The role of parvalbumin interneuron dysfunction across neurodegenerative dementias.

Parvalbumin-positive (PV+) basket neurons are fast-spiking, non-adapting inhibitory interneurons whose oscillatory activity is essential for regulating cortical excitation/inhibition balance. Their dysfunction results in cortical hyperexcitability and gamma rhythm disruption, which have recently gained substantial traction as contributing factors as well as potential therapeutic targets for the treatment of Alzheimer's Disease (AD). Recent evidence indicates that PV+ cells are also impaired in Frontotemporal Dementia (FTD) and Dementia with Lewy bodies (DLB). However, no attempt has been made to integrate these findings into a coherent pathophysiological framework addressing the contribution of PV+ interneuron dysfunction to the generation of cortical hyperexcitability and gamma rhythm disruption in FTD and DLB. To fill this gap, we epitomized the most recent evidence on PV+ interneuron impairment in AD, FTD, and DLB, focusing on its contribution to the generation of cortical hyperexcitability and gamma oscillatory disruption and their interplay with misfolded protein accumulation, neuronal death, and clinical symptoms' onset. Our work deepens the current understanding concerning the role of PV+ interneuron dysfunction across neurodegenerative dementias, highlighting commonalities and differences among AD, FTD, and DLB, thus paving the way for identifying novel biomarkers and potential therapeutic targets for the treatment of these diseases.

The Pathophysiological Underpinnings of Gamma-Band Alterations in Psychiatric Disorders.

Investigating the biophysiological substrates of psychiatric illnesses is of great interest to our understanding of disorders' etiology, the identification of reliable biomarkers, and potential new therapeutic avenues. Schizophrenia represents a consolidated model of γ alterations arising from the aberrant activity of parvalbumin-positive GABAergic interneurons, whose dysfunction is associated with perineuronal net impairment and neuroinflammation. This model of pathogenesis is supported by molecular, cellular, and functional evidence. Proof for alterations of γ oscillations and their underlying mechanisms has also been reported in bipolar disorder and represents an emerging topic for major depressive disorder. Although evidence from animal models needs to be further elucidated in humans, the pathophysiology of γ-band alteration represents a common denominator for different neuropsychiatric disorders. The purpose of this narrative review is to outline a framework of converging results in psychiatric conditions characterized by γ abnormality, from neurochemical dysfunction to alterations in brain rhythms.

rTMS of the auditory association cortex improves speech intelligibility in patients with sensorineural hearing loss.

OBJECTIVE: Sensorineural hearing-loss (SHL) is accompanied by changes in the entire ear-brain pathway and its connected regions. While hearing-aid (HA) partially compensates for SHL, speech perception abilities often continue to remain poor, resulting in consequences in everyday activities. Repetitive transcranial magnetic stimulation (rTMS) promotes cortical network plasticity and may enhance language comprehension in SHL patients. METHODS: 27 patients using HA and with SHL were randomly assigned to a treatment protocol consisting of five consecutive days of either real (Active group: 13 patients) or placebo rTMS (Sham group: 14 patients). The stimulation parameters were as follows: 2-second trains at 10 Hz, 4-second inter-train-interval, and 1800 pulses. Neuronavigated rTMS was applied over the left superior temporal sulcus. Audiological tests were administered before (T0), immediately after (T1), and one week following treatment completion (T2) to evaluate the speech reception threshold (SRT) and the Pure Tone Average (PTA). RESULTS: In the context of a general improvement likely due to learning, the treatment with real rTMS induced significant reduction of the SRT and PTA at T1 and T2 versus placebo. CONCLUSIONS: The long-lasting effects on SRT and PTA observed in the Active group indicates that rTMS administered over the auditory cortex could promote sustained neuromodulatory-induced changes in the brain, improving the perception of complex sentences and pure tones reception skills. SIGNIFICANCE: Five days of rTMS treatment enhances overall speech intelligibility and PTA in SHL patients.

Frequency-Dependent Reduction of Cybersickness in Virtual Reality by Transcranial Oscillatory Stimulation of the Vestibular Cortex.

Virtual reality (VR) applications are pervasive of everyday life, as in working, medical, and entertainment scenarios. There is yet no solution to cybersickness (CS), a disabling vestibular syndrome with nausea, dizziness, and general discomfort that most of VR users undergo, which results from an integration mismatch among visual, proprioceptive, and vestibular information. In a double-blind, controlled trial, we propose an innovative treatment for CS, consisting of online oscillatory imperceptible neuromodulation with transcranial alternating current stimulation (tACS) at 10 Hz, biophysically modelled to reach the vestibular cortex bilaterally. tACS significantly reduced CS nausea in 37 healthy subjects during a VR rollercoaster experience. The effect was frequency-dependent and placebo-insensitive. Subjective benefits were paralleled by galvanic skin response modulation in 25 subjects, addressing neurovegetative activity. Besides confirming the role of transcranially delivered oscillations in physiologically tuning the vestibular system function (and dysfunction), results open a new way to facilitate the use of VR in different scenarios and possibly to help treating also other vestibular dysfunctions.

Frequency-dependent tuning of the human vestibular "sixth sense" by transcranial oscillatory currents.

OBJECTIVE: The vestibular cortex is a multisensory associative region that, in neuroimaging investigations, is activated by slow-frequency (1-2 Hz) galvanic stimulation of peripheral receptors. We aimed to directly activate the vestibular cortex with biophysically modeled transcranial oscillatory current stimulation (tACS) in the same frequency range. METHODS: Thirty healthy subjects and one rare patient with chronic bilateral vestibular deafferentation underwent, in a randomized, double-blind, controlled trial, to tACS at slow (1 or 2 Hz) or higher (10 Hz) frequency and sham stimulations, over the Parieto-Insular Vestibular Cortex (PIVC), while standing on a stabilometric platform. Subjective symptoms of motion sickness were scored by Simulator Sickness Questionnaire and subjects' postural sways were monitored on the platform. RESULTS: tACS at 1 and 2 Hz induced symptoms of motion sickness, oscillopsia and postural instability, that were supported by posturographic sway recordings. Both 10 Hz-tACS and sham stimulation on the vestibular cortex did not affect vestibular function. As these effects persisted in a rare patient with bilateral peripheral vestibular areflexia documented by the absence of the Vestibular-Ocular Reflex, the possibility of a current spread toward peripheral afferents is unlikely. Conversely, the 10 Hz-tACS significantly reduced his chronic vestibular symptoms in this patient. CONCLUSIONS: Weak electrical oscillations in a frequency range corresponding to the physiological cortical activity of the vestibular system may generate motion sickness and postural sways, both in healthy subjects and in the case of bilateral vestibular deafferentation. SIGNIFICANCE: This should be taken into account as a new side effect of tACS in future studies addressing cognitive functions. Higher frequencies of stimulation applied to the vestibular cortex may represent a new interventional option to reduce motion sickness in different scenarios.

TMS-EEG perturbation biomarkers for Alzheimer's disease patients classification.

The combination of TMS and EEG has the potential to capture relevant features of Alzheimer's disease (AD) pathophysiology. We used a machine learning framework to explore time-domain features characterizing AD patients compared to age-matched healthy controls (HC). More than 150 time-domain features including some related to local and distributed evoked activity were extracted from TMS-EEG data and fed into a Random Forest (RF) classifier using a leave-one-subject out validation approach. The best classification accuracy, sensitivity, specificity and F1 score were of 92.95%, 96.15%, 87.94% and 92.03% respectively when using a balanced dataset of features computed globally across the brain. The feature importance and statistical analysis revealed that the maximum amplitude of the post-TMS signal, its Hjorth complexity and the amplitude of the TEP calculated in the window 45-80 ms after the TMS-pulse were the most relevant features differentiating AD patients from HC. TMS-EEG metrics can be used as a non-invasive tool to further understand the AD pathophysiology and possibly contribute to patients' classification as well as longitudinal disease tracking.

Stress Hyperglycemia in Patients With Acute Ischemic Stroke Due to Large Vessel Occlusion Undergoing Mechanical Thrombectomy.

Stress hyperglycemia may impair outcomes in patients with acute ischemic stroke (AIS) undergoing mechanical thrombectomy (MT). The glucose-to-glycated hemoglobin ratio (GAR) was used to measure stress hyperglycemia. Data from our database of consecutive patients admitted to the Udine University Hospital with AIS who were treated with MT between January 2015 and December 2020 were retrospectively analyzed. We included 204 patients in the study and stratified them into four groups according to the quartiles of GAR (Q1-Q4). The higher the GAR index, the more severe the stress hyperglycemia was considered. Patients with more severe stress hyperglycemia showed a higher prevalence of 3-month poor outcome (Q1, 53.1%; Q2, 40.4%; Q3, 63.5%; Q4, 82.4%; p = 0.001), 3-month mortality (Q1, 14.3%; Q2, 11.5%; Q3, 15.4%; Q4, 31.4%; p = 0.001), and symptomatic intracranial hemorrhage (Q1, 2%; Q2, 7.7%; Q3, 7.7%; Q4, 25.4%; p = 0.001). After controlling for several confounders, severe stress hyperglycemia remained a significant predictor of 3-month poor outcome (OR 4.52, 95% CI 1.4-14.62, p = 0.012), 3-month mortality (OR 3.55, 95% CI 1.02-12.29, p = 0.046), and symptomatic intracranial hemorrhage (OR 6.89, 95% CI 1.87-25.36, p = 0.004). In summary, stress hyperglycemia, as measured by the GAR index, is associated with a detrimental effect in patients with AIS undergoing MT.

Personalized Adaptive Training Improves Performance at a Professional First-Person Shooter Action Videogame.

First-Person Shooter (FPS) game experience can be transferred to untrained cognitive functions such as attention, visual short-term memory, spatial cognition, and decision-making. However, previous studies have been using off-the-shelf FPS games based on predefined gaming settings, therefore it is not known whether such improvement of in game performance and transfer of abilities can be further improved by creating a in-game, adaptive in-game training protocol. To address this question, we compared the impact of a popular FPS-game (Counter-Strike:Global-Offensive-CS:GO) with an ad hoc version of the game based on a personalized, adaptive algorithm modifying the artificial intelligence of opponents as well as the overall game difficulty on the basis of individual gaming performance. Two groups of FPS-naïve healthy young participants were randomly assigned to playing one of the two game versions (11 and 10 participants, respectively) 2 h/day for 3 weeks in a controlled laboratory setting, including daily in-game performance monitoring and extensive cognitive evaluations administered before, immediately after, and 3 months after training. Participants exposed to the adaptive version of the game were found to progress significantly faster in terms of in-game performance, reaching gaming scenarios up to 2.5 times more difficult than the group exposed to standard CS:GO (p < 0.05). A significant increase in cognitive performance was also observed. Personalized FPS gaming can significantly speed-up the learning curve of action videogame-players, with possible future applications for expert-video-gamers and potential relevance for clinical-rehabilitative applications.

Recanalisation theraphy for acute ischemic stroke in cancer patients.

To date, very few studies focused their attention on efficacy and safety of recanalisation therapy in acute ischemic stroke (AIS) patients with cancer, reporting conflicting results. We retrospectively analysed data from our database of consecutive patients admitted to the Udine University Hospital with AIS that were treated with recanalisation therapy, i.e. intravenous thrombolysis (IVT), mechanical thrombectomy (MT), and bridging therapy, from January 2015 to December 2019. We compared 3-month dependency, 3-month mortality, and symptomatic intracranial haemorrhage (SICH) occurrence of patients with active cancer (AC) and remote cancer (RC) with that of patients without cancer (WC) undergoing recanalisation therapy for AIS. Patients were followed up for 3 months. Among the 613 AIS patients included in the study, 79 patients (12.9%) had either AC (n = 46; 7.5%) or RC (n = 33; 5.4%). Although AC patients, when treated with IVT, had a significantly increased risk of 3-month mortality [odds ratio (OR) 6.97, 95% confidence interval (CI) 2.42-20.07, p = 0.001] than WC patients, stroke-related deaths did not differ between AC and WC patients (30% vs. 28.8%, p = 0.939). There were no significant differences between AC and WC patients, when treated with MT ± IVT, regarding 3-month dependency, 3-month mortality and SICH. Functional independence, mortality, and SICH were similar between RC and WC patients. In conclusion, recanalisation therapy might be used in AIS patients with nonmetastatic AC and with RC. Further studies are needed to explore the outcome of AIS patients with metastatic cancer undergoing recanalisation therapy.

Long-lasting connectivity changes induced by intensive first-person shooter gaming.

Action videogames have been shown to induce modifications in perceptual and cognitive systems, as well as in brain structure and function. Nevertheless, whether such changes are correlated with brain functional connectivity modifications outlasting the training period is not known. Functional magnetic resonance imaging (fMRI) was used in order to quantify acute and long-lasting connectivity changes following a sustained gaming experience on a first-person shooter (FPS) game. Thirty-five healthy participants were assigned to either a gaming or a control group prior to the acquisition of resting state fMRI data and a comprehensive cognitive assessment at baseline (T0), post-gaming (T1) and at a 3 months' follow-up (T2). Seed-based resting-state functional connectivity (rs-FC) analysis revealed a significant greater connectivity between left thalamus and left parahippocampal gyrus in the gamer group, both at T1 and at T2. Furthermore, a positive increase in the rs-FC between the cerebellum, Heschl's gyrus and the middle frontal gyrus paralleled improvements of in-gaming performance. In addition, baseline rs-FC of left supramarginal gyrus, left middle frontal gyrus and right cerebellum were associated with individual changes in videogame performance. Finally, enhancement of perceptual and attentional measures was observed at both T1 and T2, which correlated with a pattern of rs-FC changes in bilateral occipito-temporal regions belonging to the visual and attention fMRI networks. The present findings increase knowledge on functional connectivity changes induced by action videogames, pointing to a greater and long-lasting synchronization between brain regions associated with spatial orientation, visual discrimination and motor learning even after a relatively short multi-day gaming exposure.

Stress hyperglycemia is predictive of worse outcome in patients with acute ischemic stroke undergoing intravenous thrombolysis.

No study investigated the possible detrimental effect of stress hyperglycemia on patients affected acute ischemic stroke (AIS) undergoing intravenous thrombolysis (IVT). A new index, the glucose-to-glycated hemoglobin ratio (GAR), has been developed for assessing stress hyperglycemia. We retrospectively analyzed data from a prospectively collected database of consecutive patients admitted to the Udine University Hospital with AIS that were treated with IVT from January 2015 to December 2019. Four hundred and fourteen consecutive patients with AIS undergoing IVT entered the study. The patients were then stratified into four groups by quartiles of GAR (Q1-Q4). The higher GAR index was, the more severe stress hyperglycemia was considered. Prevalence of 3 months poor outcome (37.7% for Q1, 34% for Q2, 46.9% for Q3, and 66.7% for Q4, p for trend = 0.001), 3 months mortality (10.5% for Q1, 7.5% for Q2, 11.2% for Q3, and 27.1% for Q4, p for trend = 0.001), and symptomatic intracranial hemorrhage (0.9% for Q1, 0.9% for Q2, 5.1% for Q3, and 17.7% for Q4, p for trend = 0.001) was significant different among the four groups. AIS patients with severe stress hyperglycemia had a significantly increased risk of 3 months poor outcome (OR 2.43, 95% CI 1.14-5.22, p = 0.02), 3 months mortality (OR 2.38, 95% CI 1.01-5.60, p = 0.04), and symptomatic intracranial hemorrhage (OR 16.76, 95% CI 2.09-134.58, p = 0.008) after IVT. In conclusion, we demonstrated that stress hyperglycemia, as measured by the GAR index, is associated to worse outcome in AIS patients undergoing IVT.

Dynamic Hyperglycemic Patterns Predict Adverse Outcomes in Patients with Acute Ischemic Stroke Undergoing Mechanical Thrombectomy.

BACKGROUND: Admission hyperglycemia impairs outcome in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT). Since hyperglycemia in AIS represents a dynamic condition, we tested whether the dynamic patterns of hyperglycemia, defined as blood glucose levels > 140 mg/dl, affect outcomes in these patients. METHODS: We retrospectively analyzed data of 200 consecutive patients with prospective follow-up. Based on blood glucose level, patients were distinguished into 4 groups: (1) persistent normoglycemia; (2) hyperglycemia at baseline only; (3) hyperglycemia at 24-h only; and (4) persistent (at baseline plus at 24-h following MT) hyperglycemia. RESULTS: AIS patients with persistent hyperglycemia have a significantly increased risk of poor functional outcome (OR 6.89, 95% CI 1.98-23.94, p = 0.002, for three-month poor outcome; OR 11.15, 95% CI 2.99-41.52, p = 0.001, for no major neurological improvement), mortality (OR 5.37, 95% CI 1.61-17.96, p = 0.006, for in-hospital mortality; OR 4.43, 95% CI 1.40-13.97, p = 0.01, for three-month mortality), and hemorrhagic transformation (OR 6.89, 95% CI 2.35-20.21, p = 0.001, for intracranial hemorrhage; OR 5.42, 95% CI 1.54-19.15, p = 0.009, for symptomatic intracranial hemorrhage) after endovascular treatment. These detrimental effects were partially confirmed after also excluding diabetic patients. The AUC-ROC showed a very good performance for predicting three-month poor outcome (0.76) in-hospital mortality (0.79) and three-month mortality (0.79). CONCLUSIONS: Our study suggests that it is useful to perform the prolonged monitoring of glucose levels lasting 24-h after MT.

To Treat or Not to Treat: Importance of Functional Dependence in Deciding Intravenous Thrombolysis of "Mild Stroke" Patients.

Intravenous thrombolysis (IVT) in patients with a low National Institutes of Health Stroke Scale (NIHSS) score of 0-5 remains controversial. IVT should be used in patients with mild but nevertheless disabling symptoms. We hypothesize that response to IVT of patients with "mild stroke" may depend on their level of functional dependence (FD) at hospital admission. The aims of our study were to investigate the effect of IVT and to explore the role of FD in influencing the response to IVT. This study was a retrospective analysis of a prospectively collected database, including 389 patients stratified into patients receiving IVT (IVT+) and not receiving IVT (IVT -) just because of mild symptoms. Barthel index (BI) at admission was used to assess FD, dividing subjects with BI score < 80 (FD+) and with BI score > 80 (FD-). The efficacy endpoints were the rate of positive disability outcome (DO+) (3-month mRS score of 0 or 1), and the rate of positive functional outcome (FO+) (mRS score of zero or one, plus BI score of 95 or 100 at 3 months). At the multivariate analysis, IVT treatment was an independent predictor of DO+ (OR 3.12, 95% CI 1.34-7.27, p = 0.008) and FO+ (OR: 4.70, 95% CI 2.38-9.26, p = 0.001). However, FD+ IVT+ patients had a significantly higher prevalence of DO+ and FO+ than those FD+ IVT-. Differently, IVT treatment did not influence DO+ and FO+ in FD- patients. In FD+ patients, IVT treatment represented the strongest independent predictor of DO+ (OR 6.01, 95% CI 2.59-13.92, p = 0.001) and FO+ (OR 4.73, 95% CI 2.29-9.76, p = 0.001). In conclusion, alteplase seems to improve functional outcome in patients with "mild stroke". However, in our experience, this beneficial effect is strongly influenced by FD at admission.

May lamotrigine be an alternative to topiramate in the prevention of migraine with aura? Results of a retrospective study.

BACKGROUND: Evidence suggests that lamotrigine could be effective in reducing aura frequency and duration. However, studies comparing lamotrigine to other, first-line prophylactic agents solely involving patients suffering from migraine with aura are still lacking. The aim of this study was to compare the efficacy of lamotrigine and topiramate for the preventive treatment of migraine with aura. METHODS: Fifty-three patients suffering from migraine with aura treated with lamotrigine or topiramate for at least 6 months were included. Pre- and post-treatment clinical data regarding monthly aura frequency and duration, monthly migraine frequency, days of headache and rescue medication used per month were collected. RESULTS: Responder rates were similar between the two treatment groups at 6-month follow-up. Interestingly, responder rates for aura frequency and duration were higher in the lamotrigine group compared with the topiramate group (88% vs 79% and 73% vs 54%). Moreover, 50% of the lamotrigine-treated patients reported a complete disappearance of migraine aura compared with 37% of topiramate-treated patients. Side effects were more frequent in topiramate group compared with lamotrigine group (p=0.004). CONCLUSIONS: Lamotrigine should be considered in clinical practice for the preventive treatment of migraine with aura especially for patients reporting prolonged aura and who do not respond, have contraindications or discontinue topiramate treatment due to side effects.

Tacrolimus-induced severe headache associated with diffuse leukoencephalopathy: Evidence for an immune-mediated pathogenesis.

Tacrolimus-induced encephalopathy presents with acute neurological symptoms such as headache, seizures, visual disturbances, hemiplegia, and altered mental status. A 60-year-old woman, presented to our clinic with a 4-month history of severe headache. She recently underwent kidney transplantation and was taking tacrolimus. MRI scan showed diffuse and symmetric alterations involving both supratentorial and infratentorial white matter. Cerebral spinal fluid assessment for infectious diseases were negative but elevated total protein level and oligoclonal bands positivity were reported. Treatment with steroid bolus, along with tacrolimus tapering, provided clinico-radiological improvement. This is the first case of tacrolimus-induced neurotoxicity strongly suggestive of an immune-mediated pathogenesis.

Thalamic morphometric changes induced by first-person action videogame training.

Cross-sectional data suggest videogaming as promoting modifications in perceptual and cognitive skills of players, as well as inducing structural brain changes. However, whether such changes are both possible after a systematic gaming exposure, and last beyond the training period, is not known. Here, we originally quantified immediate and long-lasting cognitive and morphometric impact of a systematic gaming experience on a first-person shooter (FPS) game. Thirty-five healthy participants, assigned to a videogaming and a control group, underwent a cognitive assessment and structural magnetic resonance imaging at baseline (T0), immediately post-gaming (T1) and after  3 months (T2). Enhancements of cognitive performance were found on perceptual and attentional measures at both T1 and T2. Morphometric analysis revealed immediate structural changes involving bilateral medial and posterior thalamic nuclei, as well as bilateral superior temporal gyrus, right precentral gyrus, and left middle occipital gyrus. Notably, significant changes in pulvinar volume were still present at T2, while a voxel-wise regression analysis also linked baseline pulvinar volume and individual changes in gaming performance. Present findings extend over the notion that videogame playing might impact cognitive and brain functioning in a beneficial way, originally showing long-term brain structural changes even months after gaming practice. The involvement of posterior thalamic structures highlights a potential link between FPS games and thalamo-cortical networks related to attention mechanisms and multisensory integration processing.

Acute and long-lasting cortical thickness changes following intensive first-person action videogame practice.

Recent evidence shows how an extensive gaming experience might positively impact cognitive and perceptual functioning, leading to brain structural changes observed in cross-sectional studies. Importantly, changes seem to be game-specific, reflecting gameplay styles and therefore opening to the possibility of tailoring videogames according to rehabilitation and enhancement purposes. However, whether if such brain effects can be induced even with limited gaming experience, and whether if they can outlast the gaming period, is still unknown. Here we quantified both cognitive and grey matter thickness changes following 15 daily gaming sessions based on a modified version of a 3D first-person shooter (FPS) played in laboratory settings. Twenty-nine healthy participants were randomly assigned to a control or a gaming group and underwent a cognitive assessment, an in-game performance evaluation and structural magnetic resonance imaging before (T0), immediately after (T1) and three months after the end of the experiment (T2). At T1, a significant increase in thickness of the bilateral parahippocampal cortex (PHC), somatosensory cortex (S1), superior parietal lobule (SPL) and right insula were observed. Changes in S1 matched the hand representation bilaterally, while PHC changes corresponded to the parahippocampal place area (PPA). Surprisingly, changes in thickness were still present at T2 for S1, PHC, SPL and right insula as compared to T0. Finally, surface-based regression identified the lingual gyrus as the best predictor of changes in game performance at T1. Results stress the specific impact of core game elements, such as spatial navigation and visuomotor coordination on structural brain properties, with effects outlasting even a short intensive gaming period.