Stimulation of caudal inferior and middle frontal gyri disrupts planning during spoken interaction.

Turn-taking is a central feature of conversation across languages and cultures.1,2,3,4 This key social behavior requires numerous sensorimotor and cognitive operations1,5,6 that can be organized into three general phases: comprehension of a partner's turn, preparation of a speaker's own turn, and execution of that turn. Using intracranial electrocorticography, we recently demonstrated that neural activity related to these phases is functionally distinct during turn-taking.7 In particular, networks active during the perceptual and articulatory stages of turn-taking consisted of structures known to be important for speech-related sensory and motor processing,8,9,10,11,12,13,14,15,16,17 while putative planning dynamics were most regularly observed in the caudal inferior frontal gyrus (cIFG) and the middle frontal gyrus (cMFG). To test if these structures are necessary for planning during spoken interaction, we used direct electrical stimulation (DES) to transiently perturb cortical function in neurosurgical patient-volunteers performing a question-answer task.7,18,19 We found that stimulating the cIFG and cMFG led to various response errors9,13,20,21 but not gross articulatory deficits, which instead resulted from DES of structures involved in motor control8,13,20,22 (e.g., the precentral gyrus). Furthermore, perturbation of the cIFG and cMFG delayed inter-speaker timing-consistent with slowed planning-while faster responses could result from stimulation of sites located in other areas. Taken together, our findings suggest that the cIFG and cMFG contain critical preparatory circuits that are relevant for interactive language use.

A frontal cortical network is critical for language planning during spoken interaction.

Many brain areas exhibit activity correlated with language planning, but the impact of these dynamics on spoken interaction remains unclear. Here we use direct electrical stimulation to transiently perturb cortical function in neurosurgical patient-volunteers performing a question-answer task. Stimulating structures involved in speech motor function evoked diverse articulatory deficits, while perturbations of caudal inferior and middle frontal gyri - which exhibit preparatory activity during conversational turn-taking - led to response errors. Perturbation of the same planning-related frontal regions slowed inter-speaker timing, while faster responses could result from stimulation of sites located in other areas. Taken together, these findings further indicate that caudal inferior and middle frontal gyri constitute a critical planning network essential for interactive language use.

The Reticulon-4 3-bp Deletion/Insertion Polymorphism Is Associated with Structural mRNA Changes and the Risk of Breast Cancer: A Population-Based Case-Control Study with Bioinformatics Analysis.

Breast cancer (BC) is a complex disease caused by molecular events that disrupt cellular survival and death. Discovering novel biomarkers is still required to better understand and treat BC. The reticulon-4 (RTN4) gene, encoding Nogo proteins, plays a critical role in apoptosis and cancer development, with genetic variations affecting its function. We investigated the rs34917480 in RTN4 and its association with BC risk in an Iranian population sample. We also predicted the rs34917480 effect on RTN4 mRNA structure and explored the RTN4's protein-protein interaction network (PPIN) and related pathways. In this case-control study, 437 women (212 BC and 225 healthy) were recruited. The rs34917480 was genotyped using AS-PCR, mRNA secondary structure was predicted with RNAfold, and PPIN was constructed using the STRING database. Our findings revealed that this variant was associated with a decreased risk of BC in heterozygous (p = 0.012), dominant (p = 0.015), over-dominant (p = 0.017), and allelic (p = 0.035) models. Our prediction model showed that this variant could modify RTN4's mRNA thermodynamics and potentially its translation. RTN4's PPIN also revealed a strong association with apoptosis regulation and key signaling pathways highly implicated in BC. Consequently, our findings, for the first time, demonstrate that rs34917480 could be a protective factor against BC in our cohort, probably via preceding mechanisms.

Allergen Induces Depression-like Behavior in Association with Altered Prefrontal-hippocampal Circuit in Male Rats.

Allergic asthma is a common chronic inflammatory condition associated with psychiatric comorbidities. Notably depression, correlated with adverse outcomes in asthmatic patients. Peripheral inflammation's role in depression has been shown previously. However, evidence regarding the effects of allergic asthma on the medial prefrontal cortex (mPFC)-ventral hippocampus (vHipp) interactions, an important neurocircuitry in affective regulation, is yet to be demonstrated. Herein, we investigated the effects of allergen exposure in sensitized rats on the immunoreactivity of glial cells, depression-like behavior, brain regions volume, as well as activity and connectivity of the mPFC-vHipp circuit. We found that allergen-induced depressive-like behavior was associated with more activated microglia and astrocytes in mPFC and vHipp, as well as reduced hippocampus volume. Intriguingly, depressive-like behavior was negatively correlated with mPFC and hippocampus volumes in the allergen-exposed group. Moreover, mPFC and vHipp activity were altered in asthmatic animals. Allergen disrupted the strength and direction of functional connectivity in the mPFC-vHipp circuit so that, unlike normal conditions, mPFC causes and modulates vHipp activity. Our results provide new insight into the underlying mechanism of allergic inflammation-induced psychiatric disorders, aiming to develop new interventions and therapeutic approaches for improving asthma complications.

Remembering the legacy of Professor Mohammad Hashemi: a pioneer in molecular genetic studies in southeast Iran (1965-2019).

Professor Mohammad Hashemi was a clinical biochemist and cancer genetic scientist. He has been chair and head of Department of Clinical Biochemistry at Zahedan University of Medical Sciences, Zahedan, Iran. He has played an important role in the improvement of understanding of genetics of disease in southeast Iran. He was also a part of international team for the discovery of the role of calprotectin (S100A8/A9) in cancer biology via regulation of cell fate in tumor cells. He had over 300 peer-reviewed scientific publications and trained significant numbers of high quality personals (>40) in the field of biomedical sciences. His sudden death in 2019 shocked national and international scientific society but his scientific legacy will remain alive forever.

Non-contiguous multilevel spinal tuberculosis: A case report of unusual spinal tuberculosis resembling spinal metastasis.

Spinal tuberculosis (TB) is diagnostically challenging, particularly in atypical forms. Non-contiguous multilevel spinal TB (NMLST) is a rare presentation of spinal TB, mimicking spinal malignancies. We reported an unusual NMLST case with a paraspinal and epidural abscess in a young patient with misleading clinical and imaging presentations.

Large infratentorial cystic oligodendroglioma in a pregnant patient: A case report of a rare presentation and literature review.

Oligodendrogliomas (ODGs) are rare brain tumors in adults, mostly presenting as a supratentorial solid mass, while less than 10% occur infratentorially. Infratentorial cystic ODGs are extremely rare. We reported a large partially cystic cerebellar ODG in a 31-week pregnant patient with an unusual presentation and discussed the challenging management.

The olfactory bulb coordinates the ventral hippocampus-medial prefrontal cortex circuit during spatial working memory performance.

Neural oscillations synchronize the activity of brain regions during cognitive functions, such as spatial working memory. Olfactory bulb (OB) oscillations are ubiquitous rhythms that can modulate neocortical and limbic regions. However, the functional connectivity between the OB and areas contributing to spatial working memory, such as the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC), is less understood. Hence, we investigated functional interaction between OB and the vHPC-mPFC circuit during the spatial working memory performance in rats. To this end, we analyzed the simultaneously recorded local field potentials from OB, vHPC, and mPFC when rats explored the Y-maze and compared the brain activities of correct trials vs. wrong trials. We found that coupling between the vHPC and mPFC was augmented during correct trials. The enhanced coherence of OB activity with the vHPC-mPFC circuit at delta (< 4 Hz) and gamma (50-80 Hz) ranges were observed during correct trials. The cross-frequency analysis revealed that the OB delta phase increased the mPFC gamma power within corrected trials, indicating a modulatory role of OB oscillations on mPFC activity during correct trials. Moreover, the correlation between OB oscillations and the vHPC-mPFC circuit was increased at the delta range during correct trials, exhibiting enhanced synchronized activity of these regions during the cognitive task. We demonstrated a functional engagement of OB connectivity with the vHPC-mPFC circuit during spatial working memory task performance.

Disrupted connectivity in the olfactory bulb-entorhinal cortex-dorsal hippocampus circuit is associated with recognition memory deficit in Alzheimer's disease model.

Neural synchrony in brain circuits is the mainstay of cognition, including memory processes. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disrupts neural synchrony in specific circuits, associated with memory dysfunction before a substantial neural loss. Recognition memory impairment is a prominent cognitive symptom in the early stages of AD. The entorhinal-hippocampal circuit is critically engaged in recognition memory and is known as one of the earliest circuits involved due to AD pathology. Notably, the olfactory bulb is closely connected with the entorhinal-hippocampal circuit and is suggested as one of the earliest regions affected by AD. Therefore, we recorded simultaneous local field potential from the olfactory bulb (OB), entorhinal cortex (EC), and dorsal hippocampus (dHPC) to explore the functional connectivity in the OB-EC-dHPC circuit during novel object recognition (NOR) task performance in a rat model of AD. Animals that received amyloid-beta (Aß) showed a significant impairment in task performance and a marked reduction in OB survived cells. We revealed that Aß reduced coherence and synchrony in the OB-EC-dHPC circuit at theta and gamma bands during NOR performance. Importantly, our results exhibit that disrupted functional connectivity in the OB-EC-dHPC circuit was correlated with impaired recognition memory induced by Aß. These findings can elucidate dynamic changes in neural activities underlying AD, helping to find novel diagnostic and therapeutic targets.

Asthma induces psychiatric impairments in association with default mode and salience networks alteration: A resting-state EEG study.

Asthma is a chronic inflammatory disease associated with a high prevalence of psychiatric disorders. There are specific brain networks responsible for emotional processes, including two important networks associated with psychiatric problems: the default mode network (DMN), which is more active in the resting state, and the salience network (SN), which is structurally connected to DMN. Although previous studies suggested that neuro-phenotypes of asthma may be recognizable by the neural activity of brain circuits, an association between the brain's functional alterations and psychiatric impairments induced by asthma remains unknown. We aimed to assess DMN and SN activity and its association with psychiatric indices and clinical parameters in asthmatic patients. Electroencephalography was recorded during the resting state with an awake and eyes-open condition in thirty-eight sex and age-matched subjects (19 atopic asthma patients and 19 healthy participants). Power spectrum and functional connectivity were computed for DMN and SN. We examined psychiatric disorders (including depression, anxiety, and stress) and pulmonary function using the DASS questionnaire and spirometry test, respectively. The results showed that DASS scores were significantly higher in asthmatic patients compared to healthy subjects. Asthmatic patients also demonstrate a significant enhancement in power and functional connectivity in the two networks. Notably, these power enhancements of the networks were correlated with psychiatric problems scores, pulmonary function, asthma duration, and poor asthma control. These results introduce new evidence for the association between altered brain activity, the existence of psychiatric disorders, and asthma-related features, including pulmonary function. Also, we provide new insights into asthma-induced inflammatory response and the importance of developing novel interventions and therapeutic strategies for managing allergic inflammation patients who suffer from concurrent psychiatric disorders.

Nasal Air Puff Promotes Default Mode Network Activity in Mechanically Ventilated Comatose Patients: A Noninvasive Brain Stimulation Approach.

OBJECTIVES: Coma state and loss of consciousness are associated with impaired brain activity, particularly gamma oscillations, that integrate functional connectivity in neural networks, including the default mode network (DMN). Mechanical ventilation (MV) in comatose patients can aggravate brain activity, which has decreased in coma, presumably because of diminished nasal airflow. Nasal airflow, known to drive functional neural oscillations, synchronizing distant brain networks activity, is eliminated by tracheal intubation and MV. Hence, we proposed that rhythmic nasal air puffing in mechanically ventilated comatose patients may promote brain activity and improve network connectivity. MATERIALS AND METHODS: We recorded electroencephalography (EEG) from 15 comatose patients (seven women) admitted to the intensive care unit because of opium poisoning and assessed the activity, complexity, and connectivity of the DMN before and during the nasal air-puff stimulation. Nasal cavity air puffing was done through a nasal cannula controlled by an electrical valve (open duration of 630 ms) with a frequency of 0.2 Hz (ie, 12 puff/min). RESULTS: Our analyses demonstrated that nasal air puffing enhanced the power of gamma oscillations (30-100 Hz) in the DMN. In addition, we found that the coherence and synchrony between DMN regions were increased during nasal air puffing. Recurrence quantification and fractal dimension analyses revealed that EEG global complexity and irregularity, typically seen in wakefulness and conscious state, increased during rhythmic nasal air puffing. CONCLUSIONS: Rhythmic nasal air puffing, as a noninvasive brain stimulation method, opens a new window to modifying the brain connectivity integration in comatose patients. This approach may potentially influence comatose patients' outcomes by increasing brain reactivity and network connectivity.

Association between angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin-II receptor 1 (AGTR1) polymorphisms and COVID-19 infection in the southeast of Iran: a preliminary case-control study.

BACKGROUND: The COVID-19 pandemic remains an emerging public health crisis with serious adverse effects. The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV--2) infection, targeting angiotensin-converting enzyme-2 (ACE2) receptor for cell entry. However, changes in the renin-angiotensin system (RAS) balance alter an individual's susceptibility to COVID-19 infection. We aimed to evaluate the association between AGT rs699 C > T, ACE rs4646994 I/D, and AGTR1 rs5186 C > A variants and the risk of COVID-19 infection and the severity in a sample of the southeast Iranian population. METHODS: A total of 504 subjects, including 258 COVID-19 positives, and 246 healthy controls, were recruited. Genotyping of the ACE gene rs4646994, and AGT rs699, and AGTR1 rs5186 polymorphisms was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP), respectively. RESULTS: Our results showed that the II genotype of ACE rs4646994 and the I allele decreased the risk of COVID-19 infection. Moreover, we found that the TC genotype and C allele of AGT rs699 increased the risk of COVID-19 infection. The AGTR1 rs5186 was not associated with COVID-19 infection. Also, we did not find any association between these polymorphisms and the severity of the disease. However, we found a significantly higher age and prevalence of diabetes and hypertension in patients with severe disease than a non-severe disease. CONCLUSIONS: These findings suggest that ACE rs4646994 and AGT rs699 polymorphisms increase the risk of COVID-19 infection in a southeast Iranian population.

Association of miR-499 Polymorphism and Its Regulatory Networks with Hashimoto Thyroiditis Susceptibility: A Population-Based Case-Control Study.

Hashimoto thyroiditis (HT) is a common autoimmune disorder with a strong genetic background. Several genetic factors have been suggested, yet numerous genetic contributors remain to be fully understood in HT pathogenesis. MicroRNAs (miRs) are gene expression regulators critically involved in biological processes, of which polymorphisms can alter their function, leading to pathologic conditions, including autoimmune diseases. We examined whether miR-499 rs3746444 polymorphism is associated with susceptibility to HT in an Iranian subpopulation. Furthermore, we investigated the potential interacting regulatory network of the miR-499. This case-control study included 150 HT patients and 152 healthy subjects. Genotyping of rs3746444 was performed by the PCR-RFLP method. Also, target genomic sites of the polymorphism were predicted using bioinformatics. Our results showed that miR-499 rs3746444 was positively associated with HT risk in heterozygous (OR = 3.32, 95%CI = 2.00-5.53, p < 0.001, CT vs. TT), homozygous (OR = 2.81, 95%CI = 1.30-6.10, p = 0.014, CC vs. TT), dominant (OR = 3.22, 95%CI = 1.97-5.25, p < 0.001, CT + CC vs. TT), overdominant (OR = 2.57, 95%CI = 1.62-4.09, p < 0.001, CC + TT vs. CT), and allelic (OR = 1.92, 95%CI = 1.37-2.69, p < 0.001, C vs. T) models. Mapping predicted target genes of miR-499 on tissue-specific-, co-expression-, and miR-TF networks indicated that main hub-driver nodes are implicated in regulating immune system functions, including immunorecognition and complement activity. We demonstrated that miR-499 rs3746444 is linked to HT susceptibility in our population. However, predicted regulatory networks revealed that this polymorphism is contributing to the regulation of immune system pathways.

The olfactory bulb modulates entorhinal cortex oscillations during spatial working memory.

Cognitive functions such as working memory require integrated activity among different brain regions. Notably, entorhinal cortex (EC) activity is associated with the successful working memory task. Olfactory bulb (OB) oscillations are known as rhythms that modulate rhythmic activity in widespread brain regions during cognitive tasks. Since the OB is structurally connected to the EC, we hypothesized that OB could modulate EC activity during working memory performance. Herein, we explored OB-EC functional connectivity during spatial working memory performance by simultaneous recording local field potentials when rats performed a Y-maze task. Our results showed that the coherence of delta, theta, and gamma-band oscillations between OB and EC was increased during correct trials compared to wrong trials. Cross-frequency coupling analyses revealed that the modulatory effect of OBs low-frequency phase on EC gamma power and phase was enhanced when animals correctly performed working memory task. The influx of information from OB to EC was also increased at delta and gamma bands within correct trials. These findings indicated that the modulatory influence of OB rhythms on EC oscillations might be necessary for successful working memory performance.

Prevention of COVID-19: Preventive Strategies for General Population, Healthcare Setting, and Various Professions.

The disease 2019 (COVID-19) made a public health emergency in early 2020. Despite attempts for the development of therapeutic modalities, there is no effective treatment yet. Therefore, preventive measures in various settings could help reduce the burden of disease. In this chapter, the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19, non-pharmaceutical approaches at individual and population level, chemoprevention, immunoprevention, preventive measures in different healthcare settings and other professions, special considerations in high-risk groups, and the role of organizations to hamper the psychosocial effects will be discussed.

Association of P2X7 receptor genetic polymorphisms and expression with rheumatoid arthritis susceptibility in a sample of the Iranian population: a case-control study.

OBJECTIVE: Rheumatoid arthritis (RA) is a complex inflammatory autoimmune disease with joint eruption, systemic manifestation, and numerous predisposing genetic factors. The P2X7 receptor is an essential ligand-gated channel that contributes to many physiological processes, especially inflammation. However, genetic variations can alter the P2X7 receptor function. Therefore, the present study aimed to explore the impact of P2X7 genetic polymorphisms and expression on susceptibility to RA in a sample of the Iranian population. METHODS: We enrolled 160 (145 female, 15 male) RA patients and 160 (142 female, 18 male) healthy individuals in this study. Genotyping was performed using tetra amplification refractory mutation system-polymerase chain reaction (TARMS-PCR) for rs1718119, rs2230912, rs2393799, rs28360457, rs35933842, and allele-specific PCR for rs1653624 and rs3751143. Furthermore, 44 new cases of RA and 48 healthy controls were recruited to investigate whether P2X7 mRNA expression is associated with RA susceptibility. RESULTS: The results revealed that the rs2393799 significantly increased the risk of RA in all genetic models (p<0.05), while rs3751143 in codominant (CC vs. AA, OR=0.49, 95% CI=0.26-0.92), dominant (AC+CC, OR=0.59, 95% CI=0.37-0.94), C allele (OR=0.63, 95% CI=0.46-0.88), and rs2230912 in codominant (AG vs. AA, OR=0.56, 95% CI=0.34-0.94), dominant (AG+GG vs. AA, OR=0.59, 95% CI=0.35-0.99), and overdominant (AG vs. AA+GG, OR=0.57, 95% CI=0.33-0.98) significantly decreased the RA risk (p<0.05). Furthermore, the rs1718119 and rs1653624 were not associated with susceptibility of RA (p>0.05), and rs28360457 and rs35933842 were not polymorphic in our study. The mRNA expression level of P2X7 in both groups revealed that the P2X7 gene was significantly upregulated in RA (3.18±0.43) compared to healthy subjects (1.47±0.15, p<0.001). CONCLUSION: Our results suggest that rs2393799, rs3751143, and rs2230912 variants of the P2X7 gene are associated with RA's susceptibility in a sample of the Iranian population. Also, P2X7 mRNA expression was higher in our new RA patients. The P2X7 receptor has been considered as a potential pharmacologic target in RA. Key Points • P2X7 variants (rs2393799, rs2230912, rs3751143) were associated with RA susceptibility in a sample of the Iranian population. • rs2393799 increases the risk of RA, while rs2230912 and rs3751143 decrease the risk of RA. • P2X7 expression was significantly upregulated in new RA patients compared to controls.

Allergic rhinitis impairs working memory in association with drop of hippocampal - Prefrontal coupling.

Allergic rhinitis (AR) is a chronic inflammatory disease frequently associated with a deficit in learning and memory. Working memory is an important system for decision making and guidance, which depends on interactions between the ventral hippocampus (vHipp) and the prelimbic prefrontal cortex (plPFC). It is still unclear whether AR influences the activity and coupling of these brain areas, which consequently may impair working memory. The current study aimed to examine alterations of the vHipp-plPFC circuit in a rat model of AR. Our results show decreased working memory performance in AR animals, accompanied by a reduction of theta and gamma oscillations in plPFC. Also, AR reduces coherence between vHipp and plPFC in both theta and gamma frequency bands. Cross-frequency coupling analyses confirmed a reduced interaction between hippocampal theta and plPFC gamma oscillations. Granger causality analysis revealed a reduction in the causal effects of vHipp activity on plPFC oscillations and vice versa. A significant correlation was found between working memory performance with disruption of functional connectivity in AR animals. In summary, our data show that in AR, there is a deficit of functional coupling between hippocampal and prefrontal network, and suggest that this mechanism might contribute to working memory impairment in individuals with AR.

Rhythmic air-puff into nasal cavity modulates activity across multiple brain areas: A non-invasive brain stimulation method to reduce ventilator-induced memory impairment.

Mechanical ventilation (MV) can result in long-term brain impairments that are resistant to treatment. The mechanisms underlying MV-induced brain function impairment remain unclear. Since nasal airflow modulates brain activity, here we evaluated whether reinstating airflow during MV could influence the memory performance of rats after recovery. Rats were allocated into two study groups: one group received rhythmic air-puff into the nasal cavity during MV and a control group that underwent ventilation without air-puff. During MV, air-puffs induced time-locked event potentials in OB, mPFC and vHPC and significantly increased the oscillatory activity at the air-puff frequency. Furthermore, in mPFC and vHPC, (but not in OB), delta and theta oscillations were more prominent during air-puff application. After recovery, working memory performance was significantly higher in the air-puff group compared to control. Our study thus suggests a promising non-invasive brain stimulation approach to alleviate the neurological complications of prolonged mechanical ventilation.

Fulminant and Diffuse Cerebral Toxoplasmosis as the First Manifestation of HIV Infection: A Case Presentation and Review of the Literature.

BACKGROUND One of the most common causes of central nervous system (CNS) opportunistic infections in immunocompromised patients is toxoplasmosis. It can cause focal or disseminated brain lesions leading to neurological deficit, coma, and death. Prompt management with optimal antibiotics is vital. However, the diagnosis of cerebral toxoplasmosis is challenging in infected individuals with human immunodeficiency virus (HIV). The possible diagnosis is based on clinical presentation, imaging, and specific serologic investigations. The diagnosis can be confirmed by histopathological examination and/or by finding nucleic material in the spinal cerebrospinal fluid (CSF) examination. CASE REPORT We present a review of the literature with a rare illustrative case of diffuse CNS toxoplasmosis as the first manifestation of HIV infection in a young patient. Brain MRI showed diffuse, ring-enhancing lesions, and significant midline shift. Decompressive hemicraniectomy for control of intracranial pressure and anti-infectious therapy were performed. CONCLUSIONS This should raise awareness that cerebral toxoplasmosis can occur in pediatric patients with HIV infection, and, more importantly, as the first manifestation of AIDS. Although the prognosis is often poor, early diagnosis and immediate treatment of this life-threatening opportunistic infection can improve outcomes.