with illness denial is consistent with the literature in other neuropsychiatric conditions attributing anosognosia or impaired illness awareness to left hemisphere dominance. The TPO and mPFC may represent putative targets for noninvasive treatment interventions, such as transcranial magnetic or direct current stimulation. Hum Brain Mapp, 36:391–414, 2015. © 2014 Wiley Periodicals, Inc.     

Heterogeneity of response to antipsychotics from multiple disorders in the schizophrenia spectrum

BACKGROUND: Antipsychotic response after the initiation of neuroleptic treatment shows wide variation in schizophrenic patient populations. In this overview, the authors suggest that the variance in antipsychotic drug response within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinnings. METHOD: Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological markers with possible etiologic significance are reviewed. Such studies had assessed recently hospitalized, neuroleptic-free patients undergoing exacerbation of nonaffective psychotic disorders. Prior to initiation of neuroleptic, the cohort of patients had been assessed for the quantity of the dopamine metabolite homovanillic acid in plasma (pHVA) and had undergone the first of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle volumes. A second MRI was subsequently performed during a period of (partial) remission to determine within-patient stability of ventricular volumes. These selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-means clustering. The speed and completeness of neuroleptic-induced antipsychotic response were related to 3 clusters of patients delineated by modal distributions of pHVA and of apparent rates of ventricular change. RESULTS: At least 3 unique "endophenotypes" of the "group of the schizophrenias" can be defined with respect to speed and completeness of antipsychotic response. Each endophenotype appears to show at least one unique biological feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A delayed-response psychosis had low-to-normal pHVA, clinically demonstrated persistent negative symptoms, and was associated with an excessive rate of change in ventricle volume between exacerbations of psychosis and (partial) remissions. Finally, a nonresponsive psychosis could be characterized as having both low-to-normal pHVA and rate of change of ventricle volumes similar to that of controls. Additional studies revealed that each of the endophenotypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found in their family members who had psychotic disorders. Similarly, the prominent negative symptoms of the delayed-response probands were reflected as a prominent trait in their family members also afflicted with psychosis. The endophenotypes tended to "breed true" in terms of prognosis and negative symptoms. CONCLUSION: Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related to differences in the etiology and consequent pathophysiology of illness.     

Parental schizophrenia spectrum disorders in childhood-onset and adult-onset schizophrenia

OBJECTIVE: Childhood onset of "adult" psychiatric disorders may be caused, in part, by more salient genetic risk. In this study, the rates of schizophrenia spectrum disorders among parents of patients with childhood-onset and adult-onset schizophrenia and parents of community comparison subjects were compared. METHOD: To assess the presence of axis I and axis II disorders associated with schizophrenia, parents of patients with childhood-onset schizophrenia (95 parents), patients with adult-onset schizophrenia (86 parents), and community comparison subjects (123 parents) were interviewed directly by using semistructured instruments. Information on 19 additional parents (parents of childhood-onset patients, N=2; parents of adult-onset patients, N=11; parents of community comparison subjects, N=6) was obtained by using a family history interview with the same instruments. Transcribed interviews were scored by a rater blind to group membership, and the morbid risks for schizophrenia spectrum disorders in the three groups were compared. RESULTS: Parents of patients with childhood-onset schizophrenia had a significantly higher morbid risk of schizophrenia spectrum disorders (24.74%) than parents of patients with adult-onset schizophrenia (11.35%), and parents of both patient groups had a greater risk of schizophrenia spectrum disorders than did parents of comparison subjects (1.55%). CONCLUSIONS: Parents of patients with childhood-onset schizophrenia have a higher rate of schizophrenia spectrum disorders than parents of patients with adult-onset illness. This is consistent with the hypothesis that a childhood onset of schizophrenia is due, at least in part, to a greater familial diathesis for the disorder.     

Characterizing the sensorimotor domain in schizophrenia spectrum disorders

European Archives of Psychiatry and Clinical Neuroscience - The rapidly evolving field of sensorimotor neuroscience reflects the scientific and clinical relevance of sensorimotor abnormalities as...     

Tic disorders: from pathophysiology to treatment

Tic disorders are stereotypic behaviours,more frequent than once believed, and therefore likely to be encountered by primary care physicians. Tics usually begin in childhood and are the clinical hallmark of Tourette Syndrome (TS), the most common cause of tics. TS is a relatively common neurobehavioural disorder with a spectrum of manifestations that wax and wane during its natural course. The pathophysiology of tics, at molecular and cellular level, is still unknown,whereas structural and functional neuroimaging studies have shown the involvement of the basal ganglia and related cortico–striato–thalamo–cortical circuits, and the dopaminergic neuronal system. Moreover, TS has a strong genetic background. The management of TS is often complicated by the presence of attention–deficit/hyperactivity disorder, obsessivecompulsive disorder, and other behaviour disorders. The correct diagnosis is a fundamental step for a proper management of these disorders, and a multimodal treatment is usually indicated. This approach includes educational and supportive interventions, as well as pharmacological treatments when tics are at their worst.     

The inheritance of schizophrenia spectrum disorders: a reanalysis of the Danish adoptee study data

Rosenthal and colleagues earlier compared the frequency of schizophrenia spectrum disorders in two groups of persons adopted in infancy or early childhood: those with a psychotic parent (index group) and those whose biological parents had never had a psychiatric diagnosis or treatment (control group). They found significantly more disorder in the index group. Reanalysis of the original material using DSM-III and stricter exclusionary criteria applied to the parents yielded three times as many schizophrenia spectrum disorders in the index as in the control group. This difference remained statistically significant, supporting the operation of genetic factors in the transmission of the traits comprising the schizophrenic spectrum of disorders.     

Cognitive dimensions in first-episode schizophrenia spectrum disorders

BACKGROUND: The severity and pattern of cognitive deficits in epidemiological cohorts of patients with first-episode schizophrenia spectrum disorders still remains unclear. We aimed to characterize the basic cognitive functioning of a representative sample of patients with a first-episode schizophrenia spectrum disorders. METHOD: One hundred thirty-one patients experiencing first-episode psychosis and 28 healthy volunteers were administered a comprehensive neuropsychological evaluation. To reduce the number of cognitive test measures into meaningful cognitive dimensions, before analyzing differences between patient and healthy volunteer samples, exploratory factor analysis was carried out on data collected in patients group. The method of extraction was Principal Components Analysis with oblique rotation. RESULTS: An eight-factor model including verbal learning/memory, verbal comprehensive abilities, speed of processing/executive functioning, motor dexterity, motor speed, sustained attention, and impulsivity emerged. A significant below average performance in all cognitive dimensions, except impulsivity, was found. Patient's performance in speed of processing/executive functioning, motor dexterity and sustained attention dimensions exceeded one standard deviation below healthy comparison subjects. CONCLUSIONS: At early stages of the illness, patients display a marked impairment in several functionally relevant cognitive domains.     

Symptomatic determinants of insight in schizophrenia spectrum disorders

Impaired insight in schizophrenia spectrum disorders has been linked to several psychopathologic features including positive symptoms, although not all dimensions of psychopathology have been studied and confounds from other symptoms have not been ruled out. In addition, the nature of the association between insight and specific positive symptoms, in particular delusions, remains unclear. The present investigation examined whether, in patients with schizophrenia spectrum disorders insight is associated with specific symptom dimensions including delusional severity. The factor structure was determined from scores of 151 patients rated on the Signs and Symptoms of Psychotic Illness scale. Associations of the Signs and Symptoms of Psychotic Illness insight item with the resulting components and delusions were assessed using regression-based methodology. Principal component analysis revealed 4 orthogonal symptom clusters. Correlational analyses demonstrated that only depression/anxiety and psychomotor excitation were significantly related to insight. Hierarchical regression indicated that delusions explained unique variance in insight over and above depression/anxiety and psychomotor excitation. These results suggest that depression/anxiety is associated with better insight and that psychomotor excitation and delusions are associated with poorer insight.     

Dynamic functional network reconfiguration underlying the pathophysiology of schizophrenia and autism spectrum disorder

The dynamics of the human brain span multiple spatial scales, from connectivity associated with a specific region/network to the global organization, each representing different brain mechanisms. Yet brain reconfigurations at different spatial scales are seldom explored and whether they are associated with the neural aspects of brain disorders is far from understood. In this study, we introduced a dynamic measure called step‐wise functional network reconfiguration (sFNR) to characterize how brain configuration rewires at different spatial scales. We applied sFNR to two independent datasets, one includes 160 healthy controls (HCs) and 151 patients with schizophrenia (SZ) and the other one includes 314 HCs and 255 individuals with autism spectrum disorder (ASD). We found that both SZ and ASD have increased whole‐brain sFNR and sFNR between cerebellar and subcortical/sensorimotor domains. At the ICN level, the abnormalities in SZ are mainly located in ICNs within subcortical, sensory, and cerebellar domains, while the abnormalities in ASD are more widespread across domains. Interestingly, the overlap SZ‐ASD abnormality in sFNR between cerebellar and sensorimotor domains was correlated with the reasoning‐problem‐solving performance in SZ (r = −.1652, p = .0058) as well as the Autism Diagnostic Observation Schedule in ASD (r = .1853, p = .0077). Our findings suggest that dynamic reconfiguration deficits may represent a key intersecting point for SZ and ASD. The investigation of brain dynamics at different spatial scales can provide comprehensive insights into the functional reconfiguration, which might advance our knowledge of cognitive decline and other pathophysiology in brain disorders.     

Somatoform disorders: perspectives from Pakistan

Somatoform disorders represent widespread and largely unsolved problems at the border between psychiatry and medicine. Patients with somatoform disorders often present difficult diagnostic and management problems. A series of three community-based epidemiological surveys of rural and urban populations in Pakistan found high prevalence of common mental disorders where the core presentations were somatic complaints. All the three epidemiological surveys used the Bradford Somatic Inventory (BSI), which was developed from symptom reports by psychiatric patients in Pakistan; these enquired about somatic symptoms in the local language, taking into account local cultural idioms of distress. At a conservative estimate, 66% of women and 25% men suffered from anxiety and depressive disorders whereby the complaints predominantly were somatic in nature. People in rural non-Western cultures are not psychologically minded and do not have abstract language or concepts of emotional distress and therefore communicate their emotions somatically. In Pakistan somatoform disorders possess a prominent diagnostic dilemma. The cornerstone of the management is a comprehensive medical, psychiatric and psychosocial evaluation of the patient. Patients with multiple somatic complaints not only present formidable management problems but also often have severe functional impairments that may outweigh those of patients with other so-called severe mental illnesses. Since somatoform disorders are the most common psychiatric disorders to present in non-psychiatric settings, it is important that training about them begin at undergraduate level. It should also be incorporated in the training of a wide variety of non-psychiatric specialists, both medical and non-medical.