Neurology International

Sustained cognitive deficits are a common and debilitating feature of “long COVID”, but currently there are no FDA-approved treatments. The cognitive functions of the dorsolateral prefrontal cortex (dlPFC) are the most consistently afflicted by long COVID, including deficits in working memory, motivation, and executive functioning. COVID-19 infection greatly increases kynurenic acid (KYNA) and glutamate carboxypeptidase II (GCPII) in brain, both of which can be particularly deleterious to PFC function. KYNA blocks both NMDA and nicotinic-alpha-7 receptors, the two receptors required for dlPFC neurotransmission, and GCPII reduces mGluR3 regulation of cAMP-calcium-potassium channel signaling, which weakens dlPFC network connectivity and reduces dlPFC neuronal firing. Two agents approved for other indications may be helpful in restoring dlPFC physiology: the antioxidant N-acetyl cysteine inhibits the production of KYNA, and the α2A-adrenoceptor agonist guanfacine regulates cAMP-calcium-potassium channel signaling in dlPFC and is also anti-inflammatory. Thus, these agents may be helpful in treating the cognitive symptoms of long COVID. Full article

Background: Patients with age-related white matter changes (ARWMC) frequently present a gait disorder, depression and cognitive impairment. Our aims are to define which alterations in the gait parameters are associated with motor or neuro-psychological impairment and to assess the role of motor, mood or cognitive dysfunction in explaining the variance of the gait parameters. Methods: Patients with gait disorders admitted to a Neuro-rehabilitation Department, affected by vascular leukoencephalopathy who had ARWMC confirmed by a brain MRI, were consecutively enrolled, classified by a neuroradiological scale (Fazekas 1987) and compared to healthy controls. We excluded subjects unable to walk independently, subjects with hydrocephalus or severe aphasia, with orthopaedic and other neurological pathologies conditioning the walking pattern. Patients and controls were assessed by clinical and functional scales (Mini Mental State Examination, Geriatric Depression Scale, Nevitt Motor Performance Scale, Berg Balance Scale, Functional Independence Measure), and computerised gait analysis was performed to assess the spatial and temporal gait parameters in a cross-sectional study. Results: We recruited 76 patients (48 males, aged 78.3 ± 6.2 years) and 14 controls (6 males, aged 75.8 ± 5 years). In the multiple regression analysis, the gait parameter with overall best model summary values, associated with the ARWMC severity, was the stride length even after correction for age, sex, weight and height (R² = 0.327). The motor performances justified at least in part of the gait disorder (R² change = 0.220), but the mood state accounted independently for gait alterations (R² change = 0.039). The increase in ARWMC severity, the reduction of motor performance and a depressed mood state were associated with a reduction of stride length (R = 0.766, R² = 0.587), reduction of gait speed (R² = 0.573) and an increase in double support time (R² = 0.421). Conclusion: The gait disorders in patients with ARWMC are related to motor impairment, but the presence of depression is an independent factor for determining gait alterations and functional status. These data pave the way for longitudinal studies, including gait parameters, to quantitatively assess gait changes after treatment or to monitor the natural progression of the gait disorders. Full article

Introduction: Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which is marked by symptoms such as inappropriate levels of inattention, hyperactivity, and impulsivity that can affect academic, social, and personal functioning in children and adolescents. This review summarizes clinical trials demonstrating the effectiveness of Alpha-2 agonists in reducing symptoms of inattention, hyperactivity, and impulsivity in children with ADHD. Studies were identified through a systematic search of PubMed and Cochrane databases. However, these medications’ long-term safety and efficacy remain uncertain, with a lack of data on their effects on growth, cardiovascular function, and other adverse events. Further studies are required to determine these medications’ optimal dose and treatment duration. Methods: Medications that target the noradrenergic system, such as Alpha-2 agonists, have been increasingly used as a treatment option for ADHD, with guanfacine and clonidine being two of the most commonly used medications. They function by selectively targeting Alpha-2 adrenergic receptors in the brain leading to improved attention and reduced hyperactivity and impulsivity symptoms in children with ADHD. Results: Clinical trials have demonstrated the effectiveness of Alpha-2 agonists in treating ADHD in children by reducing symptoms of inattention, hyperactivity, and impulsivity. However, these medications’ long-term safety and efficacy still need to be completely understood. Due to a lack of information on the effects of Alpha-2 agonists on growth, cardiovascular function, and other long-term adverse events, more studies must investigate the optimal dose and treatment duration for these medications. Conclusions: Despite these concerns, Alpha-2 agonists remain a valuable treatment option for ADHD in children, especially those unable to tolerate stimulant medications or who have coexisting conditions such as tic disorders. Future research should continue to explore the safety and efficacy of Alpha-2 agonists in the long term. In conclusion, Alpha-2 agonists show promise as a treatment for ADHD in children; however, the safety and efficacy of these drugs in the long term are not yet completely understood. Additional studies are required to investigate the optimal dose and treatment duration for these medications in their use as a treatment for this debilitating disease. Full article

Stroke is a major cause of functional disability and is increasing in frequency. Therefore, stroke prognosis must be both accurate and timely. Among other biomarkers, heart rate variability (HRV) is investigated in terms of prognostic accuracy within stroke patients. The literature research of two databases (MEDLINE and Scopus) is performed to trace all relevant studies published within the last decade addressing the potential utility of HRV for stroke prognosis. Only the full-text articles published in English are included. In total, forty-five articles have been traced and are included in the present review. The prognostic value of biomarkers of autonomic dysfunction (AD) in terms of mortality, neurological deterioration, and functional outcome appears to be within the range of known clinical variables, highlighting their utility as prognostic tools. Moreover, they may provide additional information regarding poststroke infections, depression, and cardiac adverse events. AD biomarkers have demonstrated their utility not only in the setting of acute ischemic stroke but also in transient ischemic attack, intracerebral hemorrhage, and traumatic brain injury, thus representing a promising prognostic tool whose clinical application may greatly facilitate individualized stroke care. Full article

In this paper, the data are presented concerning different reactions to seven daily injections of atomoxetine in two mouse strains differing in relative brain weight. Atomoxetine affected the performance in a puzzle-box cognitive test in a complicated way—the large brain mice were less successful at task solutions (presumably because they were not afraid of the brightly lit test box), while the small brain strain of atomoxetine treated mice solved the task more successfully. The behavior of all atomoxetine treated animals was more active in an aversive situation (an unescapable slippery funnel, (analogous to the Porsolt test) and the time of immobility decreased significantly in all atomoxetine treated mice. The general patterns of behavioral reactions to atomoxetine in the cognitive test and other interstrain differences demonstrated in these experiments made it possible to suggest that differences in ascending noradrenergic projections between the two strains used exist. Further analysis of the noradrenergic system in these strains is needed (and further analysis of the effects of drugs which affect noradrenergic receptors). Full article

Traumatic brain injury (TBI) in humans can result in olfactory, cognitive, and affective changes. Surprisingly, research on the consequences of TBI often did not control for olfactory function in the investigated groups. Consequently, the affective or cognitive differences might be misleading as related rather to different olfactory performance than to a TBI experience. Hence, our study aimed to investigate whether TBI occurrence would lead to altered affective and cognitive functioning in two groups of dysosmic patients, one with TBI experience and one without. In total, 51 patients with TBI experience and 50 controls with varied causes of olfactory loss were thoroughly examined in terms of olfactory, cognitive, and affective performance. Student t-tests demonstrated that the only significant difference between the groups appeared in the depression severity, with TBI patients being more depressed (t = 2.3, p = 0.011, Cohen’s d = −0.47). Regression analyses further showed that TBI experience was significantly associated with depression severity (R2 = 0.05, F [1, 96] = 5.5, p = 0.021, beta = 1.4). In conclusion, the present study showed that TBI experience is linked to depression, which is more pronounced compared to individuals with olfactory loss without TBI. Full article

Migraine pain is frequently accompanied by cranial hyperalgesia and allodynia. Calcitonin gene-related peptide (CGRP) is implicated in migraine pathophysiology but its role in facial hypersensitivity is not entirely clear. In this study, we investigated if the anti-CGRP monoclonal antibody fremanezumab, which is therapeutically used in chronic and episodic migraines, can modify facial sensitivity recorded by a semi-automatic system. Rats of both sexes primed to drink from a sweet source had to pass a noxious mechanical or heat barrier to reach the source. Under these experimental conditions, animals of all groups tended to drink longer and more when they had received a subcutaneous injection of 30 mg/kg fremanezumab compared to control animals injected with an isotype control antibody 12–13 days prior to testing, but this was significant only for females. In conclusion, anti-CGRP antibody, fremanezumab, reduces facial sensitivity to noxious mechanical and thermal stimulation for more than one week, especially in female rats. Anti-CGRP antibodies may reduce not only headache but also cranial sensitivity in migraineurs. Full article

The possibility of epileptiform activity generation by the thalamocortical neuronal network after focal brain injuries, including traumatic brain injury (TBI), is actively debated. Presumably, posttraumatic spike–wave discharges (SWDs) involve a cortico-thalamocortical neuronal network. Differentiation of posttraumatic and idiopathic (i.e., spontaneously generated) SWDs is imperative for understanding posttraumatic epileptogenic mechanisms. Experiments were performed on male Sprague-Dawley rats with electrodes implanted into the somatosensory cortex and the thalamic ventral posterolateral nucleus. Local field potentials were recorded for 7 days before and 7 days after TBI (lateral fluid percussion injury, 2.5 atm). The morphology of 365 SWDs (89 idiopathic before craniotomy, and 262 posttraumatic that appeared only after TBI) and their appearance in the thalamus were analyzed. The occurrence of SWDs in the thalamus determined their spike–wave form and bilateral lateralization in the neocortex. Posttraumatic discharges were characterized by more “mature” characteristics as compared to spontaneously generated discharges: higher proportions of bilateral spreading, well-defined spike–wave form, and thalamus involvement. Based on SWD parameters, the etiology could be established with an accuracy of 75% (AUC 0.79). Our results support the hypothesis that the formation of posttraumatic SWDs involves a cortico-thalamocortical neuronal network. The results form a basis for further research of mechanisms associated with posttraumatic epileptiform activity and epileptogenesis. Full article

Glioblastoma (GBM) is a common and highly malignant primary tumor of the central nervous system in adults. Ever more recent papers are focusing on understanding the role of the tumor microenvironment (TME) in affecting tumorigenesis and the subsequent prognosis. We assessed the impact of macrophages in the TME on the prognosis in patients with recurrent GBM. A PubMed, MEDLINE and Scopus review was conducted to identify all studies dealing with macrophages in the GBM microenvironment from January 2016 to December 2022. Glioma-associated macrophages (GAMs) act critically in enhancing tumor progression and can alter drug resistance, promoting resistance to radiotherapy and establishing an immunosuppressive environment. M1 macrophages are characterized by increased secretion of proinflammatory cytokines, such as IL-1ß, tumor necrosis factor (TNF), IL-27, matrix metalloproteinase (MMPs), CCL2, and VEGF (vascular endothelial growth factor), IGF1, that can lead to the destruction of the tissue. In contrast, M2 is supposed to participate in immunosuppression and tumor progression, which is formed after being exposed to the macrophage M-CSF, IL-10, IL-35 and the transforming growth factor-ß (TGF-β). Because there is currently no standard of care in recurrent GBM, novel identified targeted therapies based on the complex signaling and interactions between the glioma stem cells (GSCs) and the TME, especially resident microglia and bone-marrow-derived macrophages, may be helpful in improving the overall survival of these patients in the near future. Full article

Prenatal alcohol exposure (PAE) refers to fetal exposure to alcohol during pregnancy through placental barrier transfer from maternal blood. The postnatal outcomes of PAE differ among exposed individuals and range from overt (serious) alcohol-related behavioral and neurophysiological impairments to covert (silenced) symptoms. The aims of the present investigation were to assess the postnatal neurobehavioral disturbances, particularly, motor coordination and sensory-motor function in mice with PAE. Female mice with positive vaginal plugs were divided into three groups: group 1: Et + Pyr: received two i.p injections of ethanol (1 g/kg) followed by pyrazole (100 mg/kg). Group 2: Pyr: received an i.p injection of pyrazole (100 mg/kg). Group 3: C: of saline controls received, in equal volume, saline solution (NaCl 0.9%). After birth, mice pups were weighed and subjected to behavioral tests for motor function screening using the motor ambulation test, cliff aversion, surface righting, and negative geotaxis, while at the adult stage, mice were subjected to the open field, rotarod, parallel bars, and static rods tests. Our data show an obvious decrement of body weight from the first post-natal day (P1) and continues over the adult stage. This was accompanied by an obvious impaired sensory-motor function which was maintained even at the adult stage with alteration of the locomotor and coordination abilities. The current data demonstrate the powerful neurotoxic effect of prenatal ethanol exposure on the sensory-motor and coordination functions, leading to suppose possible structural and/or functional neuronal disturbances, particularly the locomotor network. Full article

Post-polio syndrome (PPS) is characterized by recrudescence or worsening of motor neuron disease symptoms decades after recovery from acute paralytic poliovirus infection, i.e., poliomyelitis. PPS afflicts between 25% and 40% of poliomyelitis survivors and mimics motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), due to its selective impairment, degeneration, or death of motor neurons in the brainstem and spinal cord. Herein, we report a case of PPS in a 68-year-old man with a remote history of bulbar and cervical cord involvement by poliomyelitis, review the relevant literature, and contrast the salient histopathologic features that distinguish our case of PPS from ALS. Full article

Two derivatives of the numeric rating scale (NRS) and visual analog scale (VAS), namely patient-reported percentage pain reduction (PRPPR) and calculated percentage pain reduction (CPPR), are commonly used when evaluating pain reduction. A small number of studies have attempted to assess the agreement between PRPPR and CPPR. However, they have been limited in their scope by a focus on specific types of pain, or by their focus on specific treatment modalities. As far as the authors of this article are aware, this is the first study to assess the agreement between PRPPR and CPPR in chronic pain patients, as well as the first to assess how the duration of treatment affects the correlations between PRPPR and CPPR. The aim of this retrospective analysis was to determine whether the duration of treatment affects CPPR and PRPPR, and the discrepancy and agreement between the two. Additionally, the study assessed whether individual treatment modalities, or the lack there of, impacted the discrepancy and correlation between PRPPR and CPPR. The mean PRPPR and CPPR for the entire patient population were 59.98 and 40.71, respectively. The mean discrepancy between the two parameters was 19.27. The agreement between PRPPR and CPPR, as measured by the concordance correlation coefficient, was 0.984 (95% C.I., 0.982–0.986). Full article

The prevalence of stroke-induced cognitive impairment is high. Effective approaches to the treatment of these cognitive impairments after stroke remain a serious and perhaps underestimated challenge. A BCI-based task-focused training that results in repetitive recruitment of the normal motor or cognitive circuits may strengthen stroke-affected neuronal connectivity, leading to functional improvements. In the present controlled study, we attempted to evaluate the modulation of neuronal circuits under the influence of 10 days of training in a P3-based BCI speller in subacute ischemic stroke patients. Full article

In this study, we examined visual processing within primary visual areas (V1) in normal and visually impaired individuals who exhibit significant visual symptomology due to sports-related mild traumatic brain injury (mTBI). Five spatial frequency stimuli were applied to the right, left and both eyes in order to assess the visual processing of patients with sports-related mild traumatic brain injuries who exhibited visual abnormalities, i.e., photophobia, blurriness, etc., and controls. The measurement of the left/right eye and binocular integration was accomplished via the quantification of the spectral power and visual event-related potentials. The principal results have shown that the power spectral density (PSD) measurements display a distinct loss in the alpha band-width range, which corresponded to more instances of medium-sized receptive field loss. Medium-size receptive field loss may correspond to parvocellular (p-cell) processing deprecation. Our major conclusion provides a new measurement, using PSD analysis to assess mTBI conditions from primary V1 areas. The statistical analysis demonstrated significant differences between the mTBI and control cohort in the Visual Evoked Potentials (VEP) amplitude responses and PSD measurements. Additionally, the PSD measurements were able to assess the improvement in the mTBI primary visual areas over time through rehabilitation. Full article

Background: Exogenous melatonin is commonly used to treat insomnia, other sleep problems, and numerous medical illnesses, including Alzheimer’s disease, autism spectrum disorder, and mild cognitive impairment in adults and children. There is evolving information regarding issues with the use of chronic melatonin. Methods: The present investigation was a narrative review. Results: Melatonin usage has risen dramatically in recent years. Many countries only allow melatonin prescriptions. In the United States (U.S.), it is classified as a dietary supplement accessible over the counter and can be derived from animals, microorganisms, or, most commonly, made synthetically. No regulatory agency oversees its manufacturing or sale in the U.S. melatonin concentration of marketed preparations varies widely between product labels and manufacturers. Melatonin’s ability to induce sleep is detectable. However, it is modest for most people. Sleep length appears to be less important in sustained-release preparations. The optimal dosage is unknown, and routinely used amounts vary substantially. Melatonin’s short-term negative effects are minimal, resolve at medicine cessation, and do not usually prevent usage overall. Much research on long-term melatonin administration has found no difference between exogenous melatonin and placebo in terms of long-term negative effects. Conclusion: Melatonin at low to moderate dosages (approximately 5–6 mg daily or less) appears safe. Long-term usage appears to benefit certain patient populations, such as those with autism spectrum disorder. Studies investigating potential benefits in reducing cognitive decline and increased longevity are ongoing. However, it is widely agreed that the long-term effects of taking exogenous melatonin have been insufficiently studied and warrant additional investigation. Full article

This study aimed to evaluate the clinical characteristics of acute ischemic stroke (AIS) patients who experienced hypoesthesia as the initial symptom. We retrospectively analyzed the medical records of 176 hospitalized AIS patients who met our inclusion and exclusion criteria and evaluated their clinical features and MRI findings. Among this cohort, 20 (11%) patients presented with hypoesthesia as the initial symptom. MRI scans of these 20 patients identified lesions in the thalamus or pontine tegmentum in 14 and brain lesions at other sites in 6. The 20 hypoesthesia patients had higher systolic (p = 0.031) and diastolic blood pressure (p = 0.037) on admission, and a higher rate of small-vessel occlusion (p < 0.001) than patients without hypoesthesia. The patients with hypoesthesia had a significantly shorter average hospital stay (p = 0.007) but did not differ significantly from those without hypoesthesia in National Institutes of Health Stroke Scale scores on admission (p = 0.182) or the modified Rankin Scale scores for neurologic disability on discharge (p = 0.319). In the patients with acute onset hypoesthesia, high blood pressure, and neurological deficits were more likely to be due to AIS than other causes. Since most of the lesions in AIS patients with hypoesthesia as the initial symptom were found to be small, we recommend performing MRI scans with such patients to confirm AIS. Full article

The cluster headache is a primary headache characterized by attacks of unilateral pain associated with ipsilateral cranial autonomic features. These attacks recur in clusters during the years alternating with periods of complete remission, and their onset is often during the night. This annual and nocturnal periodicity hides a strong and mysterious link among CH, sleep, chronobiology and circadian rhythm. Behind this relationship, there may be the influence of genetic components or of anatomical structures such as the hypothalamus, which are both involved in regulating the biological clock and contributing even to the periodicity of cluster headaches. The bidirectional relationship manifests itself also with the presence of sleep disturbances in patients affected by cluster headaches. What if the key to studying the physiopathology of such disease could rely on the mechanisms of chronobiology? The purpose of this review is to analyze this link in order to interpret the pathophysiology of cluster headaches and the possible therapeutic implications. Full article

On behalf of the BraYn Association Ets, we are pleased to present the Abstracts of the Fifth Brainstorming Research Assembly for Young Neuroscientists, which was held in Rome, Italy from 28–30 September 2022. We congratulate all the presenters on their research work and contribution. Full article

Background: Intravenous immunoglobulin (IVIg) is efficient and one of very few treatment options for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, finding the optimal dose of IVIg for individual CIDP patients remains challenging. The dose of IVIg needs to be adjusted individually. Considering the high healthcare costs of IVIg therapy, the overtreatment of some patients seen in placebo studies and the shortage of IVIg we recently experienced, as well as identifying factors associated with the required dose of IVIg in maintenance treatment, is extremely important. Thus, in this retrospective study, we analyze characteristics of patients with stable CIDP, which are associated with the required drug dose. Methods: 32 patients with stable CIDP treated with IVIg between July 2021 and July 2022 were identified from our database and included in this retrospective study. Patients’ characteristics were registered, and parameters were identified that were associated with the IVIg dose. Results: Age, cerebrospinal fluid protein elevation, disease duration, delay between symptom onset/diagnosis, Inflammatory Neuropathy Cause and Treatment (INCAT) score, and Medical Research Council Sum Score (MRC SS) were significantly associated with the required drug dose. In addition, an association of age, sex, elevated CSF protein, time interval between symptom onset and diagnosis, and the MRC SS with the required IVIg dose could be demonstrated in the multivariable regression analysis. Conclusions: Our model, which is based on routine parameters that are simple to address in the clinical practice, can be useful in adjusting the IVIg dose in patients with stable CIDP. Full article