Deep Brain Stimulation (DBS) has revolutionized the lives of patients of Parkinson disease, offering therapeutic options to those not benefiting entirely from medications alone. With its proven track record of outperforming the best medical management, the goal is to unlock the full potential of this therapy. Currently, the Globus Pallidus Interna (GPi) and Subthalamic Nucleus (STN) are both viable targets for DBS, and the choice of site should focus on the constellation of symptoms, both motor and nonmotor, which are key determinants to quality of life. Our article sheds light on the specific advantages and drawbacks of the two sites, highlighting the need for matching the inherent properties of a target with specific desired effects in patients. UT Southwestern Medical Center has a robust and constantly evolving DBS program and the narrative from our center provides invaluable insight into the practical realities of DBS. The ultimate decision in selecting a DBS target is complex, ideally made by a multidisciplinary team, tailored towards each patient's profile and their expectations, by drawing upon scientific evidence coupled with experience. Ongoing research is expanding our knowledge base, which should be dynamically incorporated into an institute's DBS paradigm to ensure that patients receive the optimal therapy. Therapeutic targets for ameliorating the disabling symptoms of Parkinson disease, namely, tremor, were discovered early in the 20th century by neurosurgical observations, leading to an era of ablative procedures targeting the basal ganglia, refined further by advancements such as stereotactic surgery. The advent of levodopa therapy in the 1960s resulted in a decline in surgical management; however, the eventual emergence of side effects and suboptimal control of medication related phenomena such as dyskinesias and motor fluctuations have renewed the interest in surgical interventions . This waThe Deep Brain Stimulation program at UT Southwestern Medical Center in Dallas began in 1998 following FDA approval of DBS , with steady growth in the number of procedures performed, up to 45 per year in 2016. The rapid evolution of the program mirrors the data available through various large studies, on the benefits of DBS versus medical therapy alone. Two landmark clinical trials , 11 demoMedical decision-making represents the art and science of weighing evidence based information with practice preferences, both comfort and experience, and target selection for DBS in Parkinson disease patients is no different. The availability of several studies and analyses on this topic, including some randomized controlled and blinded trials which allow a higher level of confidence in their results, provides objective and up-to-date information, which equips physicians to exercise greater scientific rigor into their decision-making process and importantly enables patients to consent with relevant prognostic data.The main targets for DBS in Parkinson disease are GPi  and STN , with the balance between the two tilting back and forth in light of new evidence. This decades-long duel has its origins in the pallidal preference for ablative procedures which was swiftly replaced by an overwhelming preference for STN when several prominent studies backed its superiority , 14. TheAt UTSW, the target for DBS surgeries for patients of Parkinson disease is selected during the neuromodulation committee meeting, a multidisciplinary board comprising neurologists , neurosurgeons, a dedicated DBS coordinator, speech language pathologists, physical therapists, and neuropsychologists. This process requires a comprehensive list of preselection tests, scales, and procedures in addition to motor scoring such as preoperative neuropsychological testing, brain MRI, physical therapy assessment, speech, and swallow assessment, to determine eligibility and site and maintain a baseline record of parameters to compare outcomes . In termA comparison of the two targets encompasses various parameters, such as therapeutic benefits, mechanisms of action, and adverse effects.The anatomical differences between the two sites, namely, their size and location, are the basis for some of the observed differences. The GPi is roughly 3 times the size of STN and thus requires a higher charge density. Studies show that the DBS stimulation settings in patients with pallidal stimulation are significantly higher in amplitude and pulse width as compared to STN stimulation (with no difference in frequency) which results in more frequent battery changes and higher opportunity for surgical complications , 22, 23.Motor control is the primary treatment goal of Parkinson disease management and both GPi and STN-DBS equally improve motor function , 25. TheAt UTSW, the DBS coordinator utilizes several scales to assess the motor performance both prior to the procedure and at follow-up visits. This includes parts 1–4 of the Unified Parkinson Disease Rating Scale, with part 3 performed on and off medications in the following combinations: stimulation off, medications off; stimulation on, medications off; and stimulation on, medications on. Specific tests are used for DBS performed for nonparkinsonian conditions such as essential tremor or dystonias.With respect to individual symptoms, resting tremor responds successfully to both GPi and STN-DBS , 26. It At UTSW, an interesting case report of a patient who did not experience optimal tremor control with bilateral STN-DBS was presented at the ANA  in 2015 and is possibly the first case of unilateral GPi lead rescue for tremor due to STN failure and stimulation related side effects . The patRigidity and Bradykinesia are motor symptoms that respond well to DBS at both targets. A study  showed greater improvement in rigidity with a unilateral STN-DBS lead versus GPi lead at a 7-month follow-up time point  but no sDyskinesia suppression is achieved at either target through fundamentally different mechanisms, direct stimulation effects of GPi-DBS and medication reduction in STN-DBS. This difference is responsible for the dyskinesia suppression in STN-DBS in the absence of active stimulation contrasted to GPi-DBS, which requires active stimulation for dyskinesia control at 3 months. However, dyskinesia control in GPi-DBS can be seen at 12 months even with stimulation off and can be attributed to long-term effects on dopaminergic pathways . While aWhile motor manifestations of Parkinson disease are often well managed medically and with DBS, there is a shift in the patient experiences towards other often disabling abnormalities of gait, posture, speech, cognition, mood, and autonomic disturbances, all of which are important determinants of quality of life.A decline in cognition significantly affects quality of life and is seen both in the natural progression of the disease and after DBS. The effects of DBS on cognition, mood, and behavior are extensively studied, with most studies revealing lower abnormalities after GPi-DBS as compared to STN-DBS, largely responsible for the “rematch,” a shifting away from the STN only approach.The issues concerning cognition and DBS are multifold. Cognitive risk factors in patients do not serve as blanket exclusion criteria for surgery; rather they influence patient counseling for postoperative expectation setting and possibly target selection. Patients with preexisting dementias are usually disqualified from DBS surgery due to risk of worsened cognitive outcomes , 34. HowAt the 24-month follow-up of the Veterans Affairs Cooperative Studies Program, to compare bilateral DBS at both targets, results showed a slight decrease in neurocognitive function in both groups with a significantly greater decline in processing speed in the STN group, especially in the visuospatial domain . At 36 mA randomized trial using bilateral STN stimulation with a constant current device had an interesting and seminal finding that the decline in verbal fluency noticed after STN-DBS occurred in both the activated (stimulation turned on) and inactive leads (implanted but never activated) allowing one to infer that these effects are likely due to surgery itself and possibly the surgical trajectory rather than specifically STN-DBS .Relying solely on cognitive screens is not always adequately sensitive to detect the often subtle postoperative cognitive changes, which require an in-depth neuropsychological assessment consisting of a wide array of tests spanning all domains . UTSW haHowever, despite preoperative cognitive screening, several patients go on to develop cognitive dysfunction including dementia, often within 6 months of surgery , 39, 40.A 67-year-old male patient living with Parkinson disease for 7 years with normal preoperative cognition underwent bilateral STN-DBS. Apart from mild global atrophy, minor word-finding difficulties, and slowed thinking, he could independently manage his finances and medications. After an uneventful surgery, he experienced relief of motor symptoms and had his medications reduced; however, cognitive changes were noticed by his family within a matter of days. He experienced prominent memory and executive function declines, including impulsiveness, disinhibition, poor judgment, and inappropriate behavior. His REM behavior disorder symptoms worsened and he was frequently angry. Neuropsychological testing after 2 months revealed frontal lobe dysfunction with significantly reduced problem solving, attention, memory, and phonemic fluency, compared to preoperative levels, unchanged by increasing his levodopa dose. Similar testing 14 months after surgery revealed global cerebral dysfunction, with major involvement of the frontal lobes, consistent with dementia. He was evaluated for undetermined spells for which EEG did not reveal abnormalities and was subsequently treated for orthostatic hypotension. The second patient was a 57-year-old man with Parkinson disease for 9 years, who underwent bilateral STN-DBS. He was preoperatively found to have mild global atrophy, past history of medication induced hallucinations, practically minor problems with memory, and mild frontal-subcortical cognitive deficits on testing, which were stable over a year. He experienced confusion after an uneventful surgery, which worsened after the battery placement. Despite motor benefits, he became inattentive and disoriented, with worsening anxiety. Neuropsychological testing 3 months after surgery revealed global decline, with prominent frontal-subcortical involvement, consistent with mild to moderate dementia. In both cases, a medical work-up was unrevealing and MRIs taken 1 month postoperatively did not show any signs of infection, hemorrhage, or infarct. A study of the lead trajectory revealed they all passed through the frontal lobe, lateral ventricle, and posterior-medial border of the STN, with the lead in Patient 1 travelling further caudal towards the midbrain-pontine junction after a year. The lead positions in the first patient were noted to be posterior-medial in the STN, rather than in the dorsal STN for optimal motor benefit, and at a much greater than intended depth. Turning the stimulation off for a few weeks did not halt the cognitive decline in the patients, which the authors suggest to be attributed to the lead positions, its trajectories, and the surgery itself hastening the process . This hiSeveral patients experience stimulation related changes in mood and behavior such as depression, hallucinations, impulse control disorder, apathy, and dopamine dysregulation syndrome. These adverse effects may be related to preexisting psychiatric illnesses, stress, medication reductions, surgery-related factors, changes in social situations following surgery, and mismatched patients' expectations versus outcomes . While tA trial to compare the effects of unilateral DBS at the STN and GPi, specifically on mood and cognition , gathered data on the impact of DBS using Visual Analogue Mood Scales (VAMS) with several subscales. Seven months after surgery, there were an overall reduction of tiredness in both groups and improved scores in “feeling happy” and “less tense”; however, feelings of anger, confusion, and irritability increased. There was no significant difference between the two sites in these subscales of mood, except for an increased anger in the STN group . Based oThe Beck Depression Inventory II, used as a measurement tool, showed an improvement in the GPi group contrasted to a decline in the STN group , with siChanges such as delirium, hallucinations, anxiety, hypomania, and apathetic mood have been noted in the perioperative period, in patients who underwent STN-DBS with no similar changes noted in patients who underwent GPi stimulation . While pThere is a wide range of effects of DBS on impulse control disorders (ICD), ranging from complete resolution of preexisting disorders partial resolution and generation of new ICDs after DBS. A study following a group of patients with bilateral STN stimulation patterned the above, with 23% of the cohort having preexisting ICDs, of which 84% of them benefited from their resolution after DBS, and the rest had an appearance of new eating disorder symptoms. There is a strong association between dopaminergic medication dose and ICD occurrence, strengthened by the observation that reducing medications after STN-DBS correspondingly reduces the incidence of ICDs; however, this cannot explain the occurrence of new ICDs in patients with already reduced doses of medication following DBS. Of the cohort that did not have preexisting ICDs, 14% developed them transiently, a year after surgery, lasting for about 15 months, all of which disappeared at the 3-year follow-up. Compulsive eating disorders were the most frequently seen behavior after STN-DBS and could account for the weight gain seen after STN-DBS , 45. TheA large concern with the neuropsychological changes seen after DBS is the increased possibility of suicide following STN-DBS. While suicide (attempts and completed) have been observed , a largeA study analyzing the subjective or patient-perceived benefits following STN-DBS revealed negative outcomes in spite of almost universal motor benefits in patients who underwent bilateral STN-DBS. Older age and longer duration of disease were not associated with perceived negatives outcomes; rather, the main predictors were axial symptoms and apathy . This stPossible explanations for the greater deterioration of cognitive and psychological parameters in STN-DBS patients include the effects of anatomical size and medication reduction. Leads placed in the STN may spread the current into the associative and limbic regions of the nucleus as well as areas such as lateral hypothalamus, zona incerta, and medial forebrain bundle, all of which have extensive limbic connections. The role of dopaminergic medications which are dramatically reduced in STN-DBS patients but relatively maintained in GPi patients may play a part in the latter's cognitive advantage. This framework can be applied to understand impulse control disorders as an imbalance between excess of dopamine with stimulation of limbic circuits leading to their hyperactivity . This neAt UTSW, mood and behavior are evaluated with cognition prior to the procedure and at follow-up visits, as explained above. The battery of tests includes the Beck Depression Inventory II, the Questionnaire for Impulsive-Compulsive Control Disorders in Parkinson disease-Rating Scale (QUIP-RS), and the Quick Inventory of Depressive Symptoms (QUIDS). Mood and behavior changes are also captured in the quality of life data which is reviewed at follow-up meetings, albeit there is lack of formalized testing in these domains in the absence of patient complaints or adverse events. Armed with this knowledge, it is imperative that patients' caregivers play an active and ever-vigilant role in the assessment for subtle changes in the patient's mood, behavior, and affect, after the DBS procedure. At UTSW, we have incorporated realistic expectation setting in our preoperative consent forms  clearly The aim of all therapy is to ultimately improve quality of life for patients; this especially holds true for interventions such as DBS which are invasive and expensive and potentially have serious adverse effects. While controlling the motor symptoms of Parkinson disease is the primary goal of medical and surgical therapy, nonmotor symptoms such as mood, cognition, sleep, autonomic dysfunction, speech, and swallowing deficits form a large part of the disease burden and are important determinants of quality of life. These symptoms are more often than not resistant to medical and DBS therapy and often negatively impact patients' perception of therapy, despite the control of the cardinal motor symptoms.Parkinson Disease Questionnaire, PDQ-39, is almost universally used as a measure of quality of life across 8 domains or subscales: mobility, activities of daily living, emotional well-being, social support, stigma, cognition, communication, and bodily discomfort.A trial comparing bilateral DBS at the 2 sites (NSTAPS) did not find a significant difference in the quality of life measured through the Parkinson disease quality of life questionnaire-PDQL, not only at the 12-month follow-up but also at the 36-month follow-up , 23. TheNursing home placement is another component, intimately linked to ability to carry out activities of daily living and quality of life. A study which followed the long-term performance of STN-DBS across a span of 10 years found 42% of their patients were admitted into a nursing home, and this had a correlation with higher age at the time of surgery . ParkinsRecently, studies have reviewed the PDQ-39 as the standard questionnaire used to assess quality of life across the various disease specific domains. Despite almost universal usage including our institution, it has its drawbacks. It does not capture various side effects seen with STN-DSB, such as apathy, speech difficulties, and impulsive behaviors and underreports axial symptoms. The PDQ-39 was designed prior to this data being available and cannot comprehensively outline the extent or magnitude of benefit or impairment experienced by the patients. Since apathy plays a major role in the patients' perceptions of benefit, the quality of life scale ought to include apathy in its computation . It is eAt UTSW, the PDQ-39 is measured by the DBS coordinator both prior to surgery and during follow-up visits. We have not incorporated this new scale in our practice at UTSW and will probably wait for a refined version which addresses some of the drawbacks. These limitations include being designed exclusively with STN-DBS patients, possible missing other target specific symptoms, as well as being constructed with patient and care-giver experiences over a period of 1 year after surgery, which may not accurately represent or capture the long-term experiences with the DBS procedure . It is iImprovements in gait and balance mirror the effects of levodopa in the “on” period, which is increased by DBS. However, this gain is often lost due to progression of the disease, possibly hastened by surgery  and lesiAxial functions such as speech and swallowing are complex functions and have a direct relation to mortality (by aspiration) and need to be addressed for optimal quality of life. A review of the effects of DBS on swallowing highlights the fact that while most studies suggest an impairment of swallowing with STN-DBS, there was no clinically significant impairment or improvement measured, and studies notably did not compare STN to GPi or unilateral versus bilateral stimulation . STN-DBSPatients with Parkinson disease often suffer from autonomic symptoms; their response to DBS remains variable and understudied and mainly in STN targets. While STN-DBS was thought to impact blood pressure and heart rate, studies have not demonstrated statistical changes. The positive effect of STN-DBS on constipation is noted but this is likely to be related to increased patient mobility. A direct effect of STN-DBS on bladder dysfunction has been theorized but is not clear .STN-DBS has demonstrated an improvement in the quality of sleep for patients, with an increase in total sleep time, time spent in REM, and slow wave sleep as measured by polysomnography and the PDSS: Parkinson disease subjective sleep scale. The improvement in scores was noticed when stimulation was off and can be attributed in part to the surgical lesioning of the STN nucleus itself. These effects were related to the extent of motor gains and the reduction of day time sleepiness due to reduced medications, thus improving night time sleep quality. The few studies tracking this data have not shown a difference between the two sites in sleep benefits . SimilarPatients of Parkinson disease experience different types of pain: musculoskeletal, dystonic, central, radicular, and somatic, exacerbated during the off period. The relief afforded by DBS to motor symptoms such as rigidity and dystonias is largely responsible for ameliorating the first 2 categories and possibly acting on central pain as well. A paradoxical effect of body discomfort is observed infrequently in patients particularly of STN-DBS as the reduced blood levels of levodopa result in a decreased pain threshold . At UTSWIt is worthwhile to investigate whether the improvement in quality of life and motor function in patients with Parkinson disease has an overall impact on mortality: is there a change in the natural progression of the disease with DBS?Patients with Parkinson's disease have a higher mortality than the general population, with an odds ratio of 2.56 and a 5-fold higher chance of being placed in a care facility. So far, while drug therapies in some studies have shown a positive influence on the disease when started early on, they have not yet shown any change in mortality or the ability to prevent the onset of dementia or falls . On the A survival gain with DBS is usually not discussed with patients while considering them for DBS, information which should be incorporated into decision-making. At UTSW, while there is no fixed age cut-off for surgery, it is a factor discussed while weighing the risk to benefits of DBS in a particular patient. We have not formally tracked mortality data on patients who have undergone DBS at our center. So far two patients with DBS ) have passed away, but circumstances around their death involved multiple compounding factors and cannot be solely attributed to DBS. It is important for our quality improvement endeavors to have this data to allow outcomes tracking, and steps to ensure completeness of our database will be put in place soon.Armed with the data showing that increased age at surgery is a risk factor for suboptimal outcomes and evidence that opting for DBS at an earlier stage of the disease rather than after exhausting all options is associated with superior motor and quality of life outcomes , a trendThere is a unanimous finding that medication  or LEDD ) is markedly reduced after STN-DBS as compared to a slight reduction after GPi-DBS. Studies have shown varying reductions such as 38% for STN-DSB versus 3% for GPi-DBS  or absolThe assumption that the reduction in medications is a pure positive effect must be examined, with evidence highlighting the complex interplay between symptoms, side effects, target stimulation, and medications. The possible increased suicidal ideation observed after STN-DBS has been linked to a reduction in dopaminergic medication . ObservaAsymmetrical symptoms are a hallmark of Parkinson disease, and although uncommon, patients with predominantly unilateral symptoms have the option to undergo a single lead placement. A trial to compare the effects of unilateral DBS at the GPi and STN on mood and cognition (COMPARE) found no significant difference in motor and cognitive outcomes between the 2 sites, with differences in verbal fluency noted in STN-DBS when not in optimal settings . A folloThrough a systematic process of testing each electrode, threshold settings are determined which elicit clinical benefit and adverse effects which are used in future programming. The stimulation settings are determined by varying voltage and pulse width along with contact points and occasionally frequency, all of which require a high level of skill to optimize thousands of combinations to attain symptom relief, with minimal DBS side effects. Programming offers the ability to manipulate advanced stimulation settings to achieve best possible outcomes even in cases with suboptimal lead placement. DBS programming and medication titration are delicately intertwined and require close monitoring until the patient experiences a stable and optimal state, a process that usually takes around 6 months. Following an optimization of settings, it is usually safe to expect that other Parkinson disease related effects cannot be managed by tweaking the DBS settings. It is also possible to anticipate DBS failures, early in the course of programming, in the case of low thresholds for adverse effects or unsustained benefits associated with a lead .Most studies and DBS programs track adverse events often with additional classification into mild, moderate, or severe to assist in analysis and comparative studies. The source of these events can be related to surgery, the device, stimulation, and medications or due to the progression of the disease itself and are not often distinguishable. It is observed that patients treated by medication alone have a higher frequency of adverse events overall; however, the patients with DBS experience a higher frequency of serious adverse events .Surgical complications include infection (4%), intracranial hemorrhage , device related problems such as migration of leads (2.4%) and lead fracture (3%), and seizures (3.2%) and are considered major or serious events . While tCertain side effects such as dysarthria were notably seen in the first 12 months after surgery, implying a relationship with DBS rather than progression of the disease. Other such symptoms linked to the DBS include dysphagia, excessive salivation, blepharospasms, and weight gain . A randoAs part of the quality improvement initiative at UTSW, adverse events and complications, either minor or transient, are recorded to allow for an analysis of trends if any and devise improvements by the neuromodulation network meeting. This analysis is possibly the next quality improvement study (cycles of plan-do-study-act) which will be undertaken at UTSW by the movement disorders section in an effort to continually optimize our outcomes. There were a total of 9 surgical or device related complications in 28 patients studied, occurring in DBS performed at the STN as well as the VIM  nucleus of the thalamus over the last 2 years .Suboptimal results from the DBS procedure are often labeled as DBS failures. Factors common to these “failures” include inadequate presurgical screening, improper patient selection, incorrectly placed leads, suboptimal programming, battery failure, and hardware related issues . PatientA randomized trial comparing DBS at the 2 sites (NSTAPS) had 8 patients of GPi-DBS  who had to undergo STN-DBS resurgery due to lack of benefits. Of these 8 patients, 5 had leads placed correctly. Similarly, 1 patient of STN-DBS  had a unilateral GPi lead implanted, and one was reoperated to correctly position the leads . A waninSince DBS is an expensive and long-term undertaking, it is important to discuss the cost-effectiveness of the procedure and accurately identify patients who will benefit from it given the risks and benefits. A study using the University HealthSystem Consortium (UHC) Clinical database found the average DBS procedure cost to be $39,152  ±  $5340 , with thA study of the cost-effectiveness of DBS with medical therapy as compared to the best medical therapy (BMT) using various analytical models from the Medicare payer perspective, considering a 10-year horizon, found total costs of DBS to be $130,510 versus $91,026 for BMT, with a gain of 1.69 QALYs more than BMT, and a total of $23,404 per QALY, with greater benefit seen in younger age and longer follow-up . A similWe at UTSW have not undertaken a cost-benefit analysis, as costs depend on and vary with differing patients' insurances which skew the relevant data; however, it is a topic that will be researched to understand the financial implication of DBS, for both the patient and the institute.While DBS is widely used in the management of Parkinson disease, there are several questions that remain open, and the quest to solve them will hopefully strengthen the success of DBS in improving the quality of life in patients.Questions regarding unilateral versus simultaneous bilateral lead implantation and the utility of the staged operations require further studies to determine benefit one way or another. The safety of unilateral implantation with concomitant decreased operative adverse effects especially in the elderly has to be weighed against the possibility of a second procedure for inadequate benefit and is usually considered in patients with extreme asymmetry of symptoms.Issues faced by patients such as gait-freezing and other axial symptoms not addressed by DBS require studies to provide potential solutions. Research into stimulating multiple leads at different locations to address specific DBS and Parkinson's related symptoms is underway.With increasing evidence for DBS at an earlier stage in the disease for superior outcomes , there iCases of DBS failures corrected by dual stimulation of alternate targets, the “rescue leads” as discussed above –30, poinWhile a majority of studies have an end point of 24 or 36 months, there are scarce long-term studies that have tracked patient outcomes over a span of 10 years [DBS has become standard of care for treating patients living with Parkinson disease as well as a wide range of other movement disorders. The aim of research in the field is to have a clear understanding of the mechanisms of action of DBS and the physiological and anatomical basis of various side effects seen, so as to design a DBS process which will allow patients to achieve maximum control of all their symptoms  with minimal side effects to enhance the quality of life. Research in this field has resulted in several potentially and therapeutically beneficial outcomes such as expanded scope, new targets, enhanced surgical techniques allowing precise target localization and trajectory such as frameless, and nonmicroelectrode recording techniques, advances in imaging such as functional and microstructural imaging, refined hardware design such as constant current devices, optimized programming sequences, and other cutting-edge techniques.Continued research to elucidate the mechanisms of action of DBS at different targets and charting the anatomical zones and fiber bundles to explain corresponding side effects observed are important aspects of DBS research to understand and avoid the neuropsychiatric effects that accompany this procedure. Refining technical aspects such as contact selection may provide a solution to avoid these unintended effects . AdvanceResearch into new targets is underway and can potentially address the gaps in therapy with DBS at the STN and GPi. Studies on the pedunculopontine nucleus (PPN), chosen for its anatomic connections with the basal ganglia and its functional role in motor modulation and locomotion, demonstrate improvements in gait and balance including gait-freezing, the results of which are variable and need to be confirmed through rigorous trials. The PPN poses surgical access complications and has zones with varying functions; hence, studies need to address technique as well as costimulation of other targets . AttemptStudies incorporating stimulation of novel targets in addition to the standard STN or GPi provide a theoretical means of addressing adverse effects or levodopa unresponsive symptoms. Experiments on the reward circuitry could address issues such as apathy, depression, and possibly other ICDs . ThroughDeep Brain Stimulation has revolutionized the lives of patients living with Parkinson disease. The very decision to undergo the procedure and the choice of the target site are in essence a series of risk-benefit analyses. This entails balancing the probability of improved quality of life, relief of tremor, rigidity and other motor symptoms, reduced medications and their side effects with the possibility of potentially fatal or disabling surgical complications and other procedure related adverse effects, such as worsened cognition or other negative psychiatric outcomes, and changing the extent of impact of declined verbal fluency. Computing the best outcomes in these complex scenarios should be done on a case by case basis, using each patient's symptom, disease, medical, risk, and demographic profile along with patient expectations to reach the optimal management plan. This tailored approach to selecting the target site for patients undergoing DBS is the result of years of data from various studies, trials, and case reports, which allows a DBS team, including the neuromodulation network at UTSW to anticipate potential adverse outcomes and plan ahead to circumvent them, for the best possible results. If a patient has a history of hallucinations or has diminished cognitive reserve, GPi-DBS may provide motor benefit without the possibility of cognitive decline, if patients suffer significant medication related dyskinesias; STN-DBS can offer relief. In a similar vein, studies have also helped in planning the lead location and trajectory, with leads in the ventral zone of the STN, associated with a greater incidence of adverse effects. This planning and refining of patient and target selection, surgical trajectory and lead localization by imaging or microelectrode recording, DBS programming, and other hardware parameters have resulted in optimizing patient outcomes and unlocking the full potential that DBS has to offer. Research endeavors aim to continually enhance the DBS process by addressing the unmet needs and unanswered questions, through expansion of our knowledge based on the process mechanisms itself, technological improvements, trials to test or observe the safety and efficacy of various therapeutic options in DBS, and other novel ideas.An indicator of the commitment of a DBS program towards its patients is the standard it holds itself up to and the accountability it has towards all its stakeholders. At UTSW, the quality improvement effort spearheaded by the movement disorders group in the department of neurology fulfills these obligations by subjecting various aspects of the program to a rigorous examination, cycles of plan-do-study-act, with the intention of ensuring these high standards. This endeavor has resulted in the design of the current processes, namely, the neuromodulation network and the formal structure in place for preoperative assessment and follow-up. An important element of this program is capturing data to allow tracking of outcomes and feedback . The ult


To provide a narrative review of the most recent data concerning the involvement of the microbiome in the pathogenesis of connective tissue diseases (CTDs) and vasculitides.  The PubMed database was searched for articles using combinations of words or terms that included systemic lupus erythematosus, systemic sclerosis, autoimmune myositis, Sjögren's syndrome, undifferentiated and mixed CTD, vasculitis, microbiota, microbiome, and dysbiosis. Papers from the reference lists of the articles and book chapters were reviewed, and relevant publications were identified. Abstracts and articles written in languages other than English were excluded.  We found some evidence that dysbiosis participates in the pathogenesis of systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, and Behçet's disease, but there are still few data concerning the role of dysbiosis in other CTDs or vasculitides.  Numerous studies suggest that alterations in human microbiota may be involved in the pathogenesis of inflammatory arthritides as a result of the aberrant activation of the innate and adaptive immune responses. Only a few studies have explored the involvement of dysbiosis in other CTDs or vasculitides, and further research is needed. The human microbiota harboured by each person consists of 10–100 trillion symbiotic microbial cells, mainly bacteria in the gut, but also viruses, yeasts, protozoa, and even helminths. The sum of human microbes and their genes existing within and on the human body (collectively known as the microbiome) has been found to be a principal factor in human health and disease [Porphyromonas gingivalis in the development of rheumatoid arthritis (RA) [The concept that human microbiota may modulate systemic autoimmunity is not new, but the underlying mechanisms of autoimmune regulation by the microbiome are just beginning to emerge . Studiestis (RA) . A recentis (RA) , but, alConnective tissue diseases (CTDs) encompass a wide group of immune-mediated diseases, characterized by the inflammation of the connective tissues of the body sustained by the activation of the immune system against self-epitopes expressed on cells and matrix. Vasculitides share similar pathogenetic mechanisms and are characterized by an immune-mediated response against components of the vascular tree. Genetic predisposition is necessary but not sufficient to give raise to these diseases, and an environmental trigger, including infections or changes in microbiome composition, is thought to be required for the onset. Given the spread of connective tissues all over the body, clinical manifestations of CTDs are polyhedral and may involve skin, joints, and visceral organs. Similarly, vasculitides have a wide range of clinical manifestations, according to the vascular district involved by the inflammatory process.Like in inflammatory arthritides, it is presumable that, in genetic predisposed individuals, dysbiosis activates several immune pathways favouring in turn the development of CTDs or vasculitides.As there are currently only limited animal and human data available concerning the potential link between the microbiome and systemic autoimmune diseases other than SpA and RA, the aim of this narrative review is to provide an updated view of the involvement of microbiome in the pathogenesis of CTDs and vasculitides.The PubMed database was searched for articles using combinations of words or terms that included connective tissue diseases , microbiota, microbiome, and dysbiosis. Papers from the reference lists of the articles and book chapters were reviewed, and relevant publications were identified. Abstracts and articles written in languages other than English were excluded.We selected 55 articles concerning the role of the microbiome in CTDs and vasculitides; the findings are described below, divided by the type of rheumatic disease.Epstein-Barr virus, cytomegalovirus, retroviruses, and human parvovirus B19), and there is some concern about the possible role of unbalanced microbial microbiota and the prevalence of some pathogens in the gut and mucosa of SLE patients [Systemic lupus erythematosus (SLE), the most emblematic CTD, mainly affects women of childbearing age. As in the case of other autoimmune diseases, it has been hypothesized that an infectious stimulus triggers the onset of SLE by inducing chronic immune system activation . No specpatients .α and IFN-β, is required to modulate the immune response leading to cell apoptosis and pathogen clearance. In SLE, type I interferons are typically overexpressed and associated to disease activity and can induce the hyperactivation of myeloid dendritic cells activating in turn autoreactive T lymphocytes that play a role in SLE pathogenesis [Up to 50–80% of SLE patients can suffer from skin and mucosal manifestations, in which changes in mucocutaneous commensal flora composition can lead to the proliferation of pathogen species driving chronic inflammation . The innogenesis .Staphylococcus aureus colonising the nasal mucosa and, although the rate of occurrence was similar to that observed in healthy controls, this may be associated with a distinct SLE phenotype characterized by renal and skin involvement and a higher likelihood of anti-dsDNA, anti-Sm, anti-SSA, anti-SSB, and anti-RNP antibody positivity [Staphylococci, although it may contribute at the same time to the virulence of some strains of these microorganisms, like strain 502A [Staphylococcus aureus colonising nasal mucosa of SLE patients, which may account for different burdens of cytokine production and different pathogenetic pathways, but only described the association between bacteria and clinical and laboratory alterations.In a study of 84 SLE patients, Conti et al. detected sitivity . The actain 502A . HoweverFretibacterium, Prevotella nigrescens, and Selenomonas spp. was higher in patients than in controls and was related to the local release of interleukin- (IL-) 6, IL-17, and IL-33 [Porphyromonas gingivalis in experimental animal models. According to Maekawa et al., neutralising C3 by adding the compstatin analogue Cp40 may prevent local inflammation and the subsequent release of IL-17 or receptor activator of nuclear factor kappa-B ligand (RANKL), perhaps by restoring dysbiosis [Periodontal inflammation has also been associated with SLE. In a study of 52 SLE patients and 52 controls, Corrêa et al. found that the risk of periodontitis sustained by nd IL-33 . The hypysbiosis . Immune ysbiosis . AlthougA number of SLE studies have investigated the composition of gut bacteria in animal models and humans and have been recently addressed in a review by Neuman and Koren . In rareBifidobacterium and Erysiopelotrichaceae, with no significant difference in Lactobacillaceae, although the levels of the latter family (and Firmicutes phylum) were significantly lower in the MRL/lpr mice than in controls and were restored after treatment with oral retinoic acid [Rhodococcus, Eggerthella, Klebsiella, Prevotella, Eubacterium, Flavonifractor, and Incertae sedis) that were significantly increased in comparison with controls [in vitro study of 37 SLE patients and 36 controls: they showed that an imbalance of Firmicutes and Bacteroidetes in fecal samples was associated with Th17 responses whereas enrichment with Bifidobacterium bifidum LMG13195 or a mixture of two clostridium strains, Ruminococcus obeum DSM25238 and Blautia coccoides DSM935, restored the number of T regulatory cells, thus providing a rationale for the use of probiotic therapy [Zhang et al. found a gender-dependent alteration in the composition of gut microbiota in stool and colon samples taken from lupus-prone MRL/Mp-Faslpr (MRL/lpr) mice: female mice had higher levels of Lachnospiraceae and Bacteroidetes S24-7 and lower levels of oic acid . Hevia eoic acid  and founcontrols . Accordicontrols . Lopez e therapy . In anotBlautia, Lactobacillus, and Bifidobacterium in a cohort of 20 SLE female patients [1 mice, the administration of acidic water restrained the course of glomerulonephritis and the production of cytokines and autoantibodies, inducing meantime a restore in the gut microbial flora (higher Lactobacillus reuteri and Turicibacter spp. colonisation in acidic water-drinking mice) [Lactobacilli GMNL-32, GMNL-89, and GMNL-263 on the course of SLE hepatitis in lupus-prone mice [Some experiments in animal models have shown that caloric restriction, as well as the assumption of polyunsaturated fatty acids, vitamins A, D, and E, and phytoestrogens may ameliorate SLE disease activity . Dietarypatients . In anotng mice) . Similarone mice .To summarise, there are emerging evidences that dysbiosis represents one rawplug inside the complex pathogenesis of SLE; however, given the modest knowledge on the beneficial effects of probiotics and prebiotics and the lack of RCTs, no clear therapeutic strategies can be currently drawn. Additionally, the use of immunomodulators and immunosuppressive drugs may alter the composition of commensal flora, selecting pathogens able to chronically stimulate the immune system.Systemic sclerosis (SSc) is a connective tissue disease that may affect the entire gastrointestinal (GI) tract in up to 90% patients , who oftSeveral studies have demonstrated that vascular damage occurs throughout the intestinal tract and that mucosal abnormalities  may be present in more than 50% of SSc patients and are usually associated with a more pronounced vasculopathic phenotype  . TogetheOnly a few published studies have so far investigated the role of dysbiosis in SSc.Faecalibacterium prausnitzii and/or Clostridiaceae) and that this was significantly associated with esophageal dysmotility, micronutrient deficiency, skin telangiectasias, pitting scars, pulmonary fibrosis, and high serum levels of inflammation markers. Volkmann et al. examined by means of Illumina HiSeq 2000 16S sequencing of cecum and sigmoid mucosal lavage samples taken from 17 SSc patients and a healthy control group and found decreased levels of commensal bacteria such as Faecalibacterium and Clostridium and increased levels of pathogenic bacteria such as Fusobacterium and g-Proteobacteria in the patients, who also had increased levels of Bifidobacterium and Lactobacillus and a reduced Bacteroides fragilis/Fusobacterium ratio, especially in the case of the most severe GI symptoms [Andréasson et al. used a genome-based microbiota test of stool samples to study the gut flora composition of 98 SSc patients  and founsymptoms .μg/g) in 93 of their 125 SSc patients and found that fecal calprotectin concentration significantly correlated with intestinal motor dysfunction and small intestinal bacterial overgrowth as assessed by means of glucose H2/CH4 breath testing [Measurement of fecal calprotectin is a noninvasive tool for monitoring bowel inflammation and may also give indirect information on the innate immune cells' activation following a microbial insult. The molecule, formed by the dimerization of the proteins S100A8 and S100A9 and mainly expressed in the cytosol of polymorphonuclear cells, prevents the infections sustained by virulent strains of bacteria or fungi, but its concentration is also arisen in autoimmune inflammatory bowel diseases (IBDs). Marie et al. detected increased levels of fecal calprotectin  [Rhodotorula glutinis sequences in the patient samples, but no significant differences in bacterial or viral characterisation [Rhodotorula can cause SSc skin fibrosis as it may activate the innate immune system and induce lung granulomatous diseases and peritoneal fibrosis, but there is a lack of studies characterising the mycobiome of unaffected skin sites and those affected by disease.Many microbial products have been postulated as inducing the activation of lung and skin macrophages and dendritic cells through TLRs. Fungi are commensal components of the microbiome of the skin and lung, and the lung mycobiome of healthy subjects is mainly represented by disease) . Howeverrisation . It can In brief, similarly to SLE, there is some evidence that SSc patients may also suffer from a multidistrict imbalance of commensal and pathogenic microorganisms and antibiotic or probiotic treatments may have some beneficial effects , 43. HowSjögren's syndrome (SS) is a chronic inflammatory autoimmune disease involving the exocrine glands  that has extraglandular systemic repercussions in 71% of cases . GlandulHowever, in a study from Lugonja et al., the authors did not find any increase in the prevalence of periodontitis in 39 SS patients in comparison with 36 RA and 23 osteoarthritis controls on the basis of a search for specific serum antibodies against ten oral/periodontal bacteria .Bifidobacterium species may influence the response of the immune system to microbial stimulation by modulating the production of salivary secretory IgA and that Bacteroides fragilis colonisation is associated with a less intense production of cytokines and chemokines by immune cells following stimulation with lipopolysaccharide (LPS) [Enterobacter, Escherichia/Shigella, and Pseudomonas) and that histological changes in their mucosae  were more pronounced after 10 days of exposure to antibiotics [Streptococcus and a decrease in Leptotrichia and Fusobacterium levels in the SS tongue samples. The fecal microbiota of the SS patients contained a higher proportion of Pseudobutyrivibrio, Escherichia/Shigella, Blautia, and Streptococcus and fewer Bacteroides, Parabacteroides, Faecalibacterium, and Prevotella. Interestingly, the severity of ocular (but not systemic) symptoms assessed using the unweighted 12-domain European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI) was significantly related to gut flora diversity.It has been hypothesized that dysbiosis may condition the activation of the immune system and influence the severity of SS. For example, it has been demonstrated that postnatal gut colonisation by different de (LPS) . de Paivibiotics . HoweverCapnocytphaga ochracea was a potent activator of T cells. C. ochracea is a gram-negative, anaerobic bacterium that is usually isolated in gingival sites and dental plaques, and so the disrupted mucosal barrier in the oral cavity or gut of SS patients may underlie the proliferation of pathogens capable of chronically activating the immune system, possibly by means of a mechanism of molecular mimicry.Szymula et al. investigated whether the production of autoantibodies against RoSSA, which represent a distinctive trait and classification criterion for SS , may be In conclusion, the altered functioning of the mucosal and cutaneous barrier observed in SS may favour the colonisation of microbial pathogen species, which may further activate the immune response by molecular mimicry or by a direct interaction with TLRs on local dendritic cells. However, given the paucity of scientific evidence, the exact role of the microbiome in SS is still unclear.No data are currently available concerning the microbial composition or pathogenic role of the microbiome in autoimmune myositides. Idiopathic autoimmune myopathies include dermatomyositis, polymyositis, necrotising autoimmune myositis, and sporadic inclusion-body myositis. Each form affects skeletal muscle and may overlap with other CTDs, but inflammatory myopathies differ in terms of their clinical aspects, histological findings, and myositis-specific antibodies .α), IL-6, and chemokines that may contribute to decreasing protein synthesis, oxidative stress, and insulin-resistance in skeletal muscle tissue. However, despite this favourable pathogenic pathway and some evidence indicating the potential development of inflammatory myopathies after infections or vaccinations [There is very little evidence supporting a pathogenic role of dysbiosis in the onset of inflammatory myopathies. A review by Bleau et al. discussed the effect of a high-fat diet on intestinal microbial composition and its further repercussions on adipose tissue and skeletal muscles . A high inations , no studThere are no available data concerning the role of the microbiome in undifferentiated CTDs (UCTDs), mixed CDT (MCTD), relapsing polychondritis, or other overlap syndromes.Chlamydia pneumoniae, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Staphylococcus, and Stenotrophomonas spp., has recently been described in a number of vascular diseases, including atherosclerosis and aneurysms [The vasculitides are a wide spectrum of diseases characterized by chronic inflammation of small, medium-sized, and large vessels. Healthy vessels may harbour their own commensal microbiome, but colonisation of the vascular tree by pathogenic microbial agents, including neurysms . AlthougPropionibacterium acnes, Escherichia coli, and Moraxella catarrhalis in both GCA and healthy samples mainly reflected external contamination [Giant cell arteritis (GCA) is a systemic granulomatous vasculitis affecting large vessels that mainly occurs in the elderly and has a typical cyclic pattern every 5–7 years. It has been postulated that an infectious stimulus may underlie its onset, but the etiological agent is still unknown. In a DNA sequencing study of the temporal artery biopsies of 17 GCA patients and five controls, Bhatt et al. did not find any distinctive microbiome signature in the patients and the isolation of mination .S. pneumonia, pseudopneumoniae, oralis, gordonii, and sanguinis) and, in some cases, the genera Rothia and Staphylococcus were the most abundantly represented microorganisms in the intestinal tract of KD patients, and their prevalence increased during the phases of disease reactivation. On the contrary, the presence Ruminococcus, Blautia, Faecalibacterium, and Roseburia bacteria increased during disease remission.Kinumaki et al. made a longitudinal metagenomic analysis to assess intestinal microbial variations in a cohort of 28 patients with Kawasaki disease (KD) , a form Escherichia coli or Citrobacter rodentium) may locally expand Th17 lymphocytes, which could then migrate to the kidney through a chemokine pathway involving C-C motif chemokine ligand 20 (CCL20) and C-C motif chemokine receptor 6 (CCR6) [There are no published data concerning dysbiosis in small vessel vasculitides, although it has been demonstrated that gut dysbiosis in glomerulonephritis mice models  . Accordi6 (CCR6) .Alloprevotella rava and increased colonisation by Haemophilus parainfluenzae, neither of which was significantly affected by concomitant immunosuppressive treatments  or genetic predisposition (HLA-B/MICA locus variants), but they were slightly restored by periodontitis treatment. The same authors reported a significant reduction in species diversity in BD patients, as measured by the inverse Simpson index.A number of studies have investigated the role of dysbiosis in the pathogenesis of Behçet's disease (BD), a variable-vessel vasculitis characterized by recurrent mouth and genital ulcers, ocular inflammation, and skin rashes. Its etiopathogenesis is still unknown, but it shares some of the traits of autoinflammatory diseases. Coit et al. investigated the oral microbiome of 31 BD patients and 15 controls by analysing salivary samples using high-throughput sequencing of the 16S rRNA V4 region  and founRothia denticariosa, whereas ulcerous BD oral cavities had higher prevalence of Streptococcus salivarius and Streptococcus sanguinis than those of the subjects in the two control groups.Seoudi et al. found differences in the microbial composition of the saliva of 54 BD patients, eight subjects affected by recurrent aphthous stomatitis, and 25 controls . NonulceRoseburia and Subdoligranulum in fecal samples of 22 BD patients in comparison with 16 controls [Roseburia (but not Subdoligranulum) colonisation. Similarly, Shimizu et al. made a metagenomic analysis of stool samples from 12 BD patients and 12 healthy subjects [Clostridia and an increased prevalence of Actinobacteria and Lactobacillus spp. in the patients, with only minimal effects of concomitant immunosuppressive treatments.Using pyrosequencing of the V3-V4 hypervariable regions of the 16rDNA gene, Consolandi et al. found a significant reduction in the genera controls . These msubjects  and founIn summary, vasculitides represent a heterogeneous group of immune-mediated diseases sustained by different immunologic pathways and involving different-sized vessels. The role of microbiome in vessel inflammation may be based on microbiome unbalance in genetically predisposed patients. However, because data concerning vascular dysbiosis are still unvailable, it can be hypothesized that inflammation may arise from the attempt to counteract dysbiotic changes occurring in other districts, such as the gut or oral mucosa. Among vasculitides, only BD showed altered microbiome in saliva and stool, but the link between alterated microbiome and vascular inflammation is still unclear. The role of the microbiome in inducing and worsening autoimmune diseases has been widely investigated over the last years. The commensal and pathogenic microorganisms resident in the skin or mucosa are in mutual balance, protected by the integrity of the skin/mucosal barrier and the active surveillance of the innate and adaptive immune systems. The broad spectrum of CTDs is characterized by profound changes in the anatomical and physiological characteristics of mucosa and skin and therefore provides a predisposing environment for the onset of dysbiosis. Once it has occurred, dysbiosis leads to the release of microbial peptides and other molecules that amplify a state of chronic inflammation as a result of the activation of effector cells belonging to both innate and adaptive immune systems. There is considerable evidence that dysbiosis can trigger autoimmune diseases, including RA and SpA, but less is known about microbial composition in CTDs or vasculitides.Nevertheless, studies of SLE and SSc have demonstrated an imbalance in the composition of the gut and muco-cutaneous flora. A reduced Firmicutes/Bacteroidetes ratio has been found in the gut of SLE patients and reduced levels of Clostridiaceae in fecal samples of SSc patients. These changes in the microbial composition are at the basis of an increased production of proinflammatory FFAs and a reduction in the amount of anti-inflammatory SCFAs, with a subsequent modulation in the cytokine pattern and in the release of leptin. Moreover, reduced gut colonisation by Firmicutes has been related to the inbalance between Th17 and T regulator lymphocytes.Staphylococcus aureus, may activate the innate immune system via the recognition of PAMPs by TLRs or NOD2, or following opsonization with C3 and immunoglobulins, thus fomenting the production of type I IFNs that represent a peculiar signature in SLE pathogenesis. So far, two studies have associated nasal colonisation by Staphylococcus aureus and periodontitis sustained by Fretibacterium, Prevotella nigrescens, and Selenomonas spp. with clinical manifestations and the production of some proinflammatory cytokines in SLE patients.Chronic infections sustained by pathogen strains, including Rhodotorula glutinis, which is known to be involved in fibrosing diseases.Alterations in the mycobiome may underlie fibrotic skin and lung diseases as the fibrotic skin areas of SSc patients may be colonised by Capnocytphaga ochracea in genetically predisposed subjects may lead to the activation of the adaptive immune system through the cross-reactivity against a von Willebrand factor type A domain protein (vWFA) that is produced by the microorganism and Ro-SSA self-antigens.Intestinal dysbiosis has also been demonstrated in SS patients, and, interestingly, gingival colonisation by The evidence that dysbiosis may be involved in the pathogenesis of myositides and vasculitides is weaker, but some studies of BD patients have found taxonomic variations in the microbial composition of the gut that were not affected by concurrent immunosuppressive therapies. Similarly to SLE and SSc, a dysbiosis consisting in a reduction in Clostridiales has been reported in fecal samples of BD patients, with a subsequent hypoproduction of SCFAs having anti-inflammatory properties.Streptococci, Staphylococci, and Rothia during disease's flares. No studies addressed the role of dysbiosis in the onset of small vessel vasculitides, although some experiments on animal models could support the role of intestinal microbiome in the activation of autoreactive Th17 cells in ANCA-associated vasculitides.An isolated study assessing the intestinal microbiome in patients affected by KD found an increased expression of molecular mimicry. Alterations in the composition of the commensal flora harboured in the intestinal tract have been detected in SLE, SSc, and SS; however, dysbiosis occurring at mucosal sites, including the mouth, nose, and lungs as well as in the skin, may represent another trigger in these diseases characterized by a high burden of skin and mucosal inflammation. The impairment of the muco-cutaneous barrier, partly related to chronic inflammation, may further favour the chronicity of this mechanism by which pathogen species could survive and maintain inflammation in already inflammed sites. Several studies on BD, characterized by recurrent mouth aphtosis, have demonstrated an unbalanced flora of the mouth, which was associated also to disease activity. Similarly, the onset of other vasculitides may be related to alterations in vessel microbiome, but studies are lacking.Overall, the contribution of dysbiosis in tuning the immune response has a rationale in CTDs and vasculitides, although there are currently less evidences than in chronic autoimmune arthritides. Moreover, the multifaceted expression of these diseases raises the questions about the primitive district in which dysbiosis would occur. In chronic autoimmune arthritides, changes in gut microbiome have been considered the main source of immune system activation. Since joints are sterile sites, the most accredited hypothesis is that effector cells could be primed and activated following the presentation of microbial peptides in the gut and then migrate into joints where they could give raise to the inflammatory cascade via a mechanism of Lactobacilli or their substrates has shown some benefits in experimental studies on SLE human and animal cohorts. Unfortunately, no RCTs on the effectiveness of such strategies are available, and currently published studies are not conclusive due to heterogenicity in methodology. It is likely that a normocaloric diet with a high fiber and vitamin content together with a weight control could help patients in reducing the inflammatory burden and could be considered beside the pharmacologic intervention in the future algorithm for the treatment of these diseases.According to above described data, counteracting dysbiosis by means of prebiotics or probiotics may represent a useful tool in preventing or limiting inflammation in CTDs and vasculitides. Implementation with In conclusion, several studies suggest that alterations in human microbiota may be involved in the pathogenesis of CTDs or vasculitides; however, due to the lack in a methodologic standardization, the absence of RCTs, the polyhedral manifestations of the diseases, and concomitant treatments as well as the still scarce amount of research in this field, further studies are needed to better understand the real impact of dysbiosis on the course of these diseases and to conceive preventive or therapeutic strategies to counteract microbiome-driven inflammation.


The prefrontal cortex (PFC) is the most frequently targeted brain region by non-invasive brain stimulation (NBS) studies. Non-invasively stimulating the PFC has been shown to both modulate affective processing and improve the clinical symptoms of several psychiatric disorders, such as depression and schizophrenia. The magnitude of the modulation depends on several factors, including the stimulation frequency, the number of stimulation sessions, and the specific sub-region of the PFC that is stimulated. Although some of the potential underlying mechanisms have been identified, the exact mechanisms that underlie these cognitive and affective changes remain unclear. The present review aims to summarize recent advances in the study of affective processing using NBS over the PFC. We will provide a theoretical framework for better understanding how affective processing changes are induced by NBS, with the goal of providing testable hypotheses for future studies. Affective processing plays a significant role in survival and adaptation functions and often interacts with other cognitive processes such as memory, learning, decision making, motivation, and reactions to environmental circumstances . SeveralTranscranial magnetic stimulation is developed on the basis of electromagnetic induction. The change of the extrinsic magnetic pulses on brain can produce an ionic current in the brain which can preferentially activate the pyramidal cells or at their axons and induce the change of neural excitability . TranscrAffective processing of rTMS over the PFC has been shown in some affective disorders, such as depression, schizophrenia, and obsessive compulsive disorder. Depression is the most thoroughly studied in the clinical trials of rTMS. Repetitive TMS, as a typical mode of antidepressant treatment, has shown favorable effects on the depression. Although many studies have investigated the neural mechanisms of TMS over the PFC in depression, however, results are not always consistent and a clear picture has yet to emerge. High-frequency rTMS applied over the left dlPFC protects against the development of negative mood symptoms and increases the susceptibility to negative emotional stimuli . High-frSeveral studies have demonstrated that important dlPFC hemispheric differences exist in MDD: the left dlPFC tends to be hypoactive, whereas the right dlPFC is generally hyperactive . This fiThe activation of the left dlPFC caused by rTMS treatment can improve the memory retrieval of positive affective memories, whereas symptoms of anxiety can be induced by the stimulation of the right dlPFC . The appThe right dlPFC is related to symptoms of anxiety, depression, and panic. Chronic low-frequency rTMS over the right dlPFC showed a significant improvement in panic symptoms after 4 weeks of treatment, with the improvement peaking approximately after 8 weeks. However, the improvement of depressive symptoms required a longer treatment duration, where approximately only half the patients showed improvements after 8 weeks of treatment . The appMultiple rTMS sessions applied to prefrontal regions may modulate the cortical excitability and improve the attentional control over emotional information. However, a single HF-rTMS session applied over the right dlPFC was shown to immediately impair the ability to inhibit negative information, whereas no significant changes were found when the left dlPFC was stimulated . Such heBesides the change of neural excitability, the alteration of various neurochemicals also contributes to neurobiological mechanisms of the antidepressant effect of rTMS. Repetitive TMS has been shown to change the endocrinological serum levels in the brain of healthy subjects . Infra-tThe dorsomedial prefrontal cortex (dmPFC) is another important brain region that is affected by depression. Gray matter density of the dmPFC is reduced in depression, and the magnitude of this reduction correlates with the severity of depression . TranscrTranscranial magnetic stimulation is also increasingly considered as a promising treatment for schizophrenia. Active HF-rTMS (10 Hz) applied to the left dlPFC can induce a significant improvement of the negative clinical symptoms of schizophrenia and associated emotional functioning . These eTranscranial direct current stimulation is another non-invasive brain neuromodulation technique that is receiving more attention within the research community. In tDCS, a constant and low intensity direct current (1–2 mA) is delivered to the brain area via electrodes on the scalp. Direct current can influence the frequency of neuronal spontaneous discharge. The frequency gets higher when the anode of tDCS closes to the soma and dendrite of neurons, while the cathode of tDCS makes it lower . BesidesTranscranial direct current stimulation may affect cortical neuronal activity in the dlPFC, and the tDCS polarity  applied to the dlPFC modulates the performance of participants during a stimulus–response compatibility task . CathodaThe effects of tDCS on depression, schizophrenia, substance use disorders, obsessive compulsive disorder, generalized anxiety disorder, and anorexia nervosa have been extensively studied . AlthougTranscranial direct current stimulation has been demonstrated as an effective, relatively safe and convenient treatment option for depression, which has been the most extensively studied clinical condition with this neuromodulation technique. The most studied brain region with tDCS in depression patients is the dlPFC, which plays a significant role in modulating emotions and motor cortex excitability. Cathodal stimulation current inhibits cortical excitability, whereas anodal current enhances it . The EurThere are two neural networks involved in the neurobiology of depression. The first network underlies “hot” cognitive processes, is implicated in affective and reward processing, and is subserved by the limbic structures and the ventral PFC. The second network underlies “cold” cognitive processes; is related to non-emotional cognitive processing; and is subserved by the dorsal anterior cingulate cortex, the hippocampus, and the dlPFC . CognitiTranscranial direct current stimulation can enhance neuronal activation in the PFC, dorsal hippocampus, ventral tegmental area, and nucleus accumbens . TranscrA recent study indicated that anodal tDCS stimulation of the left dlPFC  reduced vigilance levels in response to threat-related affective stimuli in healthy individuals . The autAlthough there is no mechanism to reveal the interactions between tDCS with antipsychotics and nonbenzodiazepine anticonvulsants in depressed patients, some antipsychotics, such as SNRIs, SSRIs, and tricyclics, can significantly enhance the improvement of tDCS . HoweverTranscranial direct current stimulation applied to the PFC has been shown to be an effective and relatively safe therapeutic option for adults and children with schizophrenia . NegativPrefrontal tDCS has also been shown to improve working memory performance and affective identification performance in patients with schizophrenia, and to enhance connectivity between brain networks in healthy individuals as measured by resting-state functional connectivity magnetic resonance imaging (fcMRI) . AuditorThe PFC also plays a critical role in developing addictions, particularly those related to drug use and smoking. Drug dependence has been associated with a reduction of brain activity within the PFC, which is believed to be subsequent to structural and functional damage to the PFC . CravingBulimia nervosa is an abnormal and excessive food craving disorder that can lead to other health problems including obesity. Some studies have indicated that the application of tDCS over either the right or the left dlPFC can enhance inhibitory control while reducing food cravings and intake . The spePosttraumatic stress disorder produces deficient fear extinction mechanisms and is associated with an abnormal activation of key brain regions that are part of the fear extinction network, which includes the ventromedial PFC, amygdala, and hippocampus . FurtherPain is a multidimensional experience involving cognitive, attentional, and affective processes. Pain is often associated with negative emotions such as unpleasantness or anxiety, which can, in turn, modulate the pain experience. The application of tDCS over the left dlPFC can alleviate affective pain by increasing the neural activity in the left dlPFC, and also by down-regulating pain inhibitory systems . This meThere are only a few studies that have investigated the effects of tACS on affective processing. These studies focused primarily on improving working memory functions in both healthy individuals and patients with schizophrenia . It has Affective processing plays a significant role in survival and adaptation functions. Disturbance of affective processing is a core factor for most psychiatric disorders, such as, anxiety, depression, schizophrenia, phobia, and addiction. Although NBS studies have provided tantalizing symptom improvement and affective processing in some psychiatric disorders, such as depression and schizophrenia, there are still lots of limits for clinical applications. As we reviewed, depression is the most thoroughly studied affective disorder in TMS and tDCS; however, there are no standardized treatment protocols in the clinical application of rTMS for depressived patients. Repetitive TMS over the left dlPFC can improve the overall mood status, bias attentional processing toward negative information, increase susceptibility to negative emotional stimuli, and improve the Hamilton depression rating scale in the patients with depression. Repetitive TMS applied over the right dlPFC produces significant improvement in panic and depressive symptoms. Repetitive TMS treatment on the right dlPFC can also affect early stage affective visual processing, and enhance differential affective responses to fearful stimuli in individuals with anxiety. Transcranial direct current stimulation applied over the dlPFC can significantly improve the depressive symptom, cognitive function, such as working memory and attention, and stress-induced working memory deficits, and modulate the negative attentional bias in patients with depression. In depression, complicated pathogenesis, diversified pathogenic factor, manifold clinical symptoms, and individual differences make it difficult for the treatment of depression. Therefore, high-quality multicenter randomized clinical trials are required to confirm the best optimal treatment for patients with depression, for instance, the frequency of rTMS, timing and course of the treatment, and evaluation of the therapeutic effect. In addition, some studies have indicated the changes of neural excitability and the alteration of various neurochemicals may be neurobiological mechanisms of the antidepressant effect of rTMS. Notwithstanding, there are also some potential mechanisms remaining to be revealed. In addition, the short- and long-term implications of NBS in patients with depression should get sufficient attention. Besides depression, other psychiatric disorders, for instance, schizophrenia, addiction, bulimia nervosa, and posttraumatic stress disorder, have exhibited favorable responses to NBS treatment. However, NBS also needs more evidence to verify the efficacy and explore physiological basis of affective processing in these psychiatric disorders.The PFC is the most frequently studied region with NBS. The application of NBS over the PFC can significantly modulate affective processing and improve the clinical symptoms of several psychiatric disorders, such as depression and schizophrenia. The effects of TMS over the PFC on affective processing depend on the exact stimulation frequency, the number of consecutive stimulation sessions, and the targeted sub-region of the PFC. Although some potential mechanisms have been identified, the overall picture is yet to be complete. The application of TMS over the left dlPFC can increase brain activity in the left dlPFC and the anterior cingulate gyrus, whereas it also decreases brain activity measured in the left fusiform gyrus, the left cerebellum, and the right dlPFC. Transcranial magnetic stimulation applied to the right dlPFC can increase event-related neural activity bilaterally in the parietal and temporal cortex, increase early stage affective visual processing, and enhance differential affective responses to fearful stimuli. Transcranial direct current stimulation can enhance neuronal activation in the PFC, dorsal hippocampus, ventral tegmental area, and nucleus accumbens. However, the exact mechanisms underlying the tDCS effects remain unclear. As more and more studies investigate the effects and underlying mechanisms of NBS, its clinical applications should continue to be scrutinized.WL, YL, XZ, ZC, and BL wrote the manuscript. WY and BL provided the critical revisions. All authors approved the final version of the manuscript for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dysregulation of the immune system and inflammation likely play a role in the development or course of schizophrenia, at least in a sub-population of patients. In particular, recent evidence has implicated the complement system in this disorder. The complement system is a key effector of innate immunity, mediating elimination of pathogens and debris via initiation of phagocytosis, inflammation and cell lysis. Intriguingly, early complement components also participate in synaptic pruning and plasticity. Further evaluation of the role of the complement system in schizophrenia may reveal novel treatment strategies.Investigations of the complement system in blood and postmortem brain tissue in schizophrenia will be reviewed. Furthermore, the relationship between blood and brain complement levels and measures of central and peripheral inflammation, genotype and synaptic density will be explored. Finally, the potential utility of anti-complement therapies in the treatment of schizophrenia will be discussed.Recent genome-wide association studies have revealed an association with genetic markers within the major histocompatibility complex locus in schizophrenia, with this association suggested to reflect diversity in complement component 4 (C4) genes. Consistent with genetic data, higher complement hemolytic activity has been reported in this disorder, while our studies in postmortem brain tissue have revealed increased expression of several complement components. Notably, C4 expression is impacted by C4 genetic architecture.Overall, data suggests a role for the complement system in schizophrenia. Increased complement expression may be indicative of an inflammatory response. However, given that early complement components have also been implicated in synaptic pruning and circuit remodeling, disturbances in complement activity may also contribute to synaptic deficits previously identified in this disorder. Anti-complement therapies are currently available, while the complement system provides numerous additional options for future drug development. Further research is required to elucidate the potential utility of anti-inflammatory therapies, including those targeting the complement system, in the treatment of schizophrenia, and to identify which patients may benefit most from this strategy and when treatment would be most effective.


Aging results in impaired neurogenesis in the two neurogenic niches of the adult mammalian brain, the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle. While significant work has characterized intrinsic cellular changes that contribute to this decline, it is increasingly apparent that the systemic environment also represents a critical driver of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis have revealed that immune-related molecular and cellular changes in the aging systemic environment negatively regulate adult neurogenesis. Interestingly, these studies have also demonstrated that age-related decline in neurogenesis can be ameliorated by exposure to the young systemic environment. While this burgeoning field of research is increasingly garnering interest, as yet, the precise mechanisms driving either the pro-aging effects of aged blood or the rejuvenating effects of young blood remain to be thoroughly defined. Here, we review how age-related changes in blood, blood-borne factors, and peripheral immune cells contribute to the age-related decline in adult neurogenesis in the mammalian brain, and posit both direct neural stem cell and indirect neurogenic niche-mediated mechanisms. Aging is a global process, resulting in disrupted homeostatic function and a loss of neurogenic capacity in the mammalian brain. Systemic interventions have recently been shown to regulate these effects in a variety of tissues, including the brain. Here, we will review the growing body of work that posits the systemic environment as a key regulator of the decline in neurogenesis observed in the aging mammalian brain, and will explore potential mechanisms by which the pro-aging and rejuvenating effects of the systemic milieu are mediated.Traditionally, the adult mammalian brain was thought to be devoid of neural stem cell (NSC) activity, reliant largely on gene expression changes and structural reorganization for plasticity. In 1965, however, Altman and Das , includiINK4a, an intrinsic factor commonly associated with senescence, within the progenitor population has also been shown to specifically impair neurogenesis within the SVZ  administration of young adult blood plasma recapitulates aspects of heterochronic parabiosis  that are elevated in young heterochronic parabionts, and whose blood concentrations inversely correlate with the age-related decline in neurogenesis , increased rates of anemia, and increased incidence of myeloid malignancies  is a highly vascular tissue located in the ventricles of the mammalian brain that produces CSF and acts as an interface between the periphery and the brain. Secreted factors from the CP bathe the SVZ neurogenic niche and are thought to influence neurogenesis in development and adulthood (Lehtinen et al. Recent evidence now suggests a direct functional role for CP aging and age-related decline in neurogenesis in the brain. For example, conditioned media from aged CP explants inhibits adult SVZ neurogenesis compared to young CP-conditioned media when infused into the lateral ventricles of young mice in vivo, or administered on young SVZ NSCs in vitro (Silva-Vargas et al. Given its highly vascular nature, it is likely that the CP may be sensitive to changes in soluble pro-aging factors in blood. Additionally, CD4+ T cells have recently been observed in the CP of healthy young and aged mice (Baruch et al. The neurogenic niche is complex, comprised of many different cell types that influence NSC function (reviewed by Aimone et al. In addition to modulating vasculature, age-related changes in the systemic milieu may also regulate neuroinflammation, and thereby affect neurogenesis by impairing the homeostatic capacity of microglia and astrocytes. While aging is associated with microgliosis, adoptive transfer of hUCB mononuclear cells or T cells decreased the number of activated microglia in the hippocampus of old rats, suggesting that young immune cells may dampen neuroinflammation in the aged neurogenic niche (Bachstetter et al. A growing body of evidence has demonstrated that the systemic environment is a key mediator of age-related decline in neurogenesis. Models of heterochronic blood exchange have revealed that the age-related decline in adult neurogenesis in both the DG and SVZ can be either ameliorated or promoted by exposure to young or aged blood, respectively (Villeda et al.


Ductal adenocarcinoma of the pancreas is one of the most aggressive forms of cancer, with only a minority of cases being resectable at the moment of their diagnosis. The accurate detection and characterization of pancreatic carcinoma is very important for patient management. Multidetector-row computed tomography (MDCT) has become the cross-sectional modality of choice in the diagnosis, staging, treatment planning, and follow-up of patients with pancreatic tumors. However, approximately 11% of ductal adenocarcinomas still remain undetected at MDCT because of the lack of attenuation gradient between the lesion and the adjacent pancreatic parenchyma. In this systematic literature review we investigate the current evolution of the CT technique, limitations, and perspectives in the evaluation of pancreatic carcinoma. Pancreatic adenocarcinoma is one of the most aggressive forms of cancer. It is the fourth most common cause of cancer-related mortality worldwide. The prognosis of pancreatic cancer is still bleak, as the 5-year survival rate is less than 5% and the mortality rate has not declined over the last few decades, with an increasing global incidence of nearly 340,000 in 2012. The incidence rate near equaling that of its mortality rate [The accurate characterization of pancreatic adenocarcinoma is very important for patient management. Computer tomography (CT) and magnetic resonance imaging (MRI) are the most important modalities for evaluating pancreatic lesions. A precise diagnosis of pancreatic tumor is not always simple because the tumor can have atypical imaging features and many other disorders may mimic pancreatic adenocarcinoma , 4. MultData for this review were identified by searches of the PubMed database using a multimodal strategy. The following search terms were employed: CT in pancreatic cancer, functional CT in pancreatic cancer, CT in advanced pancreatic cancer, CT in advanced pancreatic adenocarcinoma after chemotherapy. The inclusion criteria were: clinical study evaluating pancreatic adenocarcinoma, clinical study evaluating new functional imaging criteria in the CT study of patients with pancreatic adenocarcinoma, and clinical study evaluating follow-up after chemotherapy of patients with advanced pancreatic adenocarcinoma. Articles published in the English language from January 2003 to June 2016 were included. The references of these articles were also analyzed to identify original studies that were not identified by the search of the data. Exclusion criteria unavailability of full text and absence of original research data .A Pubmed search yielded 1821 articles for key CT in pancreatic cancer, 129 articles for functional CT in pancreatic cancer, 514 articles for CT in advanced pancreatic cancer, 77 articles for CT in advanced pancreatic adenocarcinoma after chemotherapy. Among the total number of 2541 articles, 2408 were excluded because of unmatching the inclusion criteria. In the end, there were 133 articles: 58 for CT in pancreatic cancer, 25 for functional CT in pancreatic cancer, 38 for CT in advanced pancreatic cancer, and 12 for CT in advanced pancreatic adenocarcinoma after chemotherapy. Among these, 96 articles corresponded to more than one criterion so 37 articles were included at the end  .Pancreatic parenchyma study should be carried out with a quadruple-phase scanning protocol, including unenhanced, arterial, pancreatic parenchymal, and portal venous phases. However, according to Fletcher , the acqPerfusion CT (CTp) is a clinical technique that can be used to provide maps and obtain quantitative measurements of various hemodynamic parameters on the basis of the linear relationship between CT enhancement and iodinated contrast material concentration –33. SomeTo reduce radiation dose and increase conspicuity of tumor Brook et al.  evaluateTo identify and characterize a pancreatic lesion is essential not only the phase of study but also the concentration, the injection flow rates and volumes. Yanaga et al.  evaluateAlthough radical resection is still the only curative treatment for pancreatic cancer, it is generally accepted that a multimodality strategy is necessary for its management, because at the time of diagnosis about 40% of patients with pancreatic cancer are diagnosed with metastatic disease (stage IV) and the remaining 40% are diagnosed with LAPC , 2, 39. Although MDCT is the modality of choice in the preoperative diagnosis and staging and in treatment planning and follow-up of patients with pancreatic cancer, there is an 11% of pancreatic adenocarcinoma is being unrecognized. Therefore it is necessary to optimize the technique, with a dose of the contrast medium adequate to the weight of the patient, with a proper delay after administration of the contrast medium. Parenchymal pancreatic phase is better than arterial phase. Dual-source, dual-energy MDCT and CTp improve the detection of pancreatic adenocarcinoma, increasing the conspicuity of nearly isoattenuating, small lesions. CTp, additionally, provides functional information and can aid in the assessment of residual viable tumor tissue after CRT.