Anna Castelnovo

Sleep spindle deficit in schizophrenia: contextualization of recent findings

Sleep spindles are wax and waning brain oscillations at a frequency range of 11–16 Hz, lasting 0.5–2 s, that define non-rapid eye movement sleep stage 2. Over the past few years, several independent studies pointed to a decrease of sleep spindles in schizophrenia. The aim of this review is to contextualize these findings within the growing literature on these oscillations across other neuro-psychiatric disorders. Indeed, spindles reflect the coordinated activity of thalamocortical networks, and their abnormality can be observed in a variety of conditions that disrupt local or global thalamocortical connectivity. Although the broad methodological variability across studies limits the possibility of drawing firm conclusions, impaired spindling activity has been observed in several neurodevelopmental and neurodegenerative disorders. Despite such lack of specificity, schizophrenia remains the only condition with a typical late adolescence to young adulthood onset in which impaired spindling has been consistently reported. Further research is necessary to clearly define the pathogenetic mechanisms that lead to this deficit and the validity of its widespread use as a clinical biomarker.

Stability of cognition across wakefulness and dreams in psychotic major depression

Cognitive bizarreness has been shown to be equally elevated in the dream and waking mentation of acutely symptomatic inpatients diagnosed with affective and non-affective psychoses. Although some studies have reported on dream content in non-psychotic depression, no study has previously measured this formal aspect of cognition in patients hospitalized for Psychotic Major Depression (PMD). Sixty-five dreams and 154 waking fantasy reports were collected from 11 PMD inpatients and 11 age- and sex-matched healthy controls. All narrative reports were scored by judges blind to diagnosis in terms of formal aspects of cognition (Bizarreness). Dream content was also scored (Hall/Van de Castle scoring system). Unlike controls, PMD patients had similar levels of cognitive bizarreness in their dream and waking mentation. Dreams of PMD patients also differed from those of controls in terms of content variables. In particular, Happiness, Apprehension and Dynamism were found to differ between the two groups. Whereas dream content reflects a sharp discontinuity with the depressive state, cognitive bizarreness adequately measures the stability of cognition across dreams and wakefulness in PMD inpatients.

Dreaming and the neurobiology of self: recent advances and implications for psychiatry.

Throughout most of the 20th century, dreaming was considered at the center of the leading psychotherapeutic approaches to mental disorders. Psychodynamic models of the mind stemmed from Sigmund Freuds Interpretation of Dreams, according to which knowledge of the unconscious foundations of most symptoms could be enhanced by an accurate evaluation of reported dreams. Toward the end of the century, these conceptualizations were challenged by a progressive shift of perspective in the direction of neurobiologically informed, mechanistic models of brain dysfunction. The diffusion of effective psychotropic medications developed to target specific symptoms across different disorders contributed to the requalification of psychiatry itself within the broader domain of medical sciences. A whole generation of psychiatrists turned to biology as a more scientific, rigorous and reliable framework to understand mental disorders. In parallel, new psychological techniques began to emerge that aimed to treat symptoms more directly by addressing dysfunctional cognitive constructs, leading to a relative weakening of the psychodynamic paradigm that is now considered one of several possible models in need of a neuroscientific validation. Neuroscience itself is largely based on cognitive psychology given the major simplicity of its theories in comparison to psychodynamic models, so that neurobiological research paradigms in psychiatry aim to define neural substrates of cognitive mechanisms that differ from the norm (Fusar-Poli and Broome, 2006). In line with this progression of scientific thought, modern dream research in psychiatry focuses on abnormalities of manifest dream content that can be found within different disorders. Although Post-Traumatic Stress Disorder (PTSD) is the only condition within which specific abnormalities of dream content are considered by clinicians in the diagnostic process—and become a specific target of treatment—several studies have shown that abnormal, disorder-specific dreams are reported by most subjects diagnosed with a mental disorder (Beauchemin and Hays, 1995; Sauteraud and Menny, 1997; Schredl and Engelhardt, 2001; Cartwright et al., 2006; Lusignan et al., 2009). Although several hypotheses on the relationship between dream and waking experiences have been proposed, some of which based on the known abnormalities of sleep rhythms and architecture that occur in psychiatric disorders, no definitive conclusion can be drawn. This difficulty relates to a poor understanding of mechanistic links between psychiatric diagnoses, sleep abnormalities, and chronobiological disruptions that have been recognized and studied for many decades (Wulff et al., 2010). In this opinion article, we will propose that the progressive refinement of our understanding of dream consciousness could foster significant advances for neuroscience and psychiatry as a whole.

Right hemisphere neural activations in the recall of waking fantasies and of dreams

The story‐like organization of dreams is characterized by a pervasive bizarreness of events and actions that resembles psychotic thought, and largely exceeds that observed in normal waking fantasies. Little is known about the neural correlates of the confabulatory narrative construction of dreams. In this study, dreams, fantasies elicited by ambiguous pictorial stimuli, and non‐imaginative first‐ and third‐person narratives from healthy participants were recorded, and were then studied for brain blood oxygen level‐dependent functional magnetic resonance imaging on a 3.0‐Tesla scanner while listening to their own narrative reports and attempting a retrieval of the corresponding experience. In respect to non‐bizarre reports of daytime activities, the script‐driven recall of dreams and fantasies differentially activated a right hemisphere network including areas in the inferior frontal gyrus, and superior and middle temporal gyrus. Neural responses were significantly greater for fantasies than for dreams in all regions, and inversely proportional to the degree of bizarreness observed in narrative reports. The inferior frontal gyrus, superior and middle temporal gyrus have been implicated in the semantic activation, integration and selection needed to build a coherent story representation and to resolve semantic ambiguities; in deductive and inferential reasoning; in self‐ and other‐perspective taking, theory of mind, moral and autobiographical reasoning. Their degree of activation could parallel the level of logical robustness or inconsistency experienced when integrating information and mental representations in the process of building fantasy and dream narratives.

Sleep endophenotypes of schizophrenia: slow waves and sleep spindles in unaffected first-degree relatives

Sleep spindles and slow waves are the main brain oscillations occurring in non-REM sleep. Several lines of evidence suggest that spindles are initiated within the thalamus, whereas slow waves are generated and modulated in the cortex. A decrease in sleep spindle activity has been described in Schizophrenia (SCZ), including chronic, early course, and early onset patients. In contrast, slow waves have been inconsistently found to be reduced in SCZ, possibly due to confounds like duration of illness and antipsychotic medication exposure. Nontheless, the implication of sleep spindles and slow waves in the neurobiology of SCZ and related disorders, including their heritability, remains largely unknown. Unaffected first-degree relatives (FDRs) share a similar genetic background and several neurophysiological and cognitive deficits with SCZ patients, and allow testing whether some of these measures are candidate endophenotypes. In this study, we performed sleep high-density EEG recordings to characterise the spatiotemporal features of sleep spindles and slow waves in FDRs of SCZ probands and healthy subjects (HS) with no family history of SCZ. We found a significant reduction of integrated spindle activity (ISAs) in FDRs relative to HS, whereas spindle density and spindle duration were not different between groups. FDRs also had decreased slow wave amplitude and slopes. Altogether, our results suggest that ISAs deficits might represent a candidate endophenotype for SCZ. Furthermore, given the slow wave deficits observed in FDRs, we propose that disrupted cortical synchronisation increases the risk for SCZ, but thalamic dysfunction is necessary for the disorder to fully develop.Diagnostics: Can sleep forewarn schizophrenia susceptibility?Sleep EEG recordings of schizophrenia patients’ relatives differ from healthy norms, suggesting a new hereditary biomarker of disease. Leading a collaboration of Italian and US scientists, the University of Milan’s Armando D’Agostino, Anna Castelnovo and Simone Sarasso compared the electrical activity of healthy subjects’ brains during sleep to that of first-degree relatives of schizophrenia patients. The team found a significant reduction in a parameter related to the amplitude of “sleep spindles,” one of the two major types of brainwaves in non-REM sleep, in the relatives’ brains. However, the density of sleep spindles—a schizophrenia-associated trait—was unaffected in relatives. The authors suggest that reduced sleep spindle amplitude may help to indicate an individual’s risk of developing schizophrenia. Other EEG features from relatives suggest a communication impairment between neuron groups, which may also predispose the illness.

Sleep spindles and slow waves in schizophrenia and related disorders: main findings, challenges and future perspectives

Sleep abnormalities have recently gained renewed attention in patients diagnosed with schizophrenia. Disrupted thalamocortical brain oscillations hold promise as putative biomarkers or endophenotypes of the disorder. Despite an increase in studies related to sleep spindle and slow‐wave activity, findings remain in part contradictory. Although sleep spindle deficits have been confirmed in several groups of patients with chronic, medicated schizophrenia, data on the early stages of the disorder and in unmedicated subjects are still insufficient. Findings on slow‐wave abnormalities are largely inconclusive, possibly due to the different criteria employed to define the phenomenon and to the influence of atypical antipsychotics. In this review, we aim to address the methodological and practical issues that may have limited the consistency of findings across research groups and different patient populations. Given the neurobiological relevance of these oscillations, which reflect the integrity of thalamocortical and cortico‐cortical function, research in this domain should be encouraged. To promote widespread consensus over the scientific and clinical implications of these sleep‐related phenomena, we advocate uniform and sound methodological approaches. These should encompass electroencephalographic recording and analysis techniques but also selection criteria and characterization of clinical populations.

Asenapine in the Treatment of Acute Mania: A Real-World Observational Study With 6 Months Follow-Up.

Abstract Asenapine is a second-generation antipsychotic with a unique pharmacological profile that was recently approved for the treatment of moderate/severe manic episodes. Real-world data on rapidity of action in inpatient settings are lacking. The aims of the current real-world observational study were to evaluate: (i) short-term efficacy of asenapine after 7 days (T0-T1) in patients hospitalized for a manic episode in the course of bipolar I disorder or schizoaffective disorder (group A), (ii) differences in length of stay (LoS), and (iii) rehospitalization compared to a control population (group B) with a 6-month follow-up. Twenty patients were included in each group. The mean total Young Mania Rating Scale score decreased by 12.6 (SD ±10.3; t(17) = 5.2, P < 0.005), implying a mean 37.8% improvement. A statistically significant reduction was observed for all Young Mania Rating Scale items, except for “sexual interest.” The mean total BPRS score decreased by 17.2 (SD ±14.9; t(17) = 4.9, P < 0.005). A statistically significant reduction was observed for several items, including “conceptual disorganization,” “grandiosity,” “unusual thought content,” and “excitement”. Length of stay was 17.9 (SD ±9.0) days for group A and 14.7 (SD ±12.7) days for group B; the result of the Kruskal-Wallis test showed no significant differences (&khgr;2 = 2.199, P = 0.138). Despite a high discontinuation rate, only 17.7% of patients in group A were rehospitalized in the following 6 months compared to 41.2% of those in group B (relative risk = 0.43, 95% confidence interval, 0.13–1.39). Findings from this small, preliminary study at least partially support the results of previous trials, confirming effectiveness and tolerability in the context of comorbidity and polypsychopharmacology.

P-1097 - Compliance to long-term antipsychotic treatments in schizophrenia: a descriptive study comparing adherence to oral vs depot psychopharmacotherapies

Introduction Efficacy of antipsychotic medications is nowadays confirmed, but their effectiveness is biased by the generally low compliance to therapy associated to psychotic patients. Psychiatric intramuscular depot pharmacotherapy represents a good option to increase compliance and to improve the outcome. Objective We indirectly assessed compliance to oral antipsychotic therapy by psychopathological and clinical scores, and compared it to results obtained on patients who were assuming intramuscular antipsychotic therapies, whose compliance is assumed to be total. Aim Our purpose was to discriminate differences in outcome between clients who were provided a psychopharmacological oral treatment, and those who take a depot psychopharmacotherapy. Methods We collected psychopathological and clinical data on 100 schizophrenic patients attending our outpatient psychiatric services; we divided our sample in two subgroups according to the type of therapy (oral vs depot). We matched patients depending on sex, age, schizophrenia subtype and age at onset, and compared psychopathological variables (BPRS, PANSS, NRS, SWS and number of hospitalizations) on 32 couples. Results We did not find any statistically significant difference between the two subgroups, as regards the outcome. Conclusion Efficacy to long-term oral antipsychotic therapy is similar to that shown by depot medications, suggesting that compliance between the two types of long-term therapies is high and comparable. We conclude that, balancing the pros and cons while choosing the typology of treatment, doctors should pay more attention to patients needs and preferences and to a good therapeutic alliance rather than to potential side effects and general outcome.