Neuroprotective Effects of Moderate Hypoxia: A Systematic Review.

Emerging evidence highlights moderate hypoxia as a candidate treatment for brain disorders. This systematic review examines findings and the methodological quality of studies investigating hypoxia (10-16% O2) for ≥14 days in humans, as well as the neurobiological mechanisms triggered by hypoxia in animals, and suggests optimal treatment protocols to guide future studies. We followed the preferred reporting items for systematic reviews and meta-analysis (PRISMA) 2020. Searches were performed on PubMed/MEDLINE, PsycInfo, EMBASE, and the Cochrane Library, in May-September 2023. Two authors independently reviewed the human studies with the following tools: (1) revised Cochrane collaboration's risk of bias for randomized trials 2.0; (2) the risk of bias in nonrandomized studies of interventions. We identified 58 eligible studies (k = 8 human studies with N = 274 individuals; k = 48 animal studies) reporting the effects of hypoxia on cognition, motor function, neuroimaging, neuronal/synaptic morphology, inflammation, oxidative stress, erythropoietin, neurotrophins, and Alzheimer's disease markers. A total of 75% of human studies indicated cognitive and/or neurological benefits, although all studies were evaluated ashigh risk of bias due to a lack of randomization and assessor blinding. Low-dose intermittent or continuous hypoxia repeated for 30-240 min sessions, preferably in combination with motor-cognitive training, produced beneficial effects, and high-dose hypoxia with longer (≥6 h) durations and chronic exposure produced more adverse effects. Larger and methodologically stronger translational studies are warranted.

Early longitudinal changes in brain structure and cognitive functioning in remitted patients with recently diagnosed bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) who are presenting with cognitive impairment and associated structural brain abnormalities have generally a poorer clinical outcome. This study aims to map the early longitudinal trajectories in brain structure and cognition in patients with recently diagnosed BD. METHODS: Fully or partially remitted patients with a recent diagnosis of BD and matched healthy controls (HC) underwent structural MRI and neuropsychological testing at baseline (BD n = 97; HC n = 66) and again following an average of 16 (range 6-27) months (BD n = 50; HC n = 38). We investigated the differential trajectories in BD vs. HC in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning using linear mixed models. Within patients, we further investigated whether brain structural abnormalities detected at baseline were associated with subsequent mood episodes. RESULTS: Compared to HC, patients showed a decline in total white matter volume over time and they had a larger amygdala volume, both at baseline and at follow-up time. Patients further showed lower cognitive performance at both times of investigation with no significant change over time. There were no differences between patients and HC in cortical gray matter volume or thickness, hippocampal volume, or brain-aging patterns. CONCLUSIONS: Cognitive impairment and amygdala enlargement may represent stable markers of BD early in the course of illness, whereas subtle white matter decline may result from illness progression.

Neural underpinnings of emotion regulation subgroups in remitted patients with recently diagnosed bipolar disorder.

Neuroimaging studies of bipolar disorder (BD) generally involve comparison with healthy controls (HC), which may mask neurobiological variability within the disorder. This study aims to assess the neural underpinnings of potential subgroups of BD patients based on functional activity in the emotion regulation network and its relation to illness characteristics and relapse risk. Eighty-seven remitted patients with recently diagnosed BD and 66 HC underwent functional magnetic resonance imaging (fMRI) while performing an emotion regulation task. Patients were re-assessed with clinical interviews after 16 (±5) months. Data-driven hierarchical cluster analysis was employed to investigate 'neuronal subgroups' of patients based on their neuronal activity in a pre-defined emotion regulation network. Relations between neuronal subgroups and illness characteristics and relapse rates were examined. Patients were allocated into two subgroups. Subgroup 1 (n=62, 75%) was characterized by exaggerated bilateral amygdala reactivity but normal prefrontal and temporo-parietal activation. Subgroup 2 (n= 22, 25%) showed widespread hypo-activity within all emotion regulation regions. Both subgroups were less successful at down-regulating their emotions than HC (F(2,146)=5.33, p=.006, ηp2=.07). Patients in subgroup 2 had a history of more and longer mixed episodes (ps≤.01). Importantly, heightened amygdala activity across all patients was associated with increased risk of relapse during a 16-month follow-up period (ß=3.36, 95% CI [1.49;550.35], N=60, p=.03). The identified neuronal subgroups of patients with either amygdala hyper-activity or broad network hypo-activity during emotion regulation points to neurobiological heterogeneity among remitted patients with BD. Heightened amygdala reactivity may be a neuronal target for personalized treatments to prevent relapse.

Action-based cognitive remediation in bipolar disorder improved verbal memory but had no effect on the neural response during episodic memory encoding.

Verbal memory and executive function impairments are common in remitted patients with bipolar disorder (BD). We recently found that Action-Based Cognitive Remediation (ABCR) may improve executive function and verbal memory in BD. Here, we investigated neuronal changes associated with ABCR treatment-related memory improvement in a longitudinal functional MRI (fMRI) study. Forty-five patients with remitted BD (ABCR: n = 26, control treatment: n = 19) completed a picture-encoding task during fMRI and tests of verbal memory and executive function outside the scanner before and after two weeks of ABCR/control treatment. The cognitive assessment was performed again following ten weeks of treatment. Thirty-four healthy controls underwent the same test protocol once for baseline comparisons. Patients showed a moderate improvement in a domain composite of verbal learning and memory both after two weeks and ten weeks of ABCR treatment, which correlated with improved executive function. At baseline, patients showed encoding-related hypoactivity in dorsal prefrontal cortex compared to healthy controls. However, treatment was not associated with significant task-related neuronal activity changes. Improved verbal learning and memory may have occurred through strengthened strategic processing targeted by ABCR. However, picture-encoding paradigms may be suboptimal to capture the neural correlates of this improvement, possibly by failing to engage strategic encoding processes.