COMMENTARY

Hypofrontality in schizophrenia: RIP

Schizophrenia (SCZ) is marked by working memory (WM) deficits, which predict poor functional outcome. While most functional magnetic resonance imaging studies of WM in SCZ have focused on the dorsolateral prefrontal cortex (PFC), some recent work suggests that the medial PFC (mPFC) may play a role. We investigated whether task-evoked mPFC deactivation is associated with WM performance and whether it mediates deficits in SCZ. In addition, we investigated associations between mPFC deactivation and cortical dopamine release.

Patients with SCZ (n = 41) and healthy control participants (HCs) (n = 40) performed a visual object n-back task during functional magnetic resonance imaging. Dopamine release capacity in mPFC was quantified with [¹¹C]FLB457 in a subset of participants (9 SCZ, 14 HCs) using an amphetamine challenge. Correlations between task-evoked deactivation and performance were assessed in mPFC and dorsolateral PFC masks and were further examined for relationships with diagnosis and dopamine release.

mPFC deactivation was associated with WM task performance, but dorsolateral PFC activation was not. Deactivation in the mPFC was reduced in patients with SCZ relative to HCs and mediated the relationship between diagnosis and WM performance. In addition, mPFC deactivation was significantly and inversely associated with dopamine release capacity across groups and in HCs alone, but not in patients.

Reduced WM task-evoked mPFC deactivation is a mediator of, and potential substrate for, WM impairment in SCZ, although our study design does not rule out the possibility that these findings could relate to cognition in general rather than WM specifically. We further present preliminary evidence of an inverse association between deactivation during WM tasks and dopamine release capacity in the mPFC.

Brain anomalies are frequently found in early psychoses. Although they may remain undetected for many years, their interpretation is critical for differential diagnosis. In secondary psychoses, their identification may allow specific management. They may also shed light on various pathophysiological aspects of primary psychoses. Here we reviewed cases of secondary psychoses associated with brain anomalies, reported over a 20-year period in adolescents and young adults aged 13–30 years old. We considered age at first psychotic symptoms, relevant medical history, the nature of psychiatric symptoms, clinical red flags, the nature of the brain anomaly reported, and the underlying disease. We discuss the relevance of each brain area in light of normal brain function, recent case-control studies, and postulated pathophysiology. We show that anomalies in all regions, whether diffuse, multifocal, or highly localized, may lead to psychosis, without necessarily being associated with non-psychiatric symptoms. This underlines the interest of neuroimaging in the initial workup, and supports the hypothesis of psychosis as a global network dysfunction that involves many different regions.

Brain functional changes reported in schizophrenia include reduced prefrontal cortex activation (hypofrontality), increased frontal activation (hyperfrontality) and failure of de-activation in the medial frontal cortex. The relative importance of these changes is unestablished.

A ‘discovery’ sample of 32 schizophrenic patients and 32 controls was used to establish regions of altered activation and de-activation in the patients. The discriminatory power of these regions was examined using receiver-operator characteristics (ROC) analysis in two ‘test’ samples, one of 83 patients with chronic schizophrenia and 83 healthy controls, and the other of 31 first-episode patients and 31 healthy controls.

The discovery sample revealed reduced activation in the prefrontal cortex and other regions, and failure of de-activation in the medial frontal cortex. Failure of de-activation had significantly greater power to distinguish the chronic patients from the healthy controls than hypoactivation. The pattern was similar in the first-episode patients, where additionally the discriminatory power of hypoactivation was poor. Controlling for the effects of n-back task performance tended to reduce discriminatory power overall, but this persisted for failure of de-activation in the chronic test sample.

Both hypoactivation and failure of de-activation can distinguish patients with chronic schizophrenia from healthy subjects, but the latter abnormality has more power. Failure of de-activation cannot be construed simply as a passive consequence of reduced prefrontal activation in the disorder.

Schizophrenia (SZ) is a severe mental disorder poorly elucidated from the etiopathogenesis prism. Recently, several micro- and macro-vascular abnormalities have been consistently implicated in SZ's pathophysiology. Since angiogenesis is involved in several biological functions and is a fundamental process in vascular formation and angioregulation, it can provide a framework in which some etiological factors and susceptibility genes for SZ can be linked together. We performed a comprehensive non-systematic review of the literature to explore the possible link between SZ and angiogenesis from a vascular perspective, taking into account new insights from genetic, molecular, neurochemical, animal, and neuroimaging functional studies. Recent molecular and neuroimaging studies indicate that angiogenesis could be involved in SZ etiopathogenesis through its role in neurogenesis during neurodevelopment, or by angiomodulation of cerebral blood flow (CBF). Furthermore, it has been hypothesized that the epidemiological finding of lesser predisposition of SZ patients to certain types of cancer could be derived by a putative interplay between SZ pathophysiology and angiogenesis. While it is yet unclear how a complex multivariate interplay between angiogenic factors, neurotrophins, dopamine and other neurotransmitters, brain angiogenic inhibitor molecules (BAI1–3) and patterns of regional blood flow may yield to a biological effect, the importance of further investigation and considering them as potential therapeutic targets for SZ is highlighted.

Small sample sizes and large inter-subject variations result in inconsistent findings in resting-state cerebral blood flow (CBF) in schizophrenia. The CBF connectivity alterations in schizophrenia remain unclear. Recently, three-dimensional pseudo-continuous arterial spin labeling (pcASL) imaging was performed to measure the resting-state CBF in 100 schizophrenia patients and 94 healthy comparison subjects. The normalized CBF was used to reduce the inter-subject variations. Both group comparisons in the CBF and correlations between the CBF alterations and clinical parameters were assessed. The CBF connectivity of the brain regions with regional CBF differences was also compared between the groups. Compared with the healthy controls, the schizophrenia patients exhibited increased CBF in the bilateral inferior temporal gyri, thalami and putamen and decreased CBF in the left insula and middle frontal gyrus and the bilateral anterior cingulate cortices and middle occipital gyri. In the schizophrenia patients, significant correlations were identified between the CBF and clinical parameters. Importantly, the schizophrenia patients exhibited CBF disconnections between the left thalamus and right medial superior frontal gyrus and between the left insula and left postcentral gyrus. Our results suggest that schizophrenia patients may exhibit both regional CBF abnormalities and deficits in CBF connectivity, which may underlie the clinical symptoms of schizophrenia.

Auditory verbal hallucinations (AVHs) are speech perceptions that lack an external source, phenomenologically experienced as “hearing voices”. A perceptual origin of an AVH experience in patients with schizophrenia can however not explain why the “voices” drain the attentional and cognitive capacity of the patients, making them unable to direct attention away from the “voices” and to cognitively suppress the experience. We recently reported how AVHs interfere with the perception of speech sounds, using a dichotic listening experimental paradigm. We now extend this finding by reporting on the interference caused by AVHs on attention and cognitive control, using a slight variation of the same dichotic listening paradigm. The patients (N = 148) were instructed to pay attention to and report from either the right or left ear syllable of the dichotic pair. We then correlated their PANSS score for the hallucination item (P3) with the performance score on the dichotic listening task. The results showed that AVHs interfered with the ability to report the right ear syllable when instructed to pay attention to the right side, which is a marker of inability to attend to an external speech stimulus. When instructed to pay attention to the left side, AVHs interfered with the ability to report the left ear syllable, which is a marker of inability to use cognitive control to suppress attending to the “voices”. The corresponding correlations for the emotional withdrawal (N2) negative symptom were all non-significant. The correlations were substantiated in an ANOVA with corresponding significant group differences between high versus low symptom score groups. The results thus extend our previous findings of a perceptual origination for AVHs by showing that AVHs interfere with the ability to attend to the outer world around the patient, and the ability to inhibit, or suppress, the “voices” once they occur. Future research should pin down the neuronal basis of both the origination and the attentional and cognitive control aspects of AVHs.