The Role of Anatomic Connectivity in Inhibitory Control Revealed by Combining Connectome-based Lesion-symptom Mapping with Event-related Potentials.

Inhibitory control refers to the ability to suppress cognitive or motor processes. Current neurocognitive models indicate that this function mainly involves the anterior cingulate cortex and the inferior frontal cortex. However, how the communication between these areas influence inhibitory control performance and their functional response remains unknown. We addressed this question by injecting behavioral and electrophysiological markers of inhibitory control recorded during a Go/NoGo task as the 'symptoms' in a connectome-based lesion-symptom mapping approach in a sample of 96 first unilateral stroke patients. This approach enables us to identify the white matter tracts whose disruption by the lesions causally influences brain functional activity during inhibitory control. We found a central role of left frontotemporal and frontobasal intrahemispheric connections, as well as of the connections between the left temporoparietal and right temporal areas in inhibitory control performance. We also found that connections between the left temporal and right superior parietal areas modulate the conflict-related N2 event-related potential component and between the left temporal parietal area and right temporal and occipital areas for the inhibition P3 component. Our study supports the role of a distributed bilateral network in inhibitory control and reveals that combining lesion-symptom mapping approaches with functional indices of cognitive processes could shed new light on post-stroke functional reorganization. It may further help to refine the interpretation of classical electrophysiological markers of executive control in stroke patients.

Acute right opercular stroke-associated polyopic heautoscopy and hallucinations caused by disconnection to the inferior parietal lobule through the superior longitudinal fasciculus III: A single case study.

Illusory neuropsychiatric symptoms such as hallucinations or the feeling of a presence (FOP) can occur in diffuse brain lesion or dysfunction, in psychiatric diseases as well as in healthy individuals. Their occurrence due to focal brain lesions is rare, most probably due to underreporting, which limits progress in understanding their underlying mechanisms and anatomical determinants. In this single case study, an 86-year-old patient experienced, in the context of an acute right central opercular ischemic stroke, visual hallucinatory symptoms (including palinopsia), differently lateralized auditory hallucinations and FOP. This unusual clinical constellation could be precisely documented and illustrated while still present, allowing a realistic and immersive visual experience validated by the patient. The acute stroke appeared to be their most plausible cause (after exclusion of other etiologies). Furthermore, accurate analysis of tractographic data suggested that disruption in the posterior bundle of the superior longitudinal fasciculus connecting the stroke lesion to the inferior parietal lobule was the anatomical substrate explaining the FOP and, indirectly, also hallucinations through whiter matter involvement, in coherence with existing literature. We could finally elaborate on symptoms taxonomy and phenomenology (e.g., polyopic heautoscopy, hallucinatory FOP, etc), and on patient's remarkable distancing from them (with some therapeutic implications supported by plausibly engaged mechanisms). This case not only authentically enriched the description of such rare combination of heterogenous illusory symptoms through this novel visualization-based reporting approach, but disclosed an unrevealed anatomo-clinical link relating all of them to the acute stroke lesion through an association fiber, thereby contributing to the understanding of these intriguing symptoms and their determinants.

Case Report: Variegate porphyria disclosed by post-gastric bypass complications and causing predominant painful sensorimotor axonal peripheral neuropathy.

Background and aims: Porphyrias constitute a group of rare genetic diseases due to various, mostly autosomal dominant mutations, causing enzymatic deficiency in heme biosynthesis. As a result, neurotoxic porphyrin precursors and light-sensitive porphyrins accumulate, while dysfunction in their targets determines the disease symptoms. Variegate porphyria (VP), one of the acute hepatic porphyrias, is caused by a protoporphyrinogen oxidase (PPOX) mutation. During acute attacks, among other factors, triggered by drugs, stressors, or fasting, an increase in urinary and fecal porphobilinogen (PBG), aminolevulinic acid (ALA), and porphyrins occurs, damaging the autonomous, peripheral, or central nervous system. The disease remains often latent or displays minimal symptoms usually overlooked, exposing undiagnosed patients to potentially serious complications in the presence of the aforementioned triggers. Case report: This 46-year-old woman presented, some days after a bariatric surgery, with severe flaccid tetraparesis and neuropathic pain, initially misdiagnosed as a functional neurological disorder. The severe axonal sensorimotor polyneuropathy led to further investigations, disclosing high urinary porphobilinogen, ALA, and porphyrin levels due to a new PPOX mutation. Retrospectively, it appeared that the patient had had typical VP symptoms (abdominal pain, fragile skin, and dark urine episodes) for years prior to the surgery. Treated with carbohydrate load, neurorehabilitation, and analgesics, she slowly recovered to full mobility, with partial autonomy in her daily life activities, although fatigue and severe pain persisted, preventing her from returning to work. Conclusion: This case documents gastric bypass surgery as a trigger of severe VP invalidating neurological symptoms and illustrates how the delayed diagnosis and post-interventional complications could have been prevented by screening for porphyria cardinal symptoms prior to the intervention. Likewise, this cost-effective screening should be performed before any treatment influencing the diet, which would dramatically improve the porphyria diagnosis rate and outcome.

An Ecological Monitoring and Management App (EMMA) for Older Adults With Chronic Pain: Protocol for a Design and Feasibility Study.

BACKGROUND: Chronic pain is a complex problem for many older adults that affects both physical functioning and psychological well-being. Mobile health (mHealth) technologies have shown promise in supporting older persons in managing chronic conditions. Cognitive behavior therapy is recommended for older people with chronic pain. However, web-based treatment programs for chronic pain are not aimed at the needs of older people and offer standard therapies without providing tailored treatment for this population. OBJECTIVE: To address this problem, we aim to develop a psychological web-based intervention for ecological monitoring of daily life experiences with chronic pain called EMMA to support self-management of chronic pain in older adults. METHODS: The key clinical and engagement features of the intervention were established through the integration of evidence-based material from cognitive behavioral therapy for the treatment of chronic pain in older adults. The development process uses a co-design approach and actively involves end-users in the design process by incorporating feedback from focus groups with older adults in order to inform a user-centered intervention design. For the co-design process, we will include 10 older adults with chronic pain, who will discuss the requirements for the app in workshops in order to ensure suitability of the app for older adults with chronic pain. In order to test the feasibility and acceptability of the intervention, we will include a sample of 30 older adults with chronic pain who will test all features of the intervention for a period of 8 consecutive weeks. After the trial period, validated instruments will be used to assess usability and acceptability, as well as influence on pain levels and associated physical and psychological symptoms. Participants will be invited to take part in a semistructured telephone interviews after the trial period to explore their experiences using the app. RESULTS: Digitalization of the pain diary and psychotherapeutic content has started. Recruitment of participants for the co-design workshops will start as soon as we have a functioning prototype of the electronic pain diary and EMMA intervention, which is expected to be in September 2021. The feasibility study will start as soon as the co-design process is finished and required changes have been implemented into the pain diary and the EMMA intervention. We expect to start the feasibility study early in 2022. CONCLUSIONS: Required changes to assure usability and acceptability will be directly implemented in the app. EMMA brings together a strong body of evidence using cognitive behavioral and self-management theory with contemporary mHealth principles, allowing for a cost-effective intervention that can be used to target chronic pain anywhere and anytime by older adults. Given the ubiquity of mHealth interventions for chronic conditions, the results of this study may serve to inform the development of tailored self-management interventions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/26930.

The right thalamic ventral posterolateral nucleus seems to be determinant for macrosomatognosia: a case report.

BACKGROUND: Macrosomatognosiais the illusory sensation of a substantially enlarged body part. This disorder of the body schema, also called "Alice in wonderland syndrome" is still poorly understood and requires careful documentation and analysis of cases. The patient presented here is unique owing to his unusual macrosomatognosia phenomenology, but also given the unreported localization of his most significant lesion in the right thalamus that allowed consistent anatomo-clinical analysis. CASE PRESENTATION: This 45-years old man presented mainly with long-lasting and quasi-delusional macrosomatognosia associated to sensory deficits, both involving the left upper-body, in the context of a right thalamic ischemic lesion most presumably located in the ventral posterolateral nucleus. Fine-grained probabilistic and deterministic tractography revealed the most eloquent targets of the lesion projections to be the ipsilateral precuneus, superior parietal lobule,but also the right primary somatosensory cortex and, to a lesser extent, the right primary motor cortex. Under stationary neurorehabilitation, the patient slowly improved his symptoms and could be discharged back home and, later on, partially return to work. CONCLUSION: We discuss deficient neural processing and integration of sensory inputs within the right ventral posterolateral nucleus lesion as possible mechanisms underlying macrosomatognosia in light of observed anatomo-clinical correlations. On the other hand, difficulty to classify this unique constellation of Alice in wonderland syndrome calls for an alternative taxonomy of cognitive and psychic aspects of illusory body-size perceptions.

Identification of GSK-3 as a Potential Therapeutic Entry Point for Epilepsy.

In view of the clinical need for new antiseizure drugs (ASDs) with novel modes of action, we used a zebrafish seizure model to screen the anticonvulsant activity of medicinal plants used by traditional healers in the Congo for the treatment of epilepsy, and identified a crude plant extract that inhibited pentylenetetrazol (PTZ)-induced seizures in zebrafish larvae. Zebrafish bioassay-guided fractionation of this anticonvulsant Fabaceae species, Indigofera arrecta, identified indirubin, a compound with known inhibitory activity of glycogen synthase kinase (GSK)-3, as the bioactive component. Indirubin, as well as the more potent and selective GSK-3 inhibitor 6-bromoindirubin-3'-oxime (BIO-acetoxime) were tested in zebrafish and rodent seizure assays. Both compounds revealed anticonvulsant activity in PTZ-treated zebrafish larvae, with electroencephalographic recordings revealing reduction of epileptiform discharges. Both indirubin and BIO-acetoxime also showed anticonvulsant activity in the pilocarpine rat model for limbic seizures and in the 6-Hz refractory seizure mouse model. Most interestingly, BIO-acetoxime also exhibited anticonvulsant actions in 6-Hz fully kindled mice. Our findings thus provide the first evidence for anticonvulsant activity of GSK-3 inhibition, thereby implicating GSK-3 as a potential therapeutic entry point for epilepsy. Our results also support the use of zebrafish bioassay-guided fractionation of antiepileptic medicinal plant extracts as an effective strategy for the discovery of new ASDs with novel mechanisms of action.

NKCC1 downregulation induces hyperpolarizing shift of GABA responsiveness at near term fetal stages in rat cultured dorsal root ganglion neurons.

BACKGROUND: GABAA receptor-mediated neurotransmission is greatly influenced by cation-chloride cotransporter activity during developmental stages. In embryonic neurons Na-K-2Cl (NKCC1) cotransporters mediate active chloride uptake, thus increasing the intracellular chloride concentration associated with GABA-induced depolarization. At fetal stages near term, oxytocin-induced NKCC1 downregulation has been implicated in the developmental shift from depolarizing to hyperpolarizing GABA action. Mature dorsal root ganglion neurons (DRGN), however, express high NKCC1 levels and maintain high intracellular chloride levels with consequent GABA-induced depolarization. RESULTS: Gramicidin-perforated patch-clamp recordings were used to assess the developmental change in chloride homeostasis in rat cultured small DRGN at the embryonic day 16 (E16) and 19 (E19). The results were compared to data previously obtained in fetal DRGN at E14 and in mature cells. A significant NKCC1 downregulation, leading to reduction in excitatory GABAergic transmission, was observed at E16 and E19. CONCLUSION: These results indicate that NKCC1 activity transiently decreases in DRGN at fetal stages near term. This developmental shift in GABAergic transmission may contribute to fetal analgesia and neuroprotection at birth.

Sweet taste loss in myasthenia gravis: more than a coincidence?

Sweet dysgeusia, a rare taste disorder, may be encountered in severe anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG). A 42 year-old man reported progressive loss of sweet taste evolving for almost 10 weeks, revealing an AChRAb-positive MG with thymoma. Improvement of sweet perception paralleled reduction of the MG composite score during the 15 months follow up period, with immunosuppressive and surgical treatments. We suggest that sweet dysgeusia is a non-motor manifestation of MG that may result from a thymoma-dependent autoimmune mechanism targeting gustducin-positive G-protein-coupled taste receptor cells, in line with recent data from MRL/MpJ-Fas lpr/ (MRL/lpr) transgenic mice with autoimmune disease.

Long-lasting changes in GABA responsiveness in cultured neurons.

In neuronal cells, GABA evokes an increase in chloride conductance by activating GABA(A) and GABA(C) receptors. In mature neurons, this increase in conductance generally has a hyperpolarizing and inhibitory action. Using gramicidin-based perforated patch recordings, we show that in cultured motor neurons GABA-induced currents are significantly altered following activation of GABA receptors coinciding with changes in membrane potential. Changes in intracellular chloride concentration constituted the mechanism for this modulation. Because of low resting chloride conductance and low activity of chloride transporters, changes in intracellular chloride concentration and hence GABA response were long-lasting (time constant of recovery was about 2.5 min). Cultured dorsal horn and hippocampal neurons exhibited a similar response pattern, suggesting a general property of cultured neuronal cells. These long-lasting changes in GABA responsiveness may have major implications on neuronal excitability.