Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

https://hal.archives-ouvertes.fr/hal-02926224/document

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

Enhancing cognitive control training with transcranial direct current stimulation: a systematic parameter study

Objective Misdiagnosis of bipolar disorder (BD) as unipolar disorder (UD) may cause improper treatment strategy to be chosen, especially in the early stages of disease. The aim of this study was to characterize alterations in specific brain networks for depressed patients who transformed into BD (tBD) from UD. Method The module allegiance from resting-fMRI by applying a multilayer modular method was estimated in 99 patients (33 tBD, 33 BD, 33 UD) and 33 healthy controls (HC). A classification model was trained on tBD and UD patients. HC was used to explore the functional declination patterns of BD, tBD, and UD. Results Based on our classification model, difference mainly reflected in default-mode network (DMN). Compared with HC, both BD and tBD focused on the difference of somatomotor network (SMN), while UD on the abnormity of DMN. The patterns of brain network between patients with BD and tBD were well-overlapped, except for cognitive control network (CCN). Conclusion The functional declination of internal interaction in DMN was suggested to be useful for the identification of BD from UD in the early stage. The higher recruitment of DMN may predispose patients to depressive states, while higher recruitment of SMN makes them more sensitive to external stimuli and prone to mania. Furthermore, CCN may be a critical network for identifying different stages of BD, suggesting that the onset of mania in depressed patients is accompanied by CCN related cognitive impairments.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bdi.12819

Early identification of bipolar from unipolar depression before manic episode: Evidence from dynamic rfMRI.

Large-scale network abnormality in bipolar disorder: A multimodal meta-analysis of resting-state functional and structural magnetic resonance imaging studies.

Altered dynamic functional connectivity across mood states in bipolar disorder.

Neuropsychiatric illnesses including mood disorders are accompanied by cognitive impairment, which impairs work capacity and quality of life However, there is a lack of treatment options that would lead to solid and lasting improvement of cognition This is partially due to the absence of valid and reliable neurocircuitry-based biomarkers for pro-cognitive effects This systematic review therefore examined the most consistent neural underpinnings of cognitive impairment and cognitive improvement in unipolar and bipolar disorders We identified 100 studies of the neuronal underpinnings of working memory and executive skills, learning and memory, attention, and implicit learning and 9 studies of the neuronal basis for cognitive improvements Impairments across several cognitive domains were consistently accompanied by abnormal activity in dorsal prefrontal (PFC) cognitive control regions-with the direction of this activity depending on patients' performance levels-and failure to suppress default mode network (DMN) activity Candidate cognition treatments seemed to enhance task-related dorsal PFC and temporo-parietal activity when performance increases were observed, and to reduce their activity when performance levels were unchanged These treatments also attenuated DMN hyper-activity In contrast, nonspecific cognitive improvement following symptom reduction was typically accompanied by decreased limbic reactivity and reversal of pre-treatment fronto-parietal hyper-activity Together, the findings highlight some common neural correlates of cognitive impairments and cognitive improvements Based on this evidence, studies are warranted to examine the reliability and predictive validity of target engagement in the identified neurocircuitries as a biomarker model of pro-cognitive effects

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Neuronal underpinnings of cognitive impairment and - improvement in mood disorders

Cognitive impairment has emerged as a key treatment priority in neuropsychiatric disorders. However, there is a lack of treatments with solid and lasting efficacy on cognition. A neurocircuitry-based biomarker model of pro-cognitive effects is critically needed to select among new candidate treatments. In a recent review of functional magnetic resonance imaging (fMRI) studies in mood disorders, we found that cognitive impairments are consistently accompanied by aberrant (hypo- and hyper-) activity in the dorsal prefrontal cortex (PFC) and the default mode network (DMN), and that activity change in these regions commonly occurs with cognitive improvements. Here, we (i) review the putative model from our recent review article, which explains the discrepant findings regarding the direction of aberrant dorsal PFC activity and treatment-related activity change in mood disorders. Inspired by the Research Domain Criteria project, we do this in order to (ii) examine whether a similar pattern of activity change occurs across distinct neuropsychiatric disorders and thereby provides a common biomarker for pro-cognitive effects. Lastly, we (iii) discuss whether dorsal PFC and DMN target engagement is a putative transdiagnostic neurocircuitry-based biomarker model for pro-cognitive effects, and (iv) outline the necessary next steps to address this question.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S1092852920000061

Cecilia S Petersen

Papers

Neuronal underpinnings of cognitive impairment and - improvement in mood disorders

Toward a transdiagnostic neurocircuitry-based biomarker model for pro-cognitive effects: challenges, opportunities, and next steps.