An overview on Hebephrenia, a diagnostic cornerstone in the neurodevelopmental model of Schizophrenia

Pre-Kraepelinian observations converged in Kahlbaum’s and Hecker’s description of Hebephrenia. For Kraepelin, Hebephrenia was an ‘idiopathic incurable dementia whose onset is in adolescence’. It became the core of ‘Dementia Praecox’, and then Bleulerian ‘Schizophrenia’. In recent decades, the resurgence of the ‘late neurodevelopment’ hypothesis of schizophrenia has brought into focus Hecker’s clinical reports of adolescents who, as a result of a putative loss of psychic energy, showed a rapidly progressive cognitive impairment leading to functional and behavioural disorganization. This paper summarizes the nineteenth-century conceptualization of Hebephrenia as a developmental illness.

Sensory Sensitivity and Intolerance of Uncertainty Influence Anxiety in Autistic Adults

Several models of anxiety in autistic adults have focused on the role of intolerance of uncertainty which has biological and evolutionary bases, as a cognitive explanation for the high prevalence of anxiety in autism. This framework suggests that all people are born with a healthy level of intolerance of uncertainty, and as we develop, this intolerance is lessened as we learn when situations are safe and begin to understand and manage the uncertainty. This process of learning about managing uncertainty does not happen in the same way in those who are high in autistic traits, which could be the reason for the high levels of anxiety symptoms commonly seen in this population. We examined archival data of 199 non-autistic and 55 autistic adults from prior studies in which we collected self-report measures of autistic traits, intolerance of uncertainty, sensory processing, and anxiety. We conducted two path analyses to examine the role of intolerance of uncertainty in anxiety in autistic adults. The first model tested the idea that intolerance of uncertainty, an evolutionary phenomenon common for all people, could explain some of the cognitive aspects of anxiety in autism. The second model suggests that primary neurodevelopmental differences associated with autistic traits underlie the sensory sensitivity and sensory seeking behaviors, which in turn increase intolerance of uncertainty and subsequent anxiety. We found that the “neurodevelopmental” model had better model fit than the “evolutionary stress” model, suggesting that the neurodevelopmental impact of higher levels of autistic traits could moderate a non-autistic trajectory of learning to manage uncertainty as children develop and understand that uncertainty is common and acceptable.

Frontal-posterior functional imbalance and aberrant function developmental patterns in schizophrenia

Schizophrenia (SZ) is a neurodevelopmental disorder. There remain significant gaps in understanding the neural trajectory across development in SZ. A major research focus is to clarify the developmental functional changes of SZ and to identify the specific timing, the specific brain regions, and the underlying mechanisms of brain alterations during SZ development. Regional homogeneity (ReHo) characterizing brain function was collected and analyzed on humans with SZ (hSZ) and healthy controls (HC) cross-sectionally, and methylazoxymethanol acetate (MAM) rats, a neurodevelopmental model of SZ, and vehicle rats longitudinally from adolescence to adulthood. Metabolomic and proteomic profiling in adult MAM rats and vehicle rats was examined and bioanalyzed. Compared to HC or adult vehicle rats, similar ReHo alterations were observed in hSZ and adult MAM rats, characterized by increased frontal (medial prefrontal and orbitofrontal cortices) and decreased posterior (visual and associated cortices) ReHo. Longitudinal analysis of MAM rats showed aberrant ReHo patterns as decreased posterior ReHo in adolescence and increased frontal and decreased posterior ReHo in adulthood. Accordingly, it was suggested that the visual cortex was a critical locus and adolescence was a sensitive window in SZ development. In addition, metabolic and proteomic alterations in adult MAM rats suggested that central carbon metabolism disturbance and mitochondrial dysfunction were the potential mechanisms underlying the ReHo alterations. This study proposed frontal-posterior functional imbalance and aberrant function developmental patterns in SZ, suggesting that the adolescent visual cortex was a critical locus and a sensitive window in SZ development. These findings from linking data between hSZ and MAM rats may have a significant translational contribution to the development of effective therapies in SZ.

Mitochondrial, cell cycle control and neuritogenesis alterations in an iPSC-based neurodevelopmental model for schizophrenia

Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world’s population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients and do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls. Our results revealed differentially regulated proteins in pathways related to mitochondrial function, oxidative phosphorylation, cell cycle control, DNA repair, and neuritogenesis. Moreover, metabolic analysis of NSCs revealed alterations in mitochondrial function in schizophrenia-derived cells. Hence, this study shows that changes in important cellular processes are present during neurodevelopment and could be involved with the establishment of schizophrenia, as well as the phenotypic traits observed in adult patients.