Reduced slow wave density is associated with worse positive symptoms in clinical high risk: An objective readout of symptom severity for early treatment interventions?

Individuals at clinical high risk for psychosis (CHR) present subsyndromal psychotic symptoms that can escalate and lead to the transition to a diagnosable psychotic disorder. Identifying biological parameters that are sensitive to these symptoms can therefore help objectively assess their severity and guide early interventions in CHR. Reduced slow wave oscillations (∼1 Hz) during non-rapid eye movement sleep were recently observed in first-episode psychosis patients and were linked to the intensity of their positive symptoms. Here, we collected overnight high-density EEG recordings from 37 CHR and 32 healthy control (HC) subjects and compared slow wave (SW) activity and other SW parameters (i.e., density and negative peak amplitude) between groups. We also assessed the relationships between clinical symptoms and SW parameters in CHR. While comparisons between HC and the entire CHR group showed no SW differences, CHR individuals with higher positive symptom severity (N = 18) demonstrated a reduction in SW density in an EEG cluster involving bilateral prefrontal, parietal, and right occipital regions compared to matched HC individuals. Furthermore, we observed a negative correlation between SW density and positive symptoms across CHR individuals, suggesting a potential target for early treatment interventions.

Natural Oscillatory Frequency Slowing in the Premotor Cortex of Early-Course Schizophrenia Patients: A TMS-EEG Study.

Despite the heavy burden of schizophrenia, research on biomarkers associated with its early course is still ongoing. Single-pulse Transcranial Magnetic Stimulation coupled with electroencephalography (TMS-EEG) has revealed that the main oscillatory frequency (or "natural frequency") is reduced in several frontal brain areas, including the premotor cortex, of chronic patients with schizophrenia. However, no study has explored the natural frequency at the beginning of illness. Here, we used TMS-EEG to probe the intrinsic oscillatory properties of the left premotor cortex in early-course schizophrenia patients (<2 years from onset) and age/gender-matched healthy comparison subjects (HCs). State-of-the-art real-time monitoring of EEG responses to TMS and noise-masking procedures were employed to ensure data quality. We found that the natural frequency of the premotor cortex was significantly reduced in early-course schizophrenia compared to HCs. No correlation was found between the natural frequency and age, clinical symptom severity, or dose of antipsychotic medications at the time of TMS-EEG. This finding extends to early-course schizophrenia previous evidence in chronic patients and supports the hypothesis of a deficit in frontal cortical synchronization as a core mechanism underlying this disorder. Future work should further explore the putative role of frontal natural frequencies as early pathophysiological biomarkers for schizophrenia.

Personalized Repetitive Transcranial Magnetic Stimulation for Depression.

Personalized treatments are gaining momentum across all fields of medicine. Precision medicine can be applied to neuromodulatory techniques, in which focused brain stimulation treatments such as repetitive transcranial magnetic stimulation (rTMS) modulate brain circuits and alleviate clinical symptoms. rTMS is well tolerated and clinically effective for treatment-resistant depression and other neuropsychiatric disorders. Despite its wide stimulation parameter space (location, angle, pattern, frequency, and intensity can be adjusted), rTMS is currently applied in a one-size-fits-all manner, potentially contributing to its suboptimal clinical response (∼50%). In this review, we examine components of rTMS that can be optimized to account for interindividual variability in neural function and anatomy. We discuss current treatment options for treatment-resistant depression, the neural mechanisms thought to underlie treatment, targeting strategies, stimulation parameter selection, and adaptive closed-loop treatment. We conclude that a better understanding of the wide and modifiable parameter space of rTMS will greatly improve the clinical outcome.

Sleep Abnormalities in Different Clinical Stages of Psychosis: A Systematic Review and Meta-analysis.

Importance: Abnormal sleep is frequent in psychosis; however, sleep abnormalities in different stages (ie, clinical high risk for psychosis [CHR-P], early psychosis [EP], and chronic psychosis [CP]) have not been characterized. Objective: To identify sleep abnormalities across psychosis stages. Data Sources: Web of Science and PubMed were searched between inception and June 15, 2022. Studies written in English were included. Study Selection: Sleep disturbance prevalence studies and case-control studies reporting sleep quality, sleep architecture, or sleep electroencephalography oscillations in CHR-P, EP, or CP. Data Extraction and Synthesis: This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Stage-specific and pooled random-effects meta-analyses were conducted, along with the assessment of heterogeneity, study quality, and meta-regressions (clinical stage, sex, age, medication status, and psychotic symptoms). Main Outcomes and Measures: Sleep disturbance prevalence, self-reported sleep quality, sleep architecture (total sleep time, sleep latency, sleep efficiency, nonrapid eye movement, rapid eye movement stages, and number of arousals), and sleep electroencephalography oscillations (spindle density, amplitude, and duration, and slow wave density). Results: Fifty-nine studies with up to 6710 patients (n = 5135 for prevalence) and 977 controls were included. Sleep disturbance prevalence in pooled cases was 50% (95% CI, 40%-61%) and it was similar in each psychosis stage. Sleep quality was worse in pooled cases vs controls (standardized mean difference [SMD], 1.00 [95% CI, 0.70-1.30]). Sleep architecture alterations included higher sleep onset latency (SMD [95% CI]: pooled cases, 0.96 [0.62-1.30]; EP, 0.72 [0.52-0.92]; CP, 1.36 [0.66-2.05]), higher wake after sleep onset (SMD [95% CI]: pooled cases, 0.5 [0.29-0.71]; EP, 0.62 [0.34-0.89]; CP, 0.51 [0.09-0.93]), higher number of arousals (SMD [95% CI]: pooled cases, 0.45 [0.07-0.83]; CP, 0.81 [0.30-1.32]), higher stage 1 sleep (SMD [95% CI]: pooled cases, 0.23 [0.06-0.40]; EP, 0.34 [0.15-0.53]), lower sleep efficiency (SMD [95% CI]: pooled cases, -0.75 [-0.98 to -0.52]; EP, -0.90 [-1.20 to -0.60]; CP, -0.73 [-1.14 to -0.33]), and lower rapid eye movement density (SMD [95% CI]: pooled cases, 0.37 [0.14-0.60]; CP, 0.4 [0.19-0.77]). Spindle parameter deficits included density (SMD [95% CI]: pooled cases, -1.06 [-1.50 to -0.63]; EP, -0.80 [-1.22 to -0.39]; CP, -1.39 [-2.05 to -0.74]; amplitude: pooled cases, -1.08 [-1.33 to -0.82]; EP, -0.86 [-1.24 to -0.47]; CP, -1.25 [-1.58 to -0.91]; and duration: pooled cases: -1.2 [-1.69 to -0.73]; EP, -0.71 [-1.08 to -0.34]; CP, -1.74 [-2.10 to -1.38]). Individuals with CP had more frequent arousals vs CHR-P (z = 2.24, P = .02) and reduced spindle duration vs EP (z = -3.91, P < .001). Conclusions and Relevance: In this systematic review and meta-analysis, sleep disturbances were found to be prevalent throughout the course of psychosis, and different psychosis stages showed both shared and distinct abnormalities in sleep quality, architecture, and spindles. These findings suggest that sleep should become a core clinical target and research domain from at-risk to early and chronic stages of psychosis.

Sleep spindle alterations relate to working memory deficits in individuals at clinical high-risk for psychosis.

STUDY OBJECTIVES: Sleep spindles are waxing and waning EEG waves exemplifying the main fast oscillatory activity occurring during NREM sleep. Several recent studies have established that sleep spindle abnormalities are present in schizophrenia spectrum disorders, including in early-course and first-episode patients, and those spindle deficits are associated with some of the cognitive impairments commonly observed in these patients. Cognitive deficits are often observed before the onset of psychosis and seem to predict poor functional outcomes in individuals at clinical high-risk for psychosis (CHR). Yet, the presence of spindle abnormalities and their relationship with cognitive dysfunction has not been investigated in CHR. METHODS: In this study, overnight high-density (hd)-EEG recordings were collected in 24 CHR and 24 healthy control (HC) subjects. Spindle density, duration, amplitude, and frequency were computed and compared between CHR and HC. Furthermore, WM was assessed for both HC and CHR, and its relationship with spindle parameters was examined. RESULTS: CHR had reduced spindle duration in centro-parietal and prefrontal regions, with the largest decrease in the right prefrontal area. Moderation analysis showed that the relation between spindle duration and spindle frequency was altered in CHR relative to HC. Furthermore, CHR had reduced WM performance compared to HC, which was predicted by spindle frequency, whereas in HC spindle frequency, duration, and density all predicted working memory performance. CONCLUSION: Altogether, these findings indicate that sleep spindles are altered in CHR individuals, and spindle alterations are associated with their cognitive deficits, thus representing a sleep-specific putative neurophysiological biomarker of cognitive dysfunction in psychosis risk.

Sleep abnormalities in individuals at clinical high risk for psychosis.

Youth at clinical high risk (CHR) represent a unique population enriched for precursors of major psychiatric disorders. Sleep disturbances are consistently reported in CHR individuals. However, there is a dearth of studies investigating quantifiable objective measures of sleep dysfunction in CHR youth. In this study, sleep high density (hd)-EEG recordings were collected in twenty-two CHR and twenty healthy control (HC) subjects. Sleep architecture parameters, as well as sleep EEG power spectra in five frequency bands, were computed and compared between CHR and HC groups during non-rapid eye movement (NREM) sleep. Furthermore, correlation analyses between sleep EEG power spectra, sleep architecture parameters, and clinical symptoms, assessed with the scale of prodromal symptoms (SOPS), were conducted in CHR participants. Our results show that CHR individuals had more wakefulness after sleep onset (WASO) compared to HC participants. CHR also showed a higher NREM sleep gamma EEG power, which was observed in a large fronto-parieto-occipital area, relative to HC. Additionally, higher NREM gamma activity in lateral fronto-occipital regions was associated with more WASO, and increased NREM gamma power in medial fronto/parietal areas correlated with worse SOPS negative symptoms. Altogether, these findings suggest that topographically specific increases in EEG gamma activity during NREM sleep represent neurophysiological signatures underlying some of the objectively assessed sleep disturbances and clinical symptoms of CHR individuals.