Surface area in the insula was associated with 28-month functional outcome in first-episode psychosis

Many studies have tested the relationship between demographic, clinical, and psychobiological measurements and clinical outcomes in ultra-high risk for psychosis (UHR) and first-episode psychosis (FEP). However, no study has investigated the relationship between multi-modal measurements and long-term outcomes for >2 years. Thirty-eight individuals with UHR and 29 patients with FEP were measured using one or more modalities (cognitive battery, electrophysiological response, structural magnetic resonance imaging, and functional near-infrared spectroscopy). We explored the characteristics associated with 13- and 28-month clinical outcomes. In UHR, the cortical surface area in the left orbital part of the inferior frontal gyrus was negatively associated with 13-month disorganized symptoms. In FEP, the cortical surface area in the left insula was positively associated with 28-month global social function. The left inferior frontal gyrus and insula are well-known structural brain characteristics in schizophrenia, and future studies on the pathological mechanism of structural alteration would provide a clearer understanding of the disease.


Criteria for the UHR group
The inclusion criteria for the ultra-high risk for psychosis (UHR) group were defined using the Structured Interview for Prodromal Syndromes (SIPS) criteria by assessing c) Symptoms occurred at least once per week for the last month.

2) BIPS
Satisfying all the following items (a-c): a) The presence of at least 1 of 5 SOPS positive items in the psychotic range (rating of 6). b) Symptoms began in the past 3 months. c) Symptoms occurred at least several minutes per day and at least once per month.

3) GRDS
Satisfying all the following items (a-b): a) A first degree relative had a history of a psychotic disorder, or criteria for schizotypal personality disorder were met in the patient.
b) The global assessment of functioning (GAF) score dropped at least 30% over the last month compared to 1 year ago.

EEG recording and preprocessing in MMN
Electroencephalogram (EEG) data were recorded using a 64-channel Geodesic EEG System (Electrical Geodesics Inc., Eugene, OR). The electrodes were referenced to the vertex with the impedances being maintained < 50 kΩ. The sampling rate was set at 500 Hz with the analog bandpass filter set at 0.1-100 Hz. The two paradigms were counterbalanced across participants. All stimuli were presented binaurally through earphones while participants sat watching a silent cartoon.
Obtained waveform was analyzed using EEGLAB 3 . EEG signals at each electrode were re-referenced using an average reference and digitally filtered at 0.1-20 Hz. Epochs were extracted from −100 to 500 ms relative to the stimulus onset. Then, the baseline was corrected by subtracting the mean amplitude from −100 to 0 ms. Eyeblink artifacts were extracted using an independent component analysis. Epochs exceeding ± 100 μV at each electrode were excluded. The waveforms evoked by both standard and deviant stimuli were obtained through across-trial averaging. The MMN waveform was obtained as the difference in the average waveforms between the standard and deviant stimuli. We calculated the duration and frequency MMN amplitudes as the mean amplitudes from 135 to 205 ms and from 100 to 200 ms post-stimulus, respectively. We

List of brain regions
We used the Desikian-Killiany atlas in FreeSurfer for the cortical segmentation listed as follows: Cortical surface area and thickness (34 regions per hemisphere)

fNIRS measurement procedure fNIRS instrument
A 52-channel fNIRS instrument (ETG-4000; Hitachi Medical Co., Tokyo, Japan) was used to measure the relative changes in oxygenated hemoglobin concentration that reflect cortical activity. The fNIRS probe attachment was set with 33 probes in a thermo-plastic 3 × 11 shell to cover the bilateral prefrontal and anterior temporal cortices, with the lowest probe line set along the Fp1-Fp2 line defined by the international 10-20 system commonly used in electroencephalography. The location of fNIRS measurements for each channel was estimated using a probabilistic location by a virtual registration from MRI measurements with an fNIRS probe attachment 4,5 . This method provides the probability (p) of a brain region for each channel (ch) within 1 cm of the T3-T4 segment. Using this registration, we estimated brain signals in each brain region of interest (ROI) using the formula: SignalT3T4,ROI = (Σ pch × Signalch) / psum.
The virtual registration for the 52-channel probe covered 12 brain regions in the front-temporal hemisphere using Automated Anatomical Labeling (AAL) 6 . To obtain reliable fNIRS signals in the brain regions within 25-35 cm of the T3-FPz-T4 segment according to the international 10-20 system used in EEG, we used 8 regions per hemisphere for further analyses (superior frontal gyrus, superior frontal medial cortex, middle frontal gyrus, inferior frontal gyrus triangularis, inferior frontal gyrus opercularis, inferior frontal gyrus orbitalis, superior temporal gyrus, and middle temporal gyrus). Missing values for the T3-T4 segment were substituted by the mean length for male and female participants in this study, 31 cm for male participants and 29 cm for female, respectively.

Cognitive task
Participants only needed to sit in a chair in a relaxed state with their eyes open. To minimize motion artifacts, we instructed them to refrain from physical movements such as head motions and strong biting during measurements.
We used a 160-s block-designed phonological verbal fluency task that is well adapted as an activation task during fNIRS measurements 7,8 . The task consists of 30-s pre-task, 60-s task, and 70-s post-task periods. In the 60-s task period, the participant was instructed to say as many words aloud as possible that start with a phonological syllable provided by a computer. The task period was divided into 3 sub-periods, and the instructed syllables changed every 20 s to avoid silent moments. In the 30-s pre-task and 70-s post-task periods, the participant was instructed to say Japanese vowels aloud repeatedly, to control for task-related motion artifacts and facilitate their removal. This procedure can spatio-temporally measure hemoglobin changes, mainly in the prefrontal cortex and the anterior and superior parts of the temporal cortex, because continuous word generation exercises various cognitive domains involved in verbal storage, verbal working memory, inhibition, and executive control to avoid repetition and inappropriate word use. The number of words generated during the task period was assessed as task performance.

fNIRS signal treatment
Signals for fNIRS oxygenated hemoglobin were acquired for 0.1 s. Then, the signals were focused on task-specific signal changes using a linear fitting between the last 10 s of the pre-task period and the 5 s between the 50-and 55-s time points of the post-task period. Brain activity is defined as relative hemoglobin changes during the task period compared to pre-and post-task periods (mM·mm).
For visible artifacts derived from body and head movements, we used automatic rejection software revised from our previous study 9 . We classified the artifacts contained in fNIRS signals into the following 3 types: flattened signals, Gaussian noise, and motion artifacts. We discarded the entire signal from a channel when it contained artifacts exceeding the predetermined threshold. Therefore, the available channels were different for each participant. If 27 or more channels were rejected, we excluded the measurement itself from the analysis. Finally, fNIRS oxygenated hemoglobin signals were smoothed for 5 s to clear high frequency noises such as heartbeat and small motion artifacts.