Brain ageing and neurodegeneration in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a psychiatric condition characterized by alternating episodes of mania and depression frequently associated with cognitive impairments. BD is associated with brain alterations in fronto-temporal and limbic networks. Recent conceptualizations view BD as a neurodegenerative disorder characterized by progressive deterioration of grey and white matter (GM, WM) volumes and accelerated brain ageing. Therefore, we conducted a review gathering neuroimaging evidence about neurodegenerative processes in BD. METHODS: A literature search was conducted on the PubMed, Scopus and Web of Science databases in September 2021. After title and abstract screening of the retrieved records, 19 studies that met our inclusion criteria were included in the review. RESULTS: The available evidence suggests the presence of a progressive reduction of GM volumes at the whole-brain level and in the amygdala, prefrontal regions and the anterior cingulate cortex. Conversely, WM lesions and alterations seem to emerge only in the early phases of the condition masking the effects of normal ageing. Lastly, machine learning models indicate that the gap between predicted and chronological brain age differs considerably between healthy controls and BD patients, as the latter are characterized by larger gaps. LIMITATIONS: The included studies had cross-sectional study design, small sample sizes and heterogeneous methodology, and lack of control for pharmacological treatment. CONCLUSIONS: BD seems to be associated with generalized age-related structural GM volumes reductions and functional brain alterations thus suggesting the presence of neurodegenerative processes. Future systematic reviews and meta-analyses should be conducted to quantify the magnitude of brain ageing-related effects in BD.

Inefficient white matter activity in Schizophrenia evoked during intra and inter-hemispheric communication.

Intensive cognitive tasks induce inefficient regional and network responses in schizophrenia (SCZ). fMRI-based studies have naturally focused on gray matter, but appropriately titrated visuo-motor integration tasks reliably activate inter- and intra-hemispheric white matter pathways. Such tasks can assess network inefficiency without demanding intensive cognitive effort. Here, we provide the first application of this framework to the study of white matter functional responses in SCZ. Event-related fMRI data were acquired from 28 patients (nine females, mean age 43.3, ±11.7) and 28 age- and gender-comparable controls (nine females, mean age 42.1 ± 10.1), using the Poffenberger paradigm, a rapid visual detection task used to induce intra- (ipsi-lateral visual and motor cortex) or inter-hemispheric (contra-lateral visual and motor cortex) transfer. fMRI data were pre- and post-processed to reliably isolate activations in white matter, using probabilistic tractography-based white matter tracts. For intra- and inter-hemispheric transfer conditions, SCZ evinced hyper-activations in longitudinal and transverse white matter tracts, with hyper-activation in sub-regions of the corpus callosum primarily observed during inter-hemispheric transfer. Evidence for the functional inefficiency of white matter was observed in conjunction with small (~50 ms) but significant increases in response times. Functional inefficiencies in SCZ are (1) observable in white matter, with the degree of inefficiency contextually related to task-conditions, and (2) are evoked by simple detection tasks without intense cognitive processing. These cumulative results while expanding our understanding of this dys-connection syndrome, also extend the search of biomarkers beyond the traditional realm of fMRI studies of gray matter.

Incidental findings on brain MRI in patients with first-episode and chronic psychosis.

Brain incidental findings (IFs) are unexpected brain abnormalities detected by a structural magnetic resonance (MRI) examination. We conducted a study to assess whether brain IFs are associated with first-episode psychosis (FEP) and chronic psychosis (affective vs. non-affective) compared to healthy controls (HC). Chi-squared analyses were run to compare the frequency of several IFs across groups. Logistic regression analyses were run to explore the association between group and IFs, accounting for sex, age, MRI field strength. We observed a higher frequency of most IFs in both FEP and chronic psychosis groups compared to HC, however most of the chi-squared tests did not reach significance. Patients with FEP and chronic psychosis were 3-4 times more likely to show deep white matter hyperintensities (WMH) than HC. Patients with FEP and affective chronic psychosis were 3-4 times more likely to show ventricular asymmetries than HC. All chronic patients were more likely to show periventricular WMH, liquoral spaces enlargements and ventricular system enlargements respectively. Our results suggest that deep WMH and ventricular asymmetries are associated with both the early and the chronic stages of psychosis, thus representing potential vulnerability factors already present before the onset of the symptoms, possibly due to neurodevelopmental insults.

Childhood adversities and bipolar disorder: a neuroimaging focus.

Early-life adverse events or childhood adversities (CAs) are stressors and harmful experiences severely impacting on a child's wellbeing and development. Examples of CAs include parental neglect, emotional and physical abuse and bullying. Even though the prevalence of CAs and their psychological effects in both healthy and psychiatric populations is established, only a paucity of studies have investigated the neurobiological firms associated with CAs in bipolar disorder (BD). In particular, the exact neural mechanisms and trajectories of biopsychosocial models integrating both environmental and genetic effects are still debated. Considering the potential impact of CAs on BD, including its clinical manifestations, we reviewed existing literature discussing the association between CAs and brain alterations in BD patients. Results showed that CAs are associated with volume alterations of several grey matter regions including the hippocampus, thalamus, amygdala and frontal cortex. A handful of studies suggest the presence of alterations in the corpus callosum and the pre-fronto-limbic connectivity at rest. Alterations in these regions of the brain of patients with BD are possibly due to the effect of stress produced by CAs, being hippocampus part of the hypothalamus-pituitary-adrenal axis and thalamus together with amygdala filtering sensory information and regulating emotional responses. However, results are mixed possibly due to the heterogeneity of methods and study design. Future neuroimaging studies disentangling between different types of CAs or differentiating between BD sub-types are needed in order to understand the link between CAs and BD.

Neuroimaging studies exploring the neural basis of social isolation.

According to the social brain hypothesis, the human brain includes a network designed for the processing of social information. This network includes several brain regions that elaborate social cues, interactions and contexts, i.e. prefrontal paracingulate and parietal cortices, amygdala, temporal lobes and the posterior superior temporal sulcus. While current literature suggests the importance of this network from both a psychological and evolutionary perspective, little is known about its neurobiological bases. Specifically, only a paucity of studies explored the neural underpinnings of constructs that are ascribed to the social brain network functioning, i.e. objective social isolation and perceived loneliness. As such, this review aimed to overview neuroimaging studies that investigated social isolation in healthy subjects. Social isolation correlated with both structural and functional alterations within the social brain network and in other regions that seem to support mentalising and social processes (i.e. hippocampus, insula, ventral striatum and cerebellum). However, results are mixed possibly due to the heterogeneity of methods and study design. Future neuroimaging studies with longitudinal designs are needed to measure the effect of social isolation in experimental v. control groups and to explore its relationship with perceived loneliness, ultimately helping to clarify the neural correlates of the social brain.

Decoding overt shifts of attention in depth through pupillary and cortical frequency tagging.

Objective. We have recently developed a prototype of a novel human-computer interface for assistive communication based on voluntary shifts of attention (gaze) from a far target to a near target associated with a decrease of pupil size (Pupillary Accommodative Response, PAR), an automatic vegetative response that can be easily recorded. We report here an extension of that approach based on pupillary and cortical frequency tagging.Approach. In 18 healthy volunteers, we investigated the possibility of decoding attention shifts in depth by exploiting the evoked oscillatory responses of the pupil (Pupillary Oscillatory Response, POR, recorded through a low-cost device) and visual cortex (Steady-State Visual Evoked Potentials, SSVEP, recorded from 4 scalp electrodes). With a simple binary communication protocol (focusing on a far target meaning 'No', focusing on the near target meaning 'Yes'), we aimed at discriminating when observer's overt attention (gaze) shifted from the far to the near target, which were flickering at different frequencies.Main results. By applying a binary linear classifier (Support Vector Machine, SVM, with leave-one-out cross validation) to POR and SSVEP signals, we found that, with only twenty trials and no subjects' behavioural training, the offline median decoding accuracy was 75% and 80% with POR and SSVEP signals, respectively. When the two signals were combined together, accuracy reached 83%. The number of observers for whom accuracy was higher than 70% was 11/18, 12/18 and 14/18 with POR, SVVEP and combined features, respectively. A signal detection analysis confirmed these results.Significance. The present findings suggest that exploiting frequency tagging with pupillary or cortical responses during an attention shift in the depth plane, either separately or combined together, is a promising approach to realize a device for communicating with Complete Locked-In Syndrome (CLIS) patients when oculomotor control is unreliable and traditional assistive communication, even based on PAR, is unsuccessful.

Default mode network activity in bipolar disorder.

Since its discovery in 1997, the default mode network (DMN) and its components have been extensively studied in both healthy individuals and psychiatric patients. Several studies have investigated possible DMN alterations in specific mental conditions such as bipolar disorder (BD). In this review, we describe current evidence from resting-state functional magnetic resonance imaging studies with the aim to understand possible changes in the functioning of the DMN in BD. Overall, several types of analyses including seed-based and independent component have been conducted on heterogeneous groups of patients highlighting different results. Despite the differences, findings seem to indicate that BD is associated with alterations in both frontal and posterior DMN structures, mainly in the prefrontal, posterior cingulate and inferior parietal cortices. We conclude this review by suggesting possible future research directions.

Resting state networks activity in euthymic bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is a psychiatric condition causing shifts in mood, energy and activity levels severely altering the quality of life of the patients even in the euthymic phase. Although widely accepted, the neurobiological bases of the disorder in the euthymic phase remain elusive. This study aims at characterizing resting state functional activity of the BD euthymic phase in order to better understand the pathogenesis of the disease and build future neurobiological models. METHODS: Fifteen euthymic BD patients (10 females; mean age 40.2; standard deviation 13.5; range 20-61) and 27 healthy controls (HC) (21 females; mean age 37; standard deviation 10.6; range 22-60) underwent a 3T functional MRI scan at rest. Resting state activity was extracted through independent component analysis (ICA) run with automatic dimensionality estimation. RESULTS: ICA identified 22 resting state networks (RSNs). Within-network analysis revealed decreased connectivity in the visual, temporal, motor and cerebellar RSNs of BD patients vs HC. Between-network analysis showed increased connectivity between motor area and the default mode network (DMN) partially overlapping with the fronto-parietal network (FPN) in BD patients. CONCLUSION: Within-network analysis confirmed existing evidence of altered cerebellar, temporal, motor and visual networks in BD. Increased connectivity between the DMN and the motor area network suggests the presence of alterations of the fronto-parietal regions, precuneus and cingulate cortex in the euthymic condition. These findings indicate that specific connectivity alterations might persist even in the euthymic state suggesting the importance of examining both within and between-network connectivity to achieve a global understanding of the BD euthymic condition.

Adult Mild Encephalitis With Reversible Splenial Lesion Associated With Delirious Mania: A Case Report.

Mild encephalitis with reversible splenial lesion is a rare clinic-radiological entity presenting with neurological and neuropsychiatric symptoms associated with cerebral lesion/s. Delirious mania is a severe psychiatric syndrome characterized by acute onset of delirium, excitement, and psychosis with a high mortality rate. In this paper, we present a case report of mild encephalitis with reversible splenial lesion clinically presenting as delirious mania and evolving into life-threatening multi-organ failure. The patient was treated with aripiprazole and benzodiazepine with poor effect and, after 4 days, the patient's condition significantly worsened requiring transfer to the intensive care unit where deep sedation with propofol was started. Our findings are in contrast with the traditional literature description of self-resolving and harmless mild encephalitis with reversible splenial lesion. Moreover, rapid clinical recovery and the progressive improvement of psychiatric symptoms after deep sedation with propofol in this case-considering propofol's neuroprotective and anti-inflammatory effects-supports the notion of propofol-mediated deep sedation for the treatment of severe manic symptoms associated with life-threatening conditions. Little is known about neural markers of the manic state, and the corpus callosum has been described to be involved in bipolar disorder. Abnormalities in this structure may represent a marker of vulnerability for this disorder.

Mindfulness-based interventions in the early phase of affective and non-affective psychoses: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD.

BACKGROUND: In the last 10 years, psychological approaches based on mindfulness techniques have been proposed for the management of psychotic experiences. METHOD: In this brief review we summarized, to our knowledge for the first time, published studies on mindfulness-based interventions (MBIs) applied to the early phase of major psychoses (affective and non-affective). RESULTS: Despite the great variability in terms of MBIs protocols, available studies on young people at risk to develop or with a first episode of psychosis suggest MBIs as a feasible, well-tolerated and effective approach in ameliorating symptoms, functioning, emotion regulation, and finally reducing the psychological distress associated with the onset of mania and/or psychotic experience. LIMITATIONS: The small sample size and inconsistencies between studies in terms of design, MBIs protocols and outcome measures suggest being cautious in interpreting and generalizing results. Moreover, specific guidelines are missing for the adaptation of MBIs to youth at risk of developing affective psychoses. CONCLUSIONS: Preliminary findings show that MBIs may be considered a promising adjunctive therapy for the treatment of major psychoses in the early phases of the illness. However, the conduct of further studies in larger samples and with a more rigorous methodology is warranted to confirm the beneficial effect of MBIs in the early stages of major psychoses.

Cognitive remediation in schizophrenia: the earlier the better?

Impairments in neuro and social cognition are considered core features of schizophrenia (SCZ) since they affect patients' functioning and contribute to poor socio-occupational outcomes. Therefore, the improvement of cognitive performances has become a primary goal in the care of patients with SCZ, especially in the first phases of the disease, as early interventions may favour better long-term outcomes. Cognitive remediation (CR) is a behavioural training aimed at improving cognitive functions with the goal of durability and generalisation in everyday life. Neuroimaging studies suggest that CR leads to neuroplasticity in chronic SCZ, whereas only a few studies tested the neural effects of CR in the early phase of the disease. Thus, in this review, we aimed at summarising CR-induced structural and functional brain changes in early SCZ. Existing evidence showed a protective effect of CR on grey matter volume in selected medial-temporal (i.e. hippocampus, parahippocampus and amygdala) and thalamic regions whereas functional changes affected mostly dorsolateral prefrontal and insular cortices both associated with improvements in cognitive performance and emotion regulation. Overall, CR in early SCZ appears to be associated with neural adaptations mostly allocated in prefrontal and limbic regions, however future longitudinal studies are needed to clarify whether the positive effects of cognitive training persist over time. It may also be interesting to investigate whether the application of CR in the early v. the late stage of the disease may lead to incremental benefits.

The effects of cognitive remediation on cognitive abilities and real-world functioning among people with bipolar disorder: A systematic review: Special Section on "Translational and Neuroscience Studies in Affective Disorders". Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders.

BACKGROUND: Bipolar disorder (BD) is characterized by cognitive impairments that are known to predict psychosocial functioning and quality of life. While cognitive remediation (CR) was originally developed to directly target cognitive symptoms in traumatic brain injury and psychotic illnesses, the efficacy of CR in BD has begun to emerge only in the last decade. Functional Remediation (FR) is an integrated intervention that has been developed to restore psychosocial functioning by means of ecological neurocognitive techniques that involve psychoeducation about cognitive dysfunctions and their impact on the general functioning. Because of the heterogeneity of treatment targets and mechanisms of actions, here we aim to illustrate the effects induced by existing CR/FR approaches in BD. METHODS: In this systematic review, we evaluated cognitive and functional outcomes after CR/FR in studies conducted in BD. RESULTS: Eleven studies met inclusion criteria: 3 RCTs that compared CR/FR to one or more control condition (n = 354), 5 secondary analyses that further examined data from these trials, 2 single-arm studies, and 1 naturalistic study. While features such as the use of computerized training tools and a group-based format recurred across studies, CR/FR paradigms targeting different cognitive and functional domains showed specificity of training focus to outcomes. Effect sizes were in the medium-large range, suggesting that patients with BD respond to treatment at or above the level reported in psychotic patients. Integrated approaches that combined cognitive exercises with group-based experiences were associated with both cognitive and functional improvements. CONCLUSIONS: In this review, we found support for the use of CR/FR paradigms in patients with BD with evidence of cognitive and functional improvements. The scarcity of currently published RCTs as well as of data examining mechanisms of action and neural correlates limits the generalizability of our findings.

Disentangle the neural correlates of attachment style in healthy individuals.

Since its development and theorisation in the 60s, attachment theory has greatly influenced both clinical and developmental psychology suggesting the existence of complex dynamics based on the relationship between an infant and its caregiver, that affects personality traits and interpersonal relationships in adulthood. Many studies have been conducted to explore the association between attachment styles and psychosocial functioning and mental health. By contrast, only a few studies have investigated the neurobiological underpinnings of attachment style, showing mixed results. Therefore, in this review, we described current evidence from structural and functional imaging studies with the final aim to disentangle the neural correlates of attachment style in healthy individuals. Overall, different attachment styles have been correlated with volumetric alterations mainly in the cingulate cortex, amygdala, hippocampus and anterior temporal pole. Consistently, functional imaging studies suggested patterns of activations in fronto-striatal-limbic circuits during the processing of social and attachment-related stimuli. Further studies are needed to clarify the neurobiological signature of attachment style, possibly taking into consideration a wide range of demographic, psychosocial and clinical factors that may mediate the associations between the style of attachment and brain systems (e.g., gender, personality traits, psychosocial functioning, early-life experience).