Behavioral Sciences

behavioral sciences

Brief Report Neuroinﬂammation and Neuromodulation in Neurological Diseases

Maria de los Angeles Robinson-Agramonte 1,2,*, Carlos-Alberto Gonçalves 3, Roberto Farina de Almeida 4 , Alina González Quevedo 5 , Sandra Chow 6, Luis Velázquez Pérez 7, Amado Díaz de la Fé 2, Patricia Sesterheim 8 and Diogo Onofre Gomes Souza 3 1 Cuban Society of Neuroimmunology, Havana 11300, Cuba 2 International Center for Neurological Restoration, Ave 25 # 15805 b/w 158 and 160, Havana 11300, Cuba 3 Dept of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, Brazil 4 Universidade Federal de Ouro Preto, OP 3540-00, Brazil 5 National Institute of Neurology and Neurosurgery, Havana 10400, Cuba 6 MSL N&I Centro America y el Caribe.Biopharm Medical Aﬀairs, Guatemala 7 Center for the Research and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin 80100, Cuba 8 Institute of Cardiology of Rio Grande do Sul, Experimental Center, Porto Alegre 90650-090, Brazil * Correspondence: [email protected] or [email protected]

Received: 16 July 2019; Accepted: 9 September 2019; Published: 12 September 2019

Abstract: Neuroimmunology is a relatively young science. This discipline has emerged today from the research field as a mature and fully developed innovative research area that integrates not only pure topics of neuroimmunology, but also expands on wider fields such as neuroplasticity, neuronal reserve and neuromodulation in association with clinical events, amongst which behavioral disorders stand out. The Cuban School of Neuroimmunology—a recent meeting that took place in Havana, Cuba—focused on topics based on the molecular mechanisms of neuroinflammation in neurological disorders involving behavioral manifestations, such as multiple sclerosis (MS), autism, cerebellar ataxias, Alzheimer´s disease and stroke among others, as well as on the use of new interventional technologies in neurology. Professor Luis Velazquez, from the Cuban Academy of Sciences, dictated an interesting lecture on Spinocerebellar ataxias, a genetic disorder where recent hypotheses related to the influence of neuroinflammation as a neurobiological factor influencing the progression of this disease have emerged. At the same time, the use of new interventional technologies in neurology was discussed, including those referring to novel disease modifying therapies in the course of MS and the use of transcranial magnetic stimulation in several neurological diseases, the latter reinforcing how interventional strategies in the form of non-invasive bran stimulation can contribute to physical rehabilitation in neurology. This paper summarizes the highlights of the most relevant topics presented during the First Cuban School of Neuroimmunology, organized by the Cuban Network of Neuroimmunology, held in June 2019.

Keywords: neuroimmunology; neurodevelopmental disorders; Strock neurodegenerative disorders; non-invasive brain stimulation; Demyelinating disease; SCA2 Cerebellar Ataxy; neuroimmunomodulation

1. Introduction Neuroimmunology is a relatively young science. This discipline has emerged today from the research field as a mature and fully developed innovative research area that integrates not only pure topics of neuroimmunology, but also expands on wider fields such as neuroplasticity, neuronal reserve and neuromodulation. Several diseases were revised in interesting lectures to offer a major understanding of the molecular processes underlying neuroimmune pathology in neurodegenerative, neurodevelopmental and neurovascular diseases, as well as to understand some vulnerabilities occurring in these disorders [1–5].

Behav. Sci. 2019, 9, 99; doi:10.3390/bs9090099 www.mdpi.com/journal/behavsci Behav. Sci. 2019, 9, 99 2 of 8

From this point of view, several diseases were revised in interesting lectures to offer a greater understandingBehav. Sci. of 2019 the, x molecular, x FOR PEER REVIEW processes underlying neuroimmune pathology in neurodegenerative,2 of 9 neurodevelopmentalneurodevelopmental and neurovascular and neurovascular diseases, diseases, as as well well as, as toto understandunderstand some some vulnerabilities comorbidities that affect diseaseoccurring evolution in these and disorders outcome [1–5]. [1–5]. In this context, the lecture on Spinocerebellar Ataxias type 2 presentedFrom by this Professor point of view, Luis several Velazquez diseases fromwere revised the Cuban in interesting Academy lectures of to Sciences, offer a greater showed how understanding of the molecular processes underlying neuroimmune pathology in molecular processesneurodegenerative, underlying neurodevelopmental neuroinflammation and neurovascular can also diseases, affect geneticas well as, disorders to understand influencing some onset and diseasecomorbidities progression that [1 –affect5]. disease evolution and outcome [1–5]. In this context, the lecture on Spinocerebellar Ataxias type 2 presented by Professor Luis Velazquez from the Cuban Academy of 2. LectureSciences, Highlights showed how molecular processes underlying neuroinflammation can also affect genetic disorders influencing onset and disease progression [1–5]. AstrocytesasIntegrativeElementsintheNeuroinflammationAssociatedwithNeurodegenerativeDiseases Carlos-Alberto2. Lecture Highlights Gonçalves and Elena Noris García. E mail:[email protected] AstrocytesAstrocytes are the mostas Integrative abundant Elements glial cell in in the brainNeuroinflammation tissue and, functionally,Associated with are equally, or more, heterogeneousNeurodegenerative than Diseases neurons [6]. They modulate synaptic communication, affecting clearance, Carlos-Alberto Gonçalves and Elena Noris García. E mail:[email protected] energetic support and plasticity; they also modulate the blood–brain barrier and brain immune Astrocytes are the most abundant glial cell in the brain tissue and, functionally, are equally, or response.more, Therefore, heterogeneous these cellsthan neurons integrate [6]. They diff erentmodula signals—metabolic,te synaptic communication, immune affecting and clearance, neural inputs. Astrogliosisenergetic refers tosupport astrocyte and plasticity; reactivity they in allalso forms modulate of injury the blood–brain and theincrement barrier and ofbrain glial immune fibrillary acidic protein (GFAP)response. is its Therefore, most frequent these cells marker integrate [7 ].differ However,ent signals—metabolic, GFAP up-regulation immune and on itsneural own inputs. provides little Astrogliosis refers to astrocyte reactivity in all forms of injury and the increment of glial fibrillary information concerning reactive astrocyte function [8]. From our experience, changes in extracellular acidic protein (GFAP) is its most frequent marker [7]. However, GFAP up-regulation on its own levels of S100betaprovides havelittle information been observed concerning in acute reactive and astr chronicocyte function neuroinflammatory [8]. From our experience, conditions, changes associated with neurodegenerativein extracellular levels processes, of S100beta like have those been occurring observed in acute Alzheimer and chronic´s disease neuroinflammatory and other systemic diseases displayingconditions, associated neuropsychiatric with neurodegenerative disorders processes, [2,9]. Thislike those lecture occurring highlights in Alzheimer´s how disease during injury, and other systemic diseases displaying neuropsychiatric disorders [2,9]. This lecture highlights how astrocytes are simultaneously exposed to a myriad of stimuli from microglia, blood and neurons, during injury, astrocytes are simultaneously exposed to a myriad of stimuli from microglia, blood leading toand a complex neurons, leading reactivity to a complex whose reactivity signaling whose will signaling result, orwill not, result, in or a dysfunctionalnot, in a dysfunctional cell, Figure1. At the samecell, time, Figure it 1. is At necessary the same time, to investigate it is necessary other to investigate specific other astrocyte specific astrocyte markers, markers, such such as aquaporin-4, as glutamateaquaporin-4, transporters glutamate and S100beta, transporters as and well S100beta, as the as transcription well as the transcription factors involved. factors involved. Finally, it was Finally, it was important to consider that potential targets to treat neuroinflammation such as important to consider that potential targets to treat neuroinflammation such as immune receptors immune receptors (e.g., TNFR2: tumor necrosis factor repceptor 2), protein phosphatases (e.g., (e.g., TNFR2:calcineurin) tumor and necrosis protein factor kinases repceptor (e.g., p38) also 2), are protein actively phosphatases present in astrocytes (e.g., [10,11]. calcineurin) and protein kinases (e.g., p38) also are actively present in astrocytes [10,11].

Figure 1. HeterogeneityFigure 1. Heterogeneity of reactive of reactive astrocytes astrocytes during during inflammation. inflammation. Astrocytes Astrocytes respond respond directly to directly to inflammatoryinflammatory stimulus stimulus (e.g., via(e.g., TLR4: via TLR4: toll toll like like receptor receptor 44 or or indirectly indirectly to inflammatory to inflammatory cytokines cytokines by by cytokine receptors. In basal conditions, they secrete small quantities of cytokine TNF (tumor necrosis cytokine receptors. In basal conditions, they secrete small quantities of cytokine TNF (tumor necrosis factor) and express only TNFR1 (tumor necrosis factor receptor 1). When exposed to inflammation, TNF production is increased, as well as the expression of TNFR2, which is commonly expressed by immune cells. TNFR2-astrocytes can generate both anti-inflammatory astrocytes able to express TGF (tumor growth factor) and IL-10 and pro-inflammatory astrocytes which are able to release chemokines and attract T lymphocytes, which, in turn, release interferon gamma (IFNγ), inducing the expression of MCH class II in astrocytes, and transforming them into antigen-presenting cells. Behav. Sci. 2019, 9, 99 3 of 8

Guanosine Neuroinflammation and Neuroprotection Roberto Farina de Almeida, Elaine Elisabetsky and Diogo Onofre Gomes Souza. E mail: [email protected] Inflammation in the central nervous system (CNS) plays an important role in several brain disorders [12]. Glutamate, an excitatory neurotransmitter essential for most brain activities, has been considered relevant to the pathogenesis of neuroinflammation, contributing to the development of several acute and chronic brain injuries [13]. The main process responsible for maintaining extracellular glutamate levels below toxic concentrations, thus favoring the physiological glutamatergic tonus, is the glutamate uptake activity of glutamate transporters located in neural cell membranes, mainly in astrocytes [14]. In this context, our group presented strong evidence that systemic guanosine (GUO) administration is effectively neuroprotective against glutamate toxicity and neuroinflammation in different protocols that mimic several brain disorders, in both in vitro and in vivo studies, Figure2[ 15]. These results point to a potential applicability of the neuroprotective effects of GUO in putative translational studies [16]. In this topic, the relevance of these data were discussed, accompanied by our more recent results regarding the potential antidepressive-like effect exerted by acute and chronic GUO treatment in mice submitted to a well-validated animal model of depression. In addition, we also demonstrated that GUO treatment attenuated hippocampal redox imbalance, accompanied by a significant modulation in peripheral and central (hippocampal) inflammatory cytokines. In this line of research, our results establish new perspectives for therapeutic developments regarding the latest results related with the antidepressive-like effects of acute and chronic GUO in mice subjected to olfactory bulbectomy, a well-validated rodent model of depression with translational value. In addition to the behavioral data, we show that GUO attenuates hippocampal redox imbalance and significantly Behav. Sci. 2019, x, x FOR PEER REVIEW 4 of 9 modulates peripheral and central (hippocampal) inflammatory cytokines.

Figure 2. Postulated pathways involved in GUO mechanism of action. Figure was produced with permissionFigure 2. Postulated using Biorender pathways free involved version (www.biorender.coin GUO mechanism). of A1R: action. Adenosine Figure a1was receptor, produced GLT-1: with Glutamatepermission transporter-1 using Biorender free version (www.biorender.co). A1R: Adenosine a1 receptor, GLT-1: Glutamate transporter-1 Neuroinﬂammation in Brain Ischemia Neuroinflammation in Brain Ischemia Alina González-Quevedo, Marisol Peña Sánchez, María Caridad Menéndez Saínz, Rebeca Fernández Carriera, Anay Cordero Eiriz, Melany Betacourt Loza. E mail: [email protected] According to the global burden of stroke study conducted in 2013, stroke is the second most common cause of death worldwide (11.8%), preceded only by ischemic heart disease (14.8%), and it constitutes the major cause of severe neurological deficits in the adult population, ischemic stroke accounting for ~85% of all strokes [17]. Several intricately interrelated mechanisms are known to participate in the development of the ischemic lesion, such as excitotoxicity, inflammation, blood– brain barrier disruption, complement cascade activation and increased free radical release. Nevertheless, inflammatory signaling is present throughout the ischemic cascade, from the early acute ischemic injury that follows arterial occlusion to the final regenerative processes which underlie post-ischemic tissue repair [18]. Inflammatory and immune components also prevail in conditions preluding the acute ischemic event: atherosclerosis, the basis of large and medium-sized artery disease, cerebral small vessel disease and hypertension—the main risk factor for cerebrovascular diseases (twice as important as for coronary heart disease). Activation of the immune system is thought to increase the risk of stroke. This is mainly based on the association observed between stroke and antecedent acute and chronic inflammatory states. Acute brain ischemia also exerts a potent suppressive effect on lymphoid organs, predisposing the patients to concomitant infections, thus complicating the outcome of stroke in terms of morbidity and mortality [18,19] Figure 3. Behav. Sci. 2019, 9, 99 4 of 8

Alina González-Quevedo, Marisol Peña Sánchez, María Caridad Menéndez Saínz, Rebeca Fernández Carriera, Anay Cordero Eiriz, Melany Betacourt Loza. E mail: [email protected] According to the global burden of stroke study conducted in 2013, stroke is the second most common cause of death worldwide (11.8%), preceded only by ischemic heart disease (14.8%), and it constitutes the major cause of severe neurological deficits in the adult population, ischemic stroke accounting for ~85% of all strokes [17]. Several intricately interrelated mechanisms are known to participate in the development of the ischemic lesion, such as excitotoxicity, inflammation, blood–brain barrier disruption, complement cascade activation and increased free radical release. Nevertheless, inflammatory signaling is present throughout the ischemic cascade, from the early acute ischemic injury that follows arterial occlusion to the final regenerative processes which underlie post-ischemic tissue repair [18]. Inflammatory and immune components also prevail in conditions preluding the acute ischemic event: atherosclerosis, the basis of large and medium-sized artery disease, cerebral small vessel disease and hypertension—the main risk factor for cerebrovascular diseases (twice as important as for coronary heart disease). Activation of the immune system is thought to increase the risk of stroke. This is mainly based on the association observed between stroke and antecedent acute and chronic inflammatory states. Acute brain ischemia also exerts a potent suppressive effect on lymphoid organs, predisposing Behav.the patients Sci. 2019, tox, x concomitant FOR PEER REVIEW infections, thus complicating the outcome of stroke in terms of morbidity5 of 9 and mortality [18,19] Figure3.

Figure 3. Inflammation and immunity events preceding and following acute ischemic stroke. Figure 3. Inflammation and immunity events preceding and following acute ischemic stroke. In this approach, we will engage in the involvement of inflammation and immunity in the medicalIn this conditions approach, that we antecede will engage acute in ischemic the involvement stroke, as well of inflammation as highlight how and these immunity processes in the are medicalinvolved conditions in the pathophysiology that antecede acute of the ischemic ischemic stroke, lesion onceas well established as highlight and how in the these subsequent processes repair are involvedmechanisms in the [4 pathophysiology,20]. of the ischemic lesion once established and in the subsequent repair mechanismsNovel Treatment[4,20]. Neuroimmunomodulators in Multiple Sclerosis Relapsed Remission Sandra Chow and Amado Díaz de la Fé.E mail: [email protected] NovelMultiple Treatment sclerosis Neuroimmunomodulators is the most common potential in Multiple cause of Sclerosis neurological Relapsed disability Remission in young adults withoutSandra history Chow of trauma.and Amado The Díaz disease de hasla Fé.E two mail: different [email protected] clinical phases, which reflect a dominant state of theMultiple pathological sclerosis processes: is the most (1) inflammation common potential corresponding cause of toneurological activity during disability the relapsing-remitting in young adults withoutstage and history (2) axon of trauma. degeneration The di representingsease has two the different main substrate clinical phases, of progressive which reflect disability. a dominant Most of statethe traditionalof the pathological disease-modifying processes: (1) drugs inflammation are involved corresponding in the inflammatory to activity process. during the In 2019,relapsing- three remittingmedications stage were and approved (2) axon degeneration for the progressive representi formng of the multiple main substrate sclerosis of (siponimod, progressive ocrelizumab disability. Most of the traditional disease-modifying drugs are involved in the inflammatory process. In 2019, three medications were approved for the progressive form of multiple sclerosis (siponimod, ocrelizumab and cladribine). Therefore, the question is to develop strategies that promote remyelination and prevent axonal loss. Currently, the pharmacological contribution of the therapeutic arsenal for multiple sclerosis (MS) treatment during the last 20 years has been focused on targeting the inflammatory process in the CNS. Both physicians and patients are demanding therapies, focused treatment with high efficiency, short administration, simple monitoring and a high safety profile. Figure 4 shows the disease modifying drugs in the market in recent years [21], however there are still unmet needs for both the clinician and the patient. It is important to be aware of making a good diagnosis and selecting the ideal medication for the patient at the right time. Disease-modifying therapy in MS is a key component of comprehensive MS care, along with managing MS relapses, treating symptoms and paying attention to overall health and wellness. Disease modifying medications are, at this time, the most valuable strategy available to slow the natural course of the disease, Figure 4 [22]. Even though these medications do not generally make the patient feel better, they can be looked upon as an investment for the future. Clinical studies have demonstrated that all of the medications for relapsing forms of MS reduce the frequency and severity of clinical attacks by 28–68%, reduce the development of new damaged areas in the brain and spinal cord as seen on MRI (magnetic resonance imaging), toward fewer, smaller or no new lesions on MRI scans and slow the accumulation of disability to delay progression. Behav. Sci. 2019, 9, 99 5 of 8

and cladribine). Therefore, the question is to develop strategies that promote remyelination and prevent axonal loss. Currently, the pharmacological contribution of the therapeutic arsenal for multiple sclerosis (MS) treatment during the last 20 years has been focused on targeting the inflammatory process in the CNS. Both physicians and patients are demanding therapies, focused treatment with high efficiency, short administration, simple monitoring and a high safety profile. Figure4 shows the disease modifying drugs in the market in recent years [21], however there are still unmet needs for both the clinician and the patient. It is important to be aware of making a good diagnosis and selecting Behav.the idealSci. 2019 medication, x, x FOR PEER for REVIEW the patient at the right time. 6 of 9

Figure 4. The Evolving multiple sclerosis (MS) Treatment Landscape.

Disease-modifyingFigure 4. therapy The Evolving in MS multiple is a key sclerosis component (MS) Treatment of comprehensive Landscape. MS care, along with managing MS relapses, treating symptoms and paying attention to overall health and wellness. Disease modifyingSubsequent medications research are, and at thisclinical time, experience the most valuable indicate strategy that early available treatment to slow with the these natural disease- course modifyingof the disease, drugs Figure may 4help[ 22 to]. Evenprevent though permanent these medicationsdamage in the do CNS. not generally Permanent make damage the patient to axons feel occursbetter, in they MS. can Overall be looked brain upon atrophy as an investmentshrinkage ca forn theoccur future. early Clinical in the studiesdisease, haveand demonstrateddamage can continuethat all ofeven the when medications a person for has relapsing no symptoms forms ofand MS feels reduce well. the At frequency the same time, and severity it must ofbe clinicaltaken intoattacks account by 28–68%, that the reduce FDA (Food the development and Drug Admini of new damagedstration) for areas pregnant in the brain women, and spinalor those cord who as seenare breastfeeding,on MRI (magnetic have resonance approved imaging), none of these toward medications. fewer, smaller or no new lesions on MRI scans and slow theIn accumulation the last two of decades, disability 15 tomedications delay progression. have been proposed as modifiers of the disease for MS, being Subsequentevaluated not research only in andterms clinical of effectiveness, experience but indicate also regarding that early their treatment validity with for theseintervention disease- monitoring,modifying drugstreatment may adherence, help to prevent incidence permanent of co-morbidities damage in theand CNS. secondary Permanent effects, damage among to other axons aspects.occurs inThis MS. conference Overall brain offered atrophy an updated shrinkage vision can occurto personalize early in the the disease, ideal medication and damage for canthe continuecontrol ofeven MS whenthrough a person the combination has no symptoms of these and new feels ther well.apies At therecently same time,approved it must for be RRMS taken into(Relapsing account Remmitingthat the FDA Multiple (Food Sclerosis). and Drug Administration) for pregnant women, or those who are breastfeeding, have approved none of these medications. BiomarkersIn the last twoand decades,Prodromal 15 Stage medications in Spinocerebellar have been proposedAtaxia Type as modifiers2 of the disease for MS, beingLuis evaluated Velázquez-Pérez. not only inE termsmail: [email protected] of effectiveness, but also regarding their validity for intervention monitoring,Spinocerebellar treatment Ataxias adherence, (SCAs) incidenceare a genetically of co-morbidities heterogeneous and secondarygroup of autosomal effects, among dominant other neurodegenerativeaspects. This conference disorders. offered The an global updated prevalence vision to is personalize about 3 cases/100,000 the ideal medication inhabitants for theand control the age of at onset is usually between 2 and 50 years of age. Unfortunately, there is no treatment available for these disorders. SCA3 is the most common SCA worldwide, followed by SCA2 and SCA6. Spinocerebellar ataxia type 2 (SCA2) is caused by the abnormal expansion of Cytosine-Adenine- Guanine (CAG) triplet repeats in the coding region of the ataxin-2 gene (12q24.1). The epidemiological studies have demonstrated that the highest prevalence rates of SCA2 patients and SCA2 mutations are in Holguin province, Cuba. The nationwide frequency of SCA2 in Cuba is around 85%. All patients show a progressive cerebellar syndrome characterized by gait ataxia, incoordination of the upper and lower limbs and cerebellar dysarthria. They also display slowing of saccadic eye movements, peripheral neuropathy, signs of motor neuron involvement such as fasciculations and amyotrophy, autonomic abnormalities (urinary dysfunction, hypohydrosis and constipation), sleep Behav. Sci. 2019, 9, 99 6 of 8

MS through the combination of these new therapies recently approved for RRMS (Relapsing Remmiting Multiple Sclerosis). Biomarkers and Prodromal Stage in Spinocerebellar Ataxia Type 2 Luis Velázquez-Pérez. E mail: [email protected] Spinocerebellar Ataxias (SCAs) are a genetically heterogeneous group of autosomal dominant neurodegenerative disorders. The global prevalence is about 3 cases/100,000 inhabitants and the age at onset is usually between 2 and 50 years of age. Unfortunately, there is no treatment available for these disorders. SCA3 is the most common SCA worldwide, followed by SCA2 and SCA6. Spinocerebellar ataxia type 2 (SCA2) is caused by the abnormal expansion of Cytosine-Adenine-Guanine (CAG) triplet repeats in the coding region of the ataxin-2 gene (12q24.1). The epidemiological studies have demonstrated that the highest prevalence rates of SCA2 patients and SCA2 mutations are in Holguin province, Cuba. The nationwide frequency of SCA2 in Cuba is around 85%. All patients show a progressive cerebellar syndrome characterized by gait ataxia, incoordination of the upper and lower limbs and cerebellar dysarthria. They also display slowing of saccadic Behav.eye movements,Sci. 2019, x, x FOR peripheral PEER REVIEW neuropathy, signs of motor neuron involvement such as fasciculations7 of 9 and amyotrophy, autonomic abnormalities (urinary dysfunction, hypohydrosis and constipation), disturbancessleep disturbances (restless (restless legs syndrome, legs syndrome, muscle cram muscleps and cramps insomnia) and insomnia) and cognitive and cognitivedisorders disorders(frontal- executive(frontal-executive dysfunctions dysfunctions as well verbal as well memory verbal deficits) memory [23]. deficits) [23]. TheThe identification identification of of biomarkers biomarkers is very importantimportant becausebecause they they allow allow the the selection selection of of patients patients for forclinical clinical trials, trials, improving improving clinical clinical diagnosis, diagnosis, staging staging of the of disease, the disease, evaluation evaluation of the geneticof the damage,genetic damage,providing providing the physiopathological the physiopathological clues and clues assessing and assessing efficacy ofefficacy clinical of trials. clinical They trials. can They be classified can be classifiedas neurophysiological, as neurophysiological, quantitative quantitative paraclinical, paraclinical, imaging and imaging biochemical and biomarkers.biochemical These biomarkers. objective Theseparameters objective can parameters provide quantitative can provide evidence quantitative to classify evidence SCA2 to into classify distinct SCA2 disease into stages distinct considering disease stagesthe presence considering of motor the presence and nonmotor of motor features. and nonmotor features. TheThe natural natural history history of of the the progression progression of of SCA2 SCA2 ca cann be be classified classified accordin accordingg to to the the phenotypical phenotypical featuresfeatures in in three three stages: stages: asymptomatic, asymptomatic, prodromal prodromal and and clinical clinical or ataxic or ataxic stages stages (Figure (Figure 5) [21].5)[ To21 ]. characterizeTo characterize these these phases, phases, two twoimportant important studies studies were were done: done: a cross-sectional a cross-sectional evaluation evaluation and and a longitudinala longitudinal follow-up follow-up study study in inSCA2 SCA2 preclinical preclinical subjects. subjects. In Inthe the asymptomatic asymptomatic stage, stage, no no disease disease symptomssymptoms or or signs nornor electrophysiologicalelectrophysiological abnormalities abnormalities and and imaging imaging signs signs are detectable.are detectable. This phaseThis phaseis followed is followed by the by prodromal the prodroma or preclinicall or preclinical stage, characterizedstage, characterized by unspecific by unspecific neurological neurological features featuressuch as such painful as musclepainful cramps, muscle sensorycramps, abnormalities, sensory abnormalities, subtle cerebellar subtle manifestationcerebellar manifestation (increase of (increasethe sway of during the sway tandem during gait), ta cognitivendem gait), decline, cognitive autonomic decline, disorders, autonomic olfactory disorders, dysfunction olfactory and dysfunctionhyperreflexia. and Electrophysiological hyperreflexia. Electrophysiological studies showed studies the reduction showed of the the reduction maximal saccadicof the maximal velocity, saccadicREM sleep velocity, disorders, REM increased sleep disorders, central motorincreased conduction central timemotor in transcranialconduction time magnetic in transcranial stimulation magneticand peripheral stimulation sensory and axonal peripheral damage sensory according axonal of the damage peripheral according nerve conduction of the peripheral studies [nerve3,24]. conduction studies [3,24].

Figure 5. Natural history of the progression of the SCA2 cerebellar ataxia. SARA: Scale for the Figure 5. Natural history of the progression of the SCA2 cerebellar ataxia. SARA: Scale for the Assessment and Rating of Ataxia. Assessment and Rating of Ataxia. The prodromal stage in spinocerebellar ataxia type 2 provides insight into the physiopathology of neurodegenerationThe prodromal stage before in spinocerebellar cerebellar syndrome ataxia type onset, 2 provides allowing insight the design into ofthe clinical physiopathology trials before ofataxia neurodegeneration onset—when neurodegeneration before cerebellar syndrome is still incipient—to onset, allowing slow down the design disease of progression. clinical trials This before stage ataxiaalso allowsonset—when identiﬁcation neurodegeneration of the best moment is still inci topient—to initiate therapies, slow down and disease identiﬁcation progression. of sensitive This stageoutcome also allows measures identification [24]. of the best moment to initiate therapies, and identification of sensitive outcome measures [24].

3. Conclusions Inflammatory processes have been established as major components in the pathophysiology of neurological diseases, including genetic and non-genetic disorders, which display behavioral impairment. Based on this knowledge, this meeting was focused toward the discussion of neuroimmune mechanisms and neuromodulatory therapeutic approaches related to brain diseases and tools for their modification. In conclusion, the meeting emphasized the main role of neuroinflammation in the pathophysiology of these disorders, as well as neuromodulation as an interventional tool to modify or control disease course and progression.

Author Contributions: All authors contributed equally to this paper. Funding: This study was supported, by the National Council for Scientific and Technological Development (CNPq, Brazil), Ministry of Education (MEC/CAPES, Brazil), State Foundation for Scientific Research of Rio Grande do Sul (FAPERGS) and National Institute of Science and Technology for Excitotoxicity and Neuroprotection (MCT/INCTEN).

Behav. Sci. 2019, 9, 99 7 of 8

3. Conclusions Inflammatory processes have been established as major components in the pathophysiology of neurological diseases, including genetic and non-genetic disorders, which display behavioral impairment. Based on this knowledge, this meeting was focused toward the discussion of neuroimmune mechanisms and neuromodulatory therapeutic approaches related to brain diseases and tools for their modification. In conclusion, the meeting emphasized the main role of neuroinflammation in the pathophysiology of these disorders, as well as neuromodulation as an interventional tool to modify or control disease course and progression.

Author Contributions: All authors contributed equally to this paper. Funding: This study was supported, by the National Council for Scientific and Technological Development (CNPq, Brazil), Ministry of Education (MEC/CAPES, Brazil), State Foundation for Scientific Research of Rio Grande do Sul (FAPERGS) and National Institute of Science and Technology for Excitotoxicity and Neuroprotection (MCT/INCTEN). Acknowledgments: The authors want to acknowledge speakers as the main contributors of this paper. Conflicts of Interest: The authors declare no conflict of interest.

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