Sara Dallaspezia

Aim: Bipolar disorder (BD) is characterized by circadian dysregulation, altered sleep–wake behaviors, and heterogeneous antidepressant response. Chronotherapeutic interventions such as total sleep deprivation combined with light therapy (TSD + LT) produce rapid antidepressant effects, but predictors of outcome are lacking. We investigated whether fractal dynamics of motor activity, indexed by the short‐term scaling exponent α₁, are associated with antidepressant response, sleep–wake regulation, and structural brain measures and may serve as a biomarker of treatment responsiveness. Methods: Sixty‐eight BD inpatients underwent three cycles of TSD + LT. Depressive symptoms were assessed with the Hamilton Depression Rating Scale (HDRS), and treatment response was defined as a post‐treatment HDRS score P = 0.035) and was independently associated with treatment response ( P = 0.039). Baseline α₁ was associated with sleep–wake parameters, cerebellar gray matter volume, and white‐matter microstructure, including cerebellar peduncles and thalamo‐cortical tracts. Circadian rhythmicity increased in responders and decreased in nonresponders. Conclusion: Fractal motor activity tracks clinical changes during chronotherapeutic treatment in BD and may represent a candidate marker of treatment‐related behavioral regulation. Its association with cerebellar and white‐matter measures suggests multimodal relevance, warranting validation in larger longitudinal studies.

Seasonal rhythms affect the immune system. Evidence supports the involvement of immuno-inflammatory mechanisms in bipolar disorder (BD), with the neutrophil to lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII; platelets × neutrophils/lymphocytes) consistently reported to be higher in patients with BD than in HC, but seasonal rhythms of innate and adaptive immunity have never been studied. We retrospectively studied NLR and SII in 824 participants divided into three groups: 321 consecutively admitted inpatients affected by a major depressive episode in course of BD, and 255 consecutively admitted inpatients affected by obsessive–compulsive disorder (OCD; positive psychiatric control), and 248 healthy controls (HC). Patients with BD showed markedly higher markers of systemic inflammation in autumn and winter, but not in spring and summer, in respect to both HC and patients with OCD, thus suggesting a specific effect of season on inflammatory markers in BD, independent of a shared hospital setting and drug treatment. Given that systemic inflammation is emerging as a new marker and as target for treatment in depressive disorders, we suggest that seasonal rhythms should be considered for tailoring antidepressant immuno-modulatory treatments in a precision medicine approach.

Objective: Higher thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Method: Structural T ₁ -weighted brain magnetic resonance imaging (MRI) scans from 2,649 OCD patients and 2,774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were preregistered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Results: Unmedicated pediatric OCD patients (< 12 years) had larger lateral ( d = 0.46), pulvinar ( d = 0.33), ventral ( d = 0.35) and whole thalamus ( d = 0.40) volumes at unadjusted p -values d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Conclusion: Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.

Importance: Microstructural alterations in cortico-subcortical connections are thought to be present in Obsessive-Compulsive Disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Objective: To investigate microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. Design, Setting, and Participants: In this cross-sectional case-control magnetic resonance study, we investigated diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA-OCD Working Group. Main Outcomes and Measures: We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen’s d ) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Results: Adult OCD patients showed significant FA reduction in the sagittal stratum ( d =-0.21, z=-3.21, p=0.001) and posterior thalamic radiation ( d =-0.26, z =-4.57, p<0.0001). In the sagittal stratum only, lower FA was associated with a younger age of onset (z=2.71, p=0.006), longer duration of illness (z=-2.086, p=0.036) and a higher percentage of medicated patients in the cohorts studied (z=-1.98, p=0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to matched controls. Conclusions and Relevance: Microstructural alterations in projection and association fibers to posterior brain regions were found in adult OCD, and related to disease course and medication status. Such results are relevant to models positing deficits in connectivity as a crucial mechanism in OCD. KEY POINTS: Question: Do patients with Obsessive-Compulsive Disorder (OCD) show white matter microstructural alterations, and are these alterations related to clinical features? Findings: Data from 19 sites of the ENIGMA-OCD Consortium were included, involving 700 adult patients and 645 adult controls, 174 pediatric patients and 144 pediatric controls. Diffusion tensor imaging data were meta-analyzed using a harmonized data processing and analysis protocol. Adult, but not pediatric, patients showed alterations in the sagittal stratum and posterior thalamic radiation; sagittal stratum differences were associated with clinical features. Meaning: Microstructural abnormalities found in adult but not in the pediatric cohort, are related to illness duration and medication status.

Patient diurnal mood fluctuation, sleep characteristics and factors affecting sleep homeostasis predict antidepressant response to the combination of total sleep deprivation and light therapy (TSD + LT). In order to study if chronotype could influence response to TSD+LT, we considered 194 bipolar depressed patients. Severity of depression was rated with Hamilton Depression Rating Scale; perceived mood levels were assessed by a self-administered 10-cm visual analogue scale and chronotype was assessed using the Mornigness-Eveningness Questionnaire. More than 60% of patients resulted responders to treatment with chronotype influencing the antidepressant response with evening type subjects showing higher response rates.