Functional abnormalities in the left ventrolateral prefrontal cortex during a semantic fluency task, and their association with thought disorder in patients with schizophrenia.

Thought disorder is one of the primary symptoms in schizophrenia, yet the neural correlates and related semantic processing abnormalities remain unclear. We aimed to investigate the relationship between functional prefrontal abnormalities and thought disorder in schizophrenia using 2 types of verbal fluency tasks: the letter fluency task (LFT) and the category fluency task (CFT). Fifty-six adult patients with schizophrenia and 56 healthy controls matched for age, gender, and IQ participated in the study. During completion of the 2 types of verbal fluency tasks, we measured oxy- and deoxy-hemoglobin concentration ([oxy-Hb] and [deoxy-Hb]) signal changes over a wide area of the bilateral prefrontal cortex, using a 52-channel near-infrared spectroscopy (NIRS) system. Thought disorder scores were evaluated using the positive and negative syndrome scale. CFT performance was significantly higher than LFT performance in both groups, while there was no significant difference in any prefrontal NIRS signal changes between the 2 tasks in either group. In both versions of verbal fluency task, healthy controls exhibited a significantly greater NIRS signal change than did patients with schizophrenia. On the CFT only, left ventrolateral prefrontal NIRS [deoxy-Hb] signals were significantly associated with thought disorder scores in patients with schizophrenia. Our results suggest that left ventrolateral prefrontal abnormalities in category fluency might be related to thought disorder in schizophrenia. This could lead to an improved understanding of the neural mechanisms within the left ventrolateral prefrontal cortex involved in mediating semantic processing, as well as the relationship between semantic processing abnormalities and thought disorder in schizophrenia.

Genetic influences on prefrontal activation during a verbal fluency task in adults: a twin study based on multichannel near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) studies have reported that prefrontal hemodynamic dysfunction during executive function tasks may be a promising biomarker of psychiatric disorders, because its portability and noninvasiveness allow easy measurements in clinical settings. Here, we investigated the degree to which prefrontal NIRS signals are genetically determined. Using a 52-channel NIRS system, we monitored the oxy-hemoglobin (oxy-Hb) signal changes in 38 adult pairs of right-handed monozygotic (MZ) twins and 13 pairs of same-sex right-handed dizygotic (DZ) twins during a letter version of the verbal fluency task. Heritability was estimated based on a classical twin paradigm using structured equation modeling. Significant genetic influences were estimated in the right dorsolateral prefrontal cortex and left frontal pole. The degrees of heritability were 66% and 75% in the variances, respectively. This implies that the prefrontal hemodynamic dysfunction observed during an executive function task measured by NIRS may be an efficient endophenotype for large-scale imaging genetic studies in psychiatric disorders.

Dysfunction of ventrolateral prefrontal cortex underlying social anxiety disorder: A multi-channel NIRS study.

Social anxiety disorder (SAD) is characterized by strong fear and anxiety during social interactions. Although ventrolateral prefrontal cortex (VLPFC) activity in response to emotional stimuli is related to pathological anxiety, little is known about the relationship between VLPFC activity and social anxiety. This study aimed to investigate whether VLPFC activity was involved in SAD and whether VLPFC activity was related to the level of social anxiety. Twenty-four drug-naïve patients with SAD and 35 healthy controls underwent near-infrared spectroscopy (NIRS) scanning while performing a verbal fluency task (VFT). Results indicated that, compared to the healthy controls, the SAD patients exhibited smaller changes of oxygenated hemoglobin (oxy-Hb) concentrations in the VLPFC during the VFT. Furthermore, the right VLPFC activation was negatively correlated with social avoidance. In contrast to the latter, the healthy controls exhibited a positive correlation between changes of oxy-Hb concentrations in the bilateral VLPFC and social fear. Our findings provide evidence for VLPFC dysfunction in SAD, and indicate that the VLPFC dysfunction may contribute to the difference between normal and abnormal social anxiety.

Differential spatiotemporal characteristics of the prefrontal hemodynamic response and their association with functional impairment in schizophrenia and major depression.

Recent neuroimaging studies have shown similarities and differences in prefrontal abnormalities between patients with schizophrenia (SZ) and major depressive disorder (MDD). However, the differential spatiotemporal characteristics of these abnormalities and their association with functional impairment remain unclear. To elucidate differential brain pathophysiology in these disorders, we used multichannel near-infrared spectroscopy (NIRS) to measure the spatiotemporal characteristics of prefrontal activation and investigated their association with global functioning levels. The study included 96 individuals: 32 patients with SZ, 32 patients with MDD, and 32 demographically matched healthy subjects. During a verbal fluency task, the changes in oxygenated and deoxygenated hemoglobin ([oxy-Hb] and [deoxy-Hb]) signals over the prefrontal cortex (PFC) were measured using 52-channel NIRS and compared among the 3 groups. Patients with SZ and MDD showed lesser-than-normal [oxy-Hb] activation during the task, whereas the initial slope of [oxy-Hb] activation was steeper for patients with MDD than for patients with SZ. The reduced hemodynamic response was associated with lower global functioning, and the correlative regions were different between the 2 disorders (frontopolar PFC in SZ; dorsolateral and ventrolateral PFC in MDD). The hypofrontality observed in patients with SZ and MDD is consistent with the findings of previous neuroimaging studies. Moreover, the spatiotemporal characteristics and the functional significance of the prefrontal hemodynamic response could differentiate the 2 psychiatric disorders. These results suggest a differential brain pathophysiology between SZ and MDD. Future large-scale studies are needed to determine the practical applicability of these findings for clinical diagnosis and evaluation.

Reduced but broader prefrontal activity in patients with schizophrenia during n-back working memory tasks: a multi-channel near-infrared spectroscopy study.

BACKGROUND: Caudal regions of the prefrontal cortex, including the dorsolateral (DLPFC) and ventrolateral (VLPFC) prefrontal cortex, are involved in essential cognitive functions such as working memory. In contrast, more rostral regions, such as the frontopolar cortex (FpC), have integrative functions among cognitive functions and thereby contribute crucially to real-world social activity. Previous functional magnetic resonance imaging studies have shown patients with schizophrenia had different DLPFC activity pattern in response to cognitive load changes compared to healthy controls; however, the spatial relationship between the caudal and rostral prefrontal activation has not been evaluated under less-constrained conditions. METHOD: Twenty-six patients with schizophrenia and 26 age-, sex-, and premorbid-intelligence-matched healthy controls participated in this study. Hemodynamic changes during n-back working memory tasks with different cognitive loads were measured using multi-channel near-infrared spectroscopy (NIRS). RESULTS: Healthy controls showed significant task-related activity in the bilateral VLPFC and significant task-related decreased activity in the DLPFC, with greater signal changes when the task required more cognitive load. In contrast, patients with schizophrenia showed activation in the more rostral regions, including bilateral DLPFC and FpC. Neither decreased activity nor greater activation in proportion to elevated cognitive load occurred. CONCLUSIONS: This multi-channel NIRS study demonstrated that activation intensity did not increase in patients with schizophrenia associated with cognitive load changes, suggesting hypo-frontality as cognitive impairment in schizophrenia. On the other hand, patients had broader prefrontal activity in areas such as the bilateral DLPFC and FpC regions, thus suggesting a hyper-frontality compensatory response.

Prefrontal cortex activity during response inhibition associated with excitement symptoms in schizophrenia.

Previous fMRI studies of schizophrenia have shown a prefrontal abnormality during response inhibition. However, the association with the clinical symptoms in schizophrenia remains unclear. The aim of the present study was to clarify the association of psychotic symptoms with the prefrontal function during response inhibition in patients with schizophrenia. We evaluated the prefrontal activity during the Go/NoGo task in 14 patients with schizophrenia and age- and gender-matched 40 healthy controls using multi-channel near-infrared spectroscopy. We also examined the relationship between the prefrontal function during the Go/NoGo task and psychotic symptoms assessed by the PANSS five-factor model in patients with schizophrenia. Subjects in both groups performed well on the task, and the omission and commission error rates in the NoGo condition showed no statistically significant differences. The comparison of prefrontal activation between the Go condition and the NoGo condition in each group revealed that the healthy controls had a significant deactivation during the NoGo condition in the dorsolateral prefrontal cortex (DLPFC), and such changes were not shown in patients with schizophrenia. Furthermore, in patients with schizophrenia, the excitement score of the PANSS five-factor model was positively correlated with the activation in the right prefrontal cortex and frontopolar region. These results suggested that the abnormal prefrontal activity during simple inhibition of response would be associated with excitement symptoms in patients with schizophrenia.

Association between severe dorsolateral prefrontal dysfunction during random number generation and earlier onset in schizophrenia.

OBJECTIVES: Schizophrenia involves impairment in attention, working memory and executive processes associated with prefrontal cortical function, an essential contributor of social functioning. Age at onset is a major factor for predicting social outcome in schizophrenia. In clinical settings, we need an objective assessment tool for evaluating prefrontal function and social outcome. METHODS: Participants included 22 right-handed patients with schizophrenia and 40 gender- and age-matched healthy controls. We used a 52-channel near-infrared spectroscopy (NIRS) instrument to measure oxygenated haemoglobin ([oxy-Hb]) changes over the prefrontal cortex during a random number generation (RNG) task. RESULTS: In healthy controls, we found significant [oxy-Hb] increase in the bilateral dorsolateral (DLPFC; BA9 and BA46) and ventrolateral prefrontal cortex (VLPFC; BA44, 45 and 47). The patients with schizophrenia showed significantly smaller activation than the healthy controls in the same approximate regions. In the patient group, a smaller [oxy-Hb] increase in the right DLPFC region (BA9) was significantly correlated with earlier age at onset. CONCLUSIONS: NIRS can detect prefrontal cortical dysfunction associated with an executive task, which was coupled with earlier age at onset in schizophrenia. SIGNIFICANCE: Multichannel NIRS, a non-invasive and user-friendly instrument, may be useful in evaluating cognitive function and social outcome in clinical settings in psychiatry.

Different hemodynamic response patterns in the prefrontal cortical sub-regions according to the clinical stages of psychosis.

BACKGROUND: Symptomatic and functional outcomes in schizophrenia are associated with the duration of untreated psychosis. However, no candidate biomarkers have been adopted in clinical settings. Multichannel near-infrared spectroscopy (NIRS), which can easily and noninvasively measure hemodynamics over the prefrontal cortex, is a candidate instrument for clinical use. AIMS: We intended to explore prefrontal dysfunction among individuals at different clinical stages, including ultra-high-risk (UHR), first-episode psychosis (FEP), and chronic schizophrenia (ChSZ), compared to healthy subjects. METHOD: Twenty-two UHR subjects, 27 patients with FEP, 38 patients with ChSZ, and 30 healthy subjects participated. We measured hemodynamic changes during a block-designed letter fluency task using multichannel NIRS instruments. RESULTS: We found that the activations of the bilateral ventrolateral prefrontal cortex, and the fronto-polar and anterior parts of the temporal cortical regions in the UHR group were lower than those of the controls, but similar to those of the FEP and ChSZ groups. However, the activations in the bilateral dorsolateral prefrontal cortex regions decrease with advancing clinical stage. CONCLUSIONS: To the best of our knowledge, this is the first study directly comparing differences in hemodynamic changes with respect to the 3 clinical stages of psychosis. Furthermore, this study also demonstrates different patterns of impairment according to the progression of clinical stages using NIRS instruments. NIRS measurements for UHR and FEP individuals may be candidate biomarkers for the early detection of the clinical stages of psychosis.