Neural Transm Research Articles

Encephalitis matters

Mental-health issues are the focus of this year's World Encephalitis Day, on Feb 22. On this date, in line with their Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders, WHO will release a meeting report on Why Encephalitis Matters.1WHO. Why encephalitis matters: meeting report (in press).Google Scholar Suicide is one of the top three causes of death in children and young adults.2WHOSuicide.https://www.who.int/news-room/fact-sheets/detail/suicideDate: June 17, 2021Date accessed: January 25, 2023Google Scholar In people with a neurological disorder, suicide rates might double those of people without a neurological disorder.3Erlangsen A Stenager E Conwell Y et al.Association Between Neurological Disorders and Death by Suicide in Denmark.JAMA. 2020; 323: 444-454Crossref PubMed Scopus (46) Google Scholar In fact, more than 37% of survivors of encephalitis report that they had thought about or attempted suicide4Abdat Y Butler M Zandi M et al.Mental health outcomes of encephalitis, an international web-based study.medRxi. 2023; (published online Feb 7.) (preprint).https://doi.org/10.1101/2023.02.03.23285344Google Scholar and about 12% of patients affected by autoimmune encephalitis had suicidal behaviours during the early stages of their illness, and nearly half of them carried out a suicide attempt.5Tellez-Martinez A Restrepo-Martinez M Espinola-Nadurille M et al.Suicidal thoughts and behaviors in anti-NMDAR encephalitis: psychopathological features and clinical outcomes.J Neuropsychiatry Clin Neurosci. 2023; (in press).Google Scholar The mental health issues associated with neurological diseases are usually treatable,6Gold SM Köhler-Forsberg O Moss-Morris R et al.Comorbid depression in medical diseases.Nat Rev Dis Primers. 2020; 6: 69Crossref PubMed Scopus (116) Google Scholar but the psychiatric sequelae of encephalitis have been far less investigated than neurological outcomes; hence, the need for more research addressing their nature, causes, and effects.7Hansen N Timäus C Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge.J Neural Transm. 2021; 128: 1-14Crossref PubMed Scopus (7) Google Scholar Mental health issues following encephalitis might be caused by the biological effects of inflammation on the brain during the acute stages of the disease, by psychological responses to traumatic ill-health, or by adverse effects of treatments. Stigma about mental health can be a barrier for patients and families to speaking up, and we hope that, on this World Encephalitis Day, we get closer to addressing it. Famous landmarks and buildings around the world have agreed to light up in red on Feb 22, from Niagara Falls in Canada to the Dancing House in Prague, Czech Republic. Careful risk assessment can help reduce the impact of suicidal thoughts and behaviours; anyone affected by encephalitis and mental health concerns should know that these conditions are often treatable.

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein.

SUMMARYα-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson’s disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.

Symposium

Objective:Neuromodulatory interventions like transcranial direct current stimulation (tDCS) is an emerging and potential therapeutic strategy to help in reducing craving and relapse prevention in patients of alcohol dependence syndrome (1–4). The potential target for alcohol dependence is the dorsolateral pre-frontal cortex (dlPFC) as frontal dysfunction is a hallmark of alcoholism, even in alcohol dependence subjects with no major clinical and global cognitive deficits (5). In this context, this study was designed to explore the effect of tDCS treatment on craving and relapse prevention and its correlation to dorsolateral prefrontal cortex (DLPFC) activation in alcohol dependent patients.Methodology:This study was a double blinded randomized sham control trial, conducted at National Institute of Mental Health and Neurosciences, Bangalore after approval by the Institute Ethics Committee. Twenty-four patients of alcohol dependence syndrome were recruited after informed consent. After detoxification patients underwent baseline fMRI scans. Followed by tDCS with intensity of 2mA and duration of 20 minutes per day was administered for 5 consecutive days with cathode over left dorsolateral prefrontal cortex (DLPFC) and anode over right DLPFC. On the 5th day post fMRI scans were repeated. Both investigator and subjects remained blind throughout the study period. During scans patients were exposed to visual alcohol cues using VICE (visual image- Induced craving for ethanol) paradigm. Pre- treatment and post-treatment scans were analysed using SPM-12 software.Results:At the beginning of the study, 24 subjects were selected but 2 subjects dropped out before post fMRI scan. The baseline comparison of socio-demographic and clinical variables found to have no differences among both groups.fMRI results: At baseline, the true and sham tDCS groups had comparable BOLD activation patterns and there were no between-group differences in activation pattern noted for alcohol vs. neutral cues contrast. Following 5 sessions of tDCS, there is significantly increased activation observed in true tDCS group, from Pre- to Post- treatment scans. Brain activity at DLPFC (Post-Pre) was positively associated with time to first alcohol lapse (p=0.048, Spearman’s rho =0.426). This suggests that greater the increase in brain activity at DLPFC after treatment with bilateral repetitive tDCS longer was the time to first lapse. Conclusion:This study has shown bilateral repetitive transcranial direct current stimulation in alcohol dependent subjects, activates dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) along with increase in the connectivity strength between medial frontal gyrus (MFG) and sub cortical reward centre (NAc), which facilitated abstinence from alcohol. So from this study we better understood the mechanism of tDCS in preventing relapse to alcohol by activation of dorsolateral prefrontal cortex and anterior cingulated cortex. Though the fMRI results were statistically significant for relapse and DLPFC activation, but it would be difficult to establish the clinical significance of the improvement in craving in the background of small sample size. Hence further studies with larger sample size are required in near future. Referrences: 1. Klauss J, Penido Pinheiro LC, Silva Merlo BL, Correia Santos GDA, Fregni F, Nitsche MA, et al. A randomized controlled trial of targeted prefrontal cortex modulation with tDCS in patients with alcohol dependence. Int J Neuropsychopharmacol. 2014;17(11):1793–803.2. Boggio PS, Sultani N, Fecteau S, Merabet L, Mecca T, Pascual-Leone A, et al. Prefrontal cortex modulation using transcranial DC stimulation reduces alcohol craving: A double-blind, sham-controlled study. Drug Alcohol Depend. 2008;92(1–3):55–60.3. Nakamura-Palacios EM, Lopes IBC, Souza RA, Klauss J, Batista EK, Conti CL, et al. Ventral medial prefrontal cortex (vmPFC) as a target of the dorsolateral prefrontal modulation by transcranial direct current stimulation (tDCS) in drug addiction. J Neural Transm. 2016;123(10):1179–94.4. da Silva MC, Conti CL, Klauss J, Alves LG, do Nascimento Cavalcante HM, Fregni F, et al. Behavioral effects of transcranial Direct Current Stimulation (tDCS) induced dorsolateral prefrontal cortex plasticity in alcohol dependence. J Physiol. 2013;107(6):493–502.5. Nakamura-Palacios EM, Souza RSM, Zago-Gomes MP, de Melo AMF, Braga FS, Kubo TTA, et al. Gray Matter Volume in Left Rostral Middle Frontal and Left Cerebellar Cortices Predicts Frontal Executive Performance in Alcoholic Subjects. Alcohol Clin Exp Res [Internet]. 2014 Apr 1 ;38(4):1126–33. Available from: http://doi.wiley.com/10.1111/ acer.12308

Mitochondrial A10398G Alteration in Plasma Exosome of Non-small Cell Lung Cancer Patients

This study identifies A10398G alteration of mitochondrial ND3 gene in plasma exosome of 29 non-small cell lung cancer (NSCLC) patients, 31 controls and 13 pairs of tumor tissue and adjacent tissue of NSCLC patients, thereby assessing the relationship between this alteration in plasma exosome and tissue as well as the pathological characteristics of NSCLC patients. Using the PCR-RFLP method, the homoplasmy and heteroplasmy of A10398G were initially identified in mitochondrial DNA from both exosomes and lung tissues. The rate of variant 10398G in plasma exosome was 62.1% in the NSCLC group and 61.3% in the control group. However, there was no statistically significant difference in A10398G between the patient and control groups. The alteration of A10398G in plasma exosome and in tissue correlated with each other (correlation coefficient 0.69; p = 0.009). However, this alteration was not related to age, gender, smoking, alcohol drinks status, tumor size, histological stage and TNM stage.
 Keywords
 A10398G alteration, mitochondrial DNA, plasma exosome, non-small cell lung cancer.
 References
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Positron Emission Tomography: Updates on Imaging of Addiction.

Positron Emission Tomography: Updates on Imaging of Addiction.

Respiratory-Related Leg Movements of Sleep Are Associated With Serotonergic Antidepressants But Not Bupropion.

Respiratory-related leg movements (RRLMs) may contribute to the cardiovascular risk associated with obstructive sleep apnea (OSA). Selective serotonin reuptake inhibitors (SSRIs), but not bupropion, increase periodic leg movements in sleep. This study examines whether patients with OSA using SSRIs have more RRLMs than those taking bupropion or no antidepressant. Patients with an apnea-hypopnea index (AHI) of at least 10 events/h during a full-night diagnostic study or split-night study, who were taking bupropion (n = 32), an SSRI (n = 31), or no antidepressant (n = 31), were selected from a database of prestudy questionnaires. RRLMs were scored according to World Association of Sleep Medicine 2016 standards. Patients using SSRIs had significantly greater overall RRLM% (defined as the percentage of respiratory events associated with a leg movement, including apneas, hypopneas, and respiratory effort-related arousals), RRLM index, and periodic limb movement index relative to patients using bupropion and control patients. The difference between the RRLM% in the SSRI and bupropion groups was limited to patients undergoing split-night studies, and that of the SSRI and control groups was limited to patients undergoing full-night diagnostic studies. The greater number of RRLMs and PLMs in the SSRI group may contribute to treatment-emergent insomnia often seen with SSRI use. Fragmented sleep and elevated autonomic nervous system activation associated with increased RRLMs in patients with OSA taking SSRIs might also limit the tolerability of antidepressant treatment, as well as increase the risk for cardiovascular disease.

Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes.

SummaryTauopathies such as frontotemporal dementia (FTD) remain incurable to date, partially due to the lack of translational in vitro disease models. The MAPT gene, encoding the microtubule-associated protein tau, has been shown to play an important role in FTD pathogenesis. Therefore, we used zinc finger nucleases to introduce two MAPT mutations into healthy donor induced pluripotent stem cells (iPSCs). The IVS10+16 mutation increases the expression of 4R tau, while the P301S mutation is pro-aggregant. Whole-transcriptome analysis of MAPT IVS10+16 neurons reveals neuronal subtype differences, reduced neural progenitor proliferation potential, and aberrant WNT/SHH signaling. Notably, these neurodevelopmental phenotypes could be recapitulated in neurons from patients carrying the MAPT IVS10+16 mutation. Moreover, the additional pro-aggregant P301S mutation revealed additional phenotypes, such as an increased calcium burst frequency, reduced lysosomal acidity, tau oligomerization, and neurodegeneration. This series of iPSCs could serve as a platform to unravel a potential link between pathogenic 4R tau and FTD.

Time- and Frequency-domain Parameters of Heart Rate Variability and Blood Pressure in Parkinson’s disease Patients under Dry Immersion

Time- and Frequency-domain Parameters of Heart Rate Variability and Blood Pressure in Parkinson’s disease Patients under Dry Immersion

New cerebrospinal fluid biomarkers in Alzheimer’s disease

New cerebrospinal fluid biomarkers in Alzheimer’s disease

Time resolved dosimetry of human brain exposed to low frequency pulsed magnetic fields

An accurate dosimetry is a key issue to understanding brain stimulation and related interaction mechanisms with neuronal tissues at the basis of the increasing amount of literature revealing the effects on human brain induced by low-level, low frequency pulsed magnetic fields (PMFs).Most literature on brain dosimetry estimates the maximum E field value reached inside the tissue without considering its time pattern or tissue dispersivity. Nevertheless a time-resolved dosimetry, accounting for dispersive tissues behavior, becomes necessary considering that the threshold for an effect onset may vary depending on the pulse waveform and that tissues may filter the applied stimulatory fields altering the predicted stimulatory waveform’s size and shape.In this paper a time-resolved dosimetry has been applied on a realistic brain model exposed to the signal presented in Capone et al ( J. Neural Transm. 116 257–65), accounting for the broadband dispersivity of brain tissues up to several kHz, to accurately reconstruct electric field and current density waveforms inside different brain tissues.The results obtained by exposing the Duke’s brain model to this PMF signal show that the E peak in the brain is considerably underestimated if a simple monochromatic dosimetry is carried out at the pulse repetition frequency of 75 Hz.

Rasagiline prevents cyclosporine A-sensitive superoxide flashes induced by PK11195, the initial signal of mitochondrial membrane permeabilization and apoptosis.

Rasagiline, a neuroprotective inhibitor of type B monoamine oxidase, prevented PK111195-induced apoptosis in SH-SY5Y cells through inhibition of mitochondrial apoptosis signaling (J Neural Transm 120:1539-1551, 2013, J Neural Transm 122:1399-1407, 2015). This paper presents that PK11195 induced superoxide flashes, the transit production burst, mediated by cyclosporine A-sensitive membrane permeability transition. Rasagiline prevented superoxide flashes, calcium efflux, and cell death by PK11195. Regulation of the initial pore formation at the inner mitochondrial membrane was confirmed as the decisive mechanism of neuroprotection by rasagiline.

The influence of weakness on posture control: A simulation study

[1] Lubik S, FogelW, Tronnier V, KrauseM, Konig J, JostWH. Gait analysis in patients with advanced Parkinson disease: different or additive effects on gait induced by levodopa and chronic STN stimulation. J Neural Transm 2006;113:163–73. [2] Krysthowiak P, Blatt JL, Bourriez JL, Duhamel A, PerinaM, Blond S, et al. Effects of subthalamic nucleus stimulation and levodopa treatment on gait abnormalities in Parkinson disease. Arch Neurol 2003;60:80–4. [3] Botzel K, Kraft E. Strategies for treatment of gait and posture associated deficits in movement disorders: the impact of deep brain stimulation. Neurol Neurosci 2010;28:111–8.

Cortical Activations During a Computer-Based Fraction Learning Game: Preliminary Results from a Pilot Study

Advances in educational neuroscience have made it possible for researchers to conduct studies that observe concurrent behavioral (i.e., task performance) and neural (i.e., brain activation) responses to naturalistic educational activities. Such studies are important because they help educators, clinicians, and researchers to better understand the etiology of both typical and atypical math processing. Because of its ease of use and robust tolerance of movement, functional near-infrared spectroscopy (fNIRS) provides a brain-imaging platform that is optimally suited for such studies. To that end, the focus of the current research is to use fNIRS to help better understand the neural signatures associated with real-world math learning activities. For example, the computer game “Refraction” was designed as a fun and engaging method to improve fraction knowledge in children. Data collected in previous studies have identified significant correlations between Refraction play and improvements in fraction knowledge. Here we provide the results of a pilot study that describes participants’ cortical activations in response to Refraction play. As hypothesized, Refraction play resulted in increases in parietal cortical activations at levels above those measured during spatial-specific activities. Moreover, our results were similar to another fNIRS study by Dresler et al. (J Neural Transm 116(12): 1689–1700, 2009), where children read Arabic numeral addition equations compared to written equations. Our results provide a valuable proof-of-concept for the use of Refraction within a large-scale fNIRS-based longitudinal study of fraction learning.

Brain Perfusion Characterizes First Episode of Psychosis Patients in Respect to Healthy Controls.

Introduction Vascular changes in the brain are relevant in schizophrenia [e.g. 1] and in bipolar disorder [2]. The study of first episode psychosis (FEP) allows the analysis of brain morphology and function without confounds due to chronicity. Objectives To characterize brain perfusion in FEP. Aims To see if FEP exhibit modified perfusion in respect to healthy controls (HC), and identify the most affected brain areas. Methods We acquired T1 and DSC images of 35 FEP patients (45 +/- 10 years old) and 35 HC (42 +/- 8), using Gadolinium (0.1 mmol/Kg). We computed cerebral blood volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT) [3] in the whole brain and in left and right frontal, parietal, temporal and occipital lobes, insula, caudate and cerebellum Results Mean values of all quantities resulted lower in patients, up to 12% for CBV in right frontal lobe, 11% for CBF in left cerebellum and 16% for MTT in right frontal lobe. We used a support vector machine (SVM) to classify subjects on the basis of the histogram of perfusion values. We found that the classification reached accuracies over 80%, especially in the frontal brain areas. Conclusions FEP show altered perfusion parameters, which allow automatic classification with good accuracy, showing that brain vascular characteristics can be considered as marker of psychosis. [1] Peruzzo et al (2011). J Neural Transm, 118, 4:563-70. [2] Agarwal et al (2008). J Affect Disord, 110, 1-2:106-14. [3] Ostergaard et al (1996). Magn Reson Med, 36, 5:715-25.

Glycosylphosphatidylinositol Anchoring Directs the Assembly of Sup35NM Protein into Non-fibrillar, Membrane-bound Aggregates

In prion-infected hosts, PrPSc usually accumulates as non-fibrillar, membrane-bound aggregates. Glycosylphosphatidylinositol (GPI) anchor-directed membrane association appears to be an important factor controlling the biophysical properties of PrPSc aggregates. To determine whether GPI anchoring can similarly modulate the assembly of other amyloid-forming proteins, neuronal cell lines were generated that expressed a GPI-anchored form of a model amyloidogenic protein, the NM domain of the yeast prion protein Sup35 (Sup35(GPI)). We recently reported that GPI anchoring facilitated the induction of Sup35(GPI) prions in this system. Here, we report the ultrastructural characterization of self-propagating Sup35(GPI) aggregates of either spontaneous or induced origin. Like membrane-bound PrPSc, Sup35(GPI) aggregates resisted release from cells treated with phosphatidylinositol-specific phospholipase C. Sup35(GPI) aggregates of spontaneous origin were detergent-insoluble, protease-resistant, and self-propagating, in a manner similar to that reported for recombinant Sup35NM amyloid fibrils and induced Sup35(GPI) aggregates. However, GPI-anchored Sup35 aggregates were not stained with amyloid-binding dyes, such as Thioflavin T. This was consistent with ultrastructural analyses, which showed that the aggregates corresponded to dense cell surface accumulations of membrane vesicle-like structures and were not fibrillar. Together, these results showed that GPI anchoring directs the assembly of Sup35NM into non-fibrillar, membrane-bound aggregates that resemble PrPSc, raising the possibility that GPI anchor-dependent modulation of protein aggregation might occur with other amyloidogenic proteins. This may contribute to differences in pathogenesis and pathology between prion diseases, which uniquely involve aggregation of a GPI-anchored protein, versus other protein misfolding diseases.

Examining Electrostatic Preorganization in Monoamine Oxidases A and B by Structural Comparison and pKaCalculations

Monoamine oxidases (MAO) A and B are important flavoenzymes involved in the metabolism of amine neurotransmitters. Orru et al. ( J. Neural Transm. 2013 , 120 , 847 - 851 ) recently presented experimental results that have challenged the prevailing assumption that MAO A and MAO B employ an identical catalytic mechanism. We compared the spatial configuration of ionizable groups in both isozymes and estimated the time-averaged electrostatic potential by calculating the pKa values of five active site residues. Superimposition of both experimental structures shows very close overlap and the RMSD in placements of ionizable groups within 16 Å of the reaction center is only 0.847 Å. This similarity is also reflected in the calculated pKa values, where the largest difference between the MAO A and MAO B pKa values was found for residues Tyr188 in MAO B and the corresponding Tyr197 in MAO A assuming 1.23 units. The pKa values for the other four studied residues differ by less than 0.75 units. The results show that the electrostatic preorganizations in both active sites are very similar, supporting the idea that both enzymes work by the same mechanism.

Effects of Allogeneic Bone Marrow Derived Mesenchymal Stromal Cell Therapy on Voiding Function in a Rat Model of Parkinson Disease

Cellular therapy induced transient urodynamic improvement in a rat model of Parkinson disease in which bladder dysfunction was noted after unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. We sought to prolong the effect by injecting allogeneic rat bone marrow mesenchymal stromal cells before and after microencapsulation into the substantia nigra pars compacta. Female rats underwent unilateral stereotactic injection of 6-hydroxydopamine in the medial forebrain bundle. Injection was performed in the ipsilateral substantia nigra pars compacta using vehicle alone or vehicle with nonmicroencapsulated or microencapsulated rat bone marrow derived mesenchymal stromal cells. Rats were evaluated by cystometry 7, 14, 28 and 42 days after treatment. Brains were extracted for immunostaining. At 42 days the nonmicroencapsulated group had lower threshold and intermicturition pressure, spontaneous activity and AUC than vehicle treated animals. Rats that received microencapsulated cells had lower threshold pressure at 28 days and lower spontaneous activity at 42 days than vehicle treated rats. Microencapsulated and nonmicroencapsulated rat bone marrow derived mesenchymal stromal cells were noted in the substantia nigra pars compacta up to 42 days after transplantation. At 42 days tyrosine hydroxylase positive neurons were more numerous in the substantia nigra pars compacta of the nonmicroencapsulated group, followed by the microencapsulated and vehicle treated groups. Urodynamic effects of the 6-hydroxydopamine lesion persisted up to 42 days after vehicle injection. Transplantation of nonmicroencapsulated rat bone marrow derived mesenchymal stromal cells improved urodynamic pressure by 42 days after treatment more markedly than microencapsulated cells. This was associated with more tyrosine hydroxylase positive neurons in the treated substantia nigra pars compacta of the nonmicroencapsulated group, suggesting that functional improvement requires a juxtacrine effect.

Zebrafish Tyrosine Hydroxylase 2 Gene Encodes Tryptophan Hydroxylase

The primary pathological hallmark of Parkinson disease (PD) is the profound loss of dopaminergic neurons in the substantia nigra pars compacta. To facilitate the understanding of the underling mechanism of PD, several zebrafish PD models have been generated to recapitulate the characteristics of dopaminergic (DA) neuron loss. In zebrafish studies, tyrosine hydroxylase 1 (th1) has been frequently used as a molecular marker of DA neurons. However, th1 also labels norepinephrine and epinephrine neurons. Recently, a homologue of th1, named tyrosine hydroxylase 2 (th2), was identified based on the sequence homology and subsequently used as a novel marker of DA neurons. In this study, we present evidence that th2 co-localizes with serotonin in the ventral diencephalon and caudal hypothalamus in zebrafish embryos. In addition, knockdown of th2 reduces the level of serotonin in the corresponding th2-positive neurons. This phenotype can be rescued by both zebrafish th2 and mouse tryptophan hydroxylase 1 (Tph1) mRNA as well as by 5-hydroxytryptophan, the product of tryptophan hydroxylase. Moreover, the purified Th2 protein has tryptophan hydroxylase activity comparable with that of the mouse TPH1 protein in vitro. Based on these in vivo and in vitro results, we conclude that th2 is a gene encoding for tryptophan hydroxylase and should be used as a marker gene of serotonergic neurons.

Selective Sound Sensitivity Syndrome (Misophonia) in a Patient With Tourette Syndrome

Selective Sound Sensitivity Syndrome (Misophonia) in a Patient With Tourette Syndrome