Background: Essential tremor (ET) is the most common movement disorder. In cases resistant to pharmacological treatment, functional stereotactic neurosurgery can be an alternative. Lesional surgery has largely been replaced by deep brain stimulation (DBS). The current target of choice is the ventrolateral thalamus (Vim). Vim DBS has generally shown good results, but in some cases it is associated with a suboptimal effect as well as side effects. DBS in the posterior subthalamic area/caudal zona incerta (PSA/cZi) has recently shown promising effects. Recently the role of lesional therapy in selected cases has been discussed. Aim: The aim is to evaluate stereotactic functional procedures in the treatment of ET, with special emphasis on PSA DBS. Further the effects of DBS in the PSA are evaluated. The optimal target is also assessed by evaluating the effect of Vim and PSA DBS in relation to the position of the electrode. An attempt to identify patient-specific factors of prognostic importance for the outcome after DBS will be made. The quality of life (QoL) of patients treated with PSA DBS for ET will be assessed. Finally, the aim is also to analyze retrospectively the long-term outcome of lesional procedures (thalamotomies). Method: The thesis consists of five studies. The optimal electrode location is evaluated in a study analyzing the location of the electrode contact yielding the best effect in Vim DBS and PSA DBS groups. The efficacy of PSA DBS in 21 patients is evaluated in a prospective study. The correlation between outcome, age, tremor grade and gender is established in a prospective study consisting of 68 patients. Finally, the degree of improvement in QoL is determined in 16 patients operated on in the PSA. The very long-term effect of lesional surgery has been investigated in a retrospective study of nine patients who have undergone thalamotomy. Results: In the study of PSA DBS the total score on the Essential Tremor Rating Scale (ETRS) was reduced by 60% compared to the baseline value. Tremor of the arm was improved by 95%. The study evaluating the optimal contact location showed that the best effect was in the PSA in 54% and in the Vim in 12%. The efficacy of DBS was not related to age, gender, or the severity of tremor with regard to the percentage reduction of tremor on stimulation. In patients with a more severe tremor at baseline, a higher degree of residual tremor on stimulation was seen. With regard to QoL, the activities of daily living (ADL) according to the ETRS score were significantly improved, as well as according to the ADL and psychosocial subscores on the Questionnaire for Essential Tremor (QUEST) scale. No significant changes were found on the generic Short Form (SF-36) QoL scale. Thalamotomy had some positive effects, but also a significant amount of side effects that might be attributed to the surgery. Conclusions: The effect of PSA DBS was very satisfying and compares well with the results from Vim DBS. When both Vim and PSA DBS are considered, the optimal target seems to be located in the PSA. PSA DBS shows good results in improving ADL, but the results have been difficult to demonstrate on QoL scales. The efficacy of DBS could not be shown to be associated with gender or age. Nor was it associated with the severity of tremor regarding the percentage of tremor reduction on stimulation. The preoperative severity of tremor was the most important factor regarding outcome following DBS. With regard to thalamotomies, some possible remaining benefit of the surgery could be seen along with some severe side effects.

L’ocytocine (OT) est un neuropeptide synthétisé au sein de l’hypothalamus. On sait aujourd’hui que l’OT est fortement impliquée dans la modulation de nombreux comportements et émotions. Pourtant, il reste encore difficile d’expliquer comment s’organise le système ocytocinergique, par exemple en sous-ensembles spécifiques. De même, les circuits neuronaux impliqués dans leur recrutement restent obscures, tout comme leur potentielle plasticité. C’est pourquoi, au cours de ma thèse, je me suis attachée à mieux comprendre ces différents points. Les résultats obtenus ont montré que i) un sous-ensemble spécifique de neurones OT est recruté par la peur ; ii) le système OT fait preuve d’une grande plasticité après une exposition à un contexte effrayant ; iii) le neuropeptide S est capable de recruter une sous-population de neurones OT afin d’exercer une action anxiolytique ; iv) les neurotransmetteurs monoaminergiques sont eux-mêmes capables de recruter différents sous-ensembles de neurones OT. En conclusion, mon travail a mis en évidence la plasticité de ce système peptidergique et différentes manières de recruter de manière spécifiques certains sous-ensembles existants de neurones OT. / Oxytocin (OT) is a peptide synthesized within the hypothalamus. We now know that OT is strongly involved in the modulation of many behaviors and emotions. However, it is still difficult to explain how the oxytocinergic system is organized, for example in specific sub-populations. Similarly, the neuronal circuits involved in their recruitment remain obscure, like their potential plasticity. That is why, during my thesis, I tried to better understand these different points. The results obtained showed that i) a specific sub-population of OT neurons is recruited by fear; ii) the OT system exhibits great plasticity after exposure to a scary context; iii) the neuropeptide S is able to recruit an OT neuron sub-population in order to exert an anxiolytic effect; iv) monoaminergic neurotransmitters are themselves able to recruit different sub-populations of OT neurons. In conclusion, my work has highlighted the plasticity of this peptidergic system and different ways to recruit in a specific manner some existing sub-populations of OT neurons.

Made available in DSpace on 2014-12-17T15:36:53Z (GMT). No. of bitstreams: 1 RaissaRL.pdf: 2340483 bytes, checksum: 4de24714e54fd592ed6bcfc320e45daf (MD5) Previous issue date: 2008-10-30 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The retinal projections in mammals usually reach, classically, three major functional systems: the primary visual system, the accessory optic system, and the circadian timing system. But the retinal projections also reach areas classically considered non-visual, one of which groups the neurons of the zona incerta (ZI), target this study. The primary visual system includes thalamic lateral geniculate complex is formed by the dorsal lateral geniculate nucleus, intergeniculate leaflet and the ventral lateral geniculate nucleus and other Components. The accessory optic system is composed of the small nuclei: nuclei terminal dorsal, lateral, medial and the interstitial nucleus of the superior posterior fasciculus. These nuclei are involved in visuo-motor activities. The circadian timing system is comprised of the suprachiasmatic nucleus of the hypothalamus, that act as master circadian pacemaker, entraining pathways and efferents pathways to the efectors, and the intergeniculate leaflet, that seems to act as a modulator of the pacemaker. The retinal projections too reach classically considered non-visual areas, including the zona incerta. This region is localized in the ventral thalamus and has been implicated in various functional properties including nociceptive and somatosensory processing, motor response, sociosexual behaviour, feeding and drinking, in symptoms of neurodegenerative diseases, arousal and attention. It also displays connection with several areas of central nervous system. The aim of this study was characterize the retinal projection in the zona incerta of Callithrix jacchus (sag?i), a primate of the New World through the anterograde axonal transport of the cholera toxin subunit b and analyze the citoarchicteture using Nissl and NeuN, and neurochemical substances such as serotonin, GABA, VIP, VP, GFAP and binding-calcium proteins. The zona incerta showed a different division of the literature in citoarquitetura, both by means of Nissl as neurochemical by NeuN, with a subdivision ventrolateral and dorsomedial. The neurochemical to the other substances corroborate with this subdivision. The GFAP was almost completely negative for the zona incerta, result non evidenced in previous studies yet. The 16 retinal projection in sag?i, unlike other primates and rodents, reached the caudal portion only. This work helps to make further studies are conducted based on this subdivision and the localization of the neurochemical substances associated with possible behaviors that the zona incerta is involved / As proje??es retinianas em mam?feros costumam ser agrupadas, classicamente, em tr?s grandes sistemas funcionais: O sistema visual prim?rio, o sistema ?ptico acess?rio e o sistema de temporiza??o circadiana. Por?m as proje??es retinianas tamb?m alcan?am locais considerados como classicamente n?o-visuais, um dos quais agrupa os neur?nios da zona incerta (ZI), alvo deste estudo. O sistema visual prim?rio inclui o complexo geniculado lateral tal?mico formado pelo n?cleo geniculado lateral dorsal, o folheto intergeniculado e o n?cleo geniculado lateral ventral, al?m de outros componentes. O sistema ?ptico acess?rio ? formado por pequenos n?cleos: n?cleos terminais dorsal, lateral, medial e o n?cleo intersticial do fasc?culo posterior superior. Estes n?cleos participam da atividade v?suo-motora. O sistema de temporiza??o circadiana ? composto pelo n?cleo supraquiasm?tico do hipot?lamo, tido como principal marcapasso circadiano, vias sincronizadoras e vias de sa?da aos efetores, e o folheto intergeniculado, que parece agir como modulador do marcapasso. As proje??es retinianas tamb?m alcan?am ?reas classicamente n?o-visuais, entre elas, a zona incerta. Esta regi?o est? localizada no t?lamo ventral e tem sido implicada em v?rias propriedades funcionais incluindo processamento somatosens?rio e nociceptivo, resposta motora, comportamento s?cio-sexual, de comer e beber, em sintomas de doen?as neurodegenerativas, despertar e aten??o. Apresenta tamb?m conex?o com diversas ?reas do sistema nervoso central proporcionando a esta regi?o a associa??o com diversas fun??es. O objetivo neste trabalho foi caracterizar a proje??o retiniana no Callithrix jacchus (sag?i), um primata do Novo Mundo, atrav?s do tra?ador anter?grado a unidade B da toxina col?rica, bem como analisar a citoarquitetura, utilizando o Nissl e NeuN, e a neuroqu?mica com subst?ncias neuroativas como a serotonina, o GABA, o VIP, VP, al?m de GFAP e prote?nas ligantes de c?lcio. A zona incerta apresentou uma divis?o diferenciada da presente na literatura na citoarquitetura, tanto pelo m?todo de Nissl como neuroqu?mico por NeuN, com uma subdivis?o ventrolateral e dorsomedial. A neuroqu?mica para as outras 14 subst?ncias corrobora com essa divis?o. O GFAP foi quase em completo negativo para a ZI, resultado este ainda n?o evidenciado em trabalhos anteriores. A proje??o retiniana no sag?i, diferentemente de outros primatas, e roedores, alcan?ou a por??o caudal somente. Este trabalho contribui para que novos estudos sejam realizados tomando por base essa subdivis?o bem como a localiza??o das subst?ncias neuroativas associadas a poss?veis comportamentos em que a zona incerta esteja envolvida

Made available in DSpace on 2014-12-17T15:37:21Z (GMT). No. of bitstreams: 1 PauloLAGM_DISSERT.pdf: 1515778 bytes, checksum: c044dde7997a56896121bcf83cf26e6b (MD5) Previous issue date: 2014-03-27 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The Zona Incerta (ZI) is embryologically derived from the ventral thalamus, in continuity with the reticular nucleus of the thalamus. Studies usingneural tracers technics have allowed identify a complex connectional map including the ZI. Futhermore, cytochemical, molecular and functional data have shown abundant variability in the neurochemical contend in the ZI, as well as,the involvement of the ZI in the modulation of nociception, attention, alertness, control and maintenance of posture and control of visceral activity. This work aims to characterize the cytoarchitecture, neurochemical content of the ZI in the rock cavy (Kerodon rupestris), and a direct retinal-ZI pathway present in this species. The Nissl staining is effective for the delineation and characterization of ZI citoarchitecture. ZIc receives a contralateral retinal projection showing varicosities, suggesting a modulatory character of photic information. The ZI in the rock cavy, as in others rodents and primates, is characterized by a complex neurochemical signature. The ZI neurochemistry presents great diversity, especially in the medial portion of ZIr, where we have found immunoreactivity of all neuroactive substances investigated, and that NOS-IR, GFAP and CR helped the delimitation of middle ZI in ZId and ZIv. Nevertheless, just 5-HT-IR fibers are present in all subdivisions of the ZI. These data demonstrate the great wealth of the neurochemistry of rock cavy s ZI and a direct retinal modulation in the ZI, helping to explain it s broad functional repertory / A Zona Incerta (ZI) ? um grupamento neuronal embriologicamente derivado do t?lamo ventral, em continuidade com o n?cleo reticular do t?lamo. Diversos estudos com tra?adores retr?grados e anter?grados revelaram a conex?o da ZI com diversas estruturas do sistema nervoso central. Dados moleculares e citoqu?micos revelaram que a ZI ? um dos grupamentos neuronais com maior diversidade neuroqu?mica e citoarquitet?nica do dienc?falo, e estudos hodol?gicos e neuroqu?micos permitiram considerar o envolvimento da ZI em diversas fun??es, as quais se destacam a nocicep??o, aten??o, estado de alerta, controle e manuten??o da postura e controle da atividade visceral. Este trabalho tem por objetivo caracterizar a citoarquitetura e o conte?do neuroqu?mico da ZI do moc? (Kerodon rupestris), bem como a afer?ncia ?ptica presente neste n?cleo nesta esp?cie. A t?cnica de Nissl ? eficiente para a delimita??o e caracteriza??o citoarquitet?nica da ZI do moc?; A ZIc recebe proje??o da retina contralateral, apresentando fibras Classe II ou modulator, sugerindo um car?ter modulat?rio da informa??o f?tica; A ZI do moc?, assim como em outros roedores e primatas, ? caracterizada por uma complexa rede neuroqu?mica, sobretudo na por??o medial da ZIr, onde encontramos imunorreatividade de todas as subst?ncias neuroativas investigadas, al?m de que A IR-NOS, GFAP e CR auxiliaram a delimita??o da ZI no n?vel m?dio em ZId e ZIv. Contudo, somente fibras IR 5-HT est?o presentes em todas as subdivis?es da ZI. Esses dados demonstram a grande riqueza neuroqu?mica da ZI do moc?, auxiliando para explicar o envolvimento em um amplo repertorio funcional

Bakgrund: Deep brain stimulation (DBS) i kaudala zona incerta (Zi) har en tremorreducerande effekt vid den neurologiska sjukdomen essentiell tremor (ET). Stimulering av Zi har även positiva effekter på rösttremor, men individuella variationer förekommer. Tidigare har främst effekten mellan på- och avslagen stimulering undersökts. Inga studier har jämfört effekten på rösttremor vid ökande nivåer av stimuleringsstyrka.   Mål: Att undersöka effekt på rösttremor vid ökande unilateral stimuleringsstyrka av DBS i Zi hos deltagare med ET. Samt att undersöka prevalens och att se vilken rösttremorreducerande effekt deltagarnas kliniska inställningar har.   Metod: Trettioåtta deltagare med DBS Zi, bedömdes vid tre tillstånd: utan stimulering (DBS OFF), med kliniska inställningar (DBS ON) samt med ökande stimuleringsstyrka, 0,5-4,5V (DBS+). Rösttremor bedömdes utifrån inspelningar av uthållna vokalproduktioner i programmet “Visual Sort and Rate Method” (VISOR). Vid bedömning skattades förekomst och grad av rösttremor hos deltagarna genom att deltagarens egna inspelningar jämfördes med varandra i VISOR.   Resultat: DBS Zi hade på gruppnivå en positiv effekt på rösttremor vid såväl DBS ON som vid DBS+. De individuella skillnaderna var dock stora. Flest antal deltagare blev rösttremorfria vid DBS ON och vid stimuleringsnivåerna 1,5V, 2,0V, 3,5V och 4,5V. Prevalensen av rösttremor var 71% (27 deltagare).   Slutsats: DBS Zi har på gruppnivå en positiv effekt på rösttremor. De kliniska inställningarna är stimuleringsnivån som flest deltagare blir rösttremorfria vid. Den individuella variationen gör att man inte kan förutse om en individ kommer att få reducerad rösttremor av DBS Zi. / Tal- och rösteffekter av djup hjärnstimulering hos patienter med ärftlig tremor

Background Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in Europe. Besides motor dysfunction, PD is characterized by several non-motor and secondary motor features, such as weight change, sialorrhea, constipation and swallowing problems. Of these, swallowing is one of the most critical, as it is associated with aspiration pneumonia and consequently is the comorbidity with the highest mortality rate. Swallowing problems affect four of every five patients with PD, and even mild swallowing problems have notable psychosocial effects for patients and their caregivers. Consequently, it is essential to find treatment strategies for PD that may alleviate symptoms for patients with swallowing problems and their potential consequences. Deep Brain Stimulation (DBS) is a surgical treatment option for PD, which improves overall motor function and quality of life, but its effect on swallowing function is not clear. The purpose of this thesis was to contribute to the understanding of the effect of deep brain stimulation in the subthalamic nucleus (STN DBS) and the caudal zona incerta (cZI DBS) on pharyngeal swallowing function and on swallow-specific quality of life in patients with PD. The specific aims were to assess longitudinally the effect of STN DBS and cZI DBS on swallowing at 6 and 12 months postoperatively, in order to identify possible effects of the DBS on swallowing function. In addition, the effects of cZI DBS on ratings of swallowing-related non-motor and secondary motor features such as body weight changes, sialorrhea and speech problems were to be assessed. Methods Eleven PD patients with STN DBS (Paper I) and seventeen patients with cZI DBS (Paper II-IV) were included in this thesis. All patients were evaluated preoperatively and 6 and 12 months postoperatively. The effect of STN DBS and cZI DBS on swallowing was assessed with Fibreoptic-Endoscopic Evaluation of Swallowing (FEES) according to a predefined protocol including Penetration-Aspiration scale, Secretion Severity scale, preswallow spillage, pharyngeal residue, and pharyngeal clearance. Self-assessments were addressed using a visual analogue scale. The cZI DBS patients also completed the Swallowing Quality of Life (SWAL-QOL) questionnaire. Weight changes measured by Body Mass Index, and specific items from the Unified Parkinson’s Disease Rating Scale were also examined. Nine controls without PD were included in Paper IV, by answering the SWAL-QOL questionnaire. Results No clear effect of DBS on swallowing function or swallow-specific quality of life could be observed. There was no effect of DBS on the occurrence of aspiration, secretion, pharyngeal residue or clearance in the study groups with STN DBS or cZI DBS. Patients with STN DBS reported a subjective improvement in swallowing function with DBS stimulation turned on at 6 and 12 months after surgery. In patients with cZI DBS, the median body mass index was postoperatively increased with 1.1kg/m2 and the median increase in weight were +3.0 kg after 12 months with cZI DBS. The scores from the SWAL-QOL questionnaire were high overall in the group with cZI DBS, and the scores were unaffected by the cZI DBS surgery and stimulation. The SWAL-QOL total score was not significantly different between the PD patients and the controls, but the scores from the ‘burden’ and the ‘symptom’ subscales were worse in PD patients. Conclusions STN DBS or cZI DBS did not have a negative effect on swallowing function or ratings of swallow-specific ‘quality of life’ aspects in this cohort. Patients with STN DBS reported a self-perceived improvement in swallowing function when DBS was turned on. With regard to swallowing, patients with cZI DBS had an overall good quality of life throughout the conduct of the study and their swallow-specific quality of life was not negatively affected by cZI DBS. There seems to be no increased risk for aspiration or penetration due to surgery or stimulation for either the STN DBS or the cZI DBS groups. cZI DBS caused weight gain postoperatively. Since the sample sizes in these cohorts are small, the findings need to be confirmed in larger studies.

Background In advanced Parkinson’s disease (PD) the motor symptoms can be treated with deep brain stimulation (DBS). Subthalamic nucleus (STN) has been the most common target and caudal zona incerta (cZi) is a more recent target for stimulation. Stimulation in both of these targets has proved to be positive for the motor symptoms but there is no consensus about how DBS affects the speech and the articulation. Aim The aim of this study was to investigate how fricatives are realized within patients suffering from PD treated with DBS in STN or cZi. Method 9 patients stimulated in STN and 10 patients stimulated in cZi were recorded reading a shorter text.  The recordings were made preoperatively (Pre) and 12 months after surgery with the stimulation switched off (sOff) and on (sOn). From the recordings the fricatives were extracted and assessed in a blinded and randomized procedure. Results For the patients stimulated in cZi the target fricative /s/ had significant lower correct realizations in the sOn condition compared to the other two conditions. The other target fricatives in cZi showed the same pattern as well. For the STN group no unequivocal pattern could be seen. Conclusions The results suggest that stimulation in cZi may affect the patients’ articulation of fricatives and thereby their extended articulatory movements more negative than stimulation in STN.

Background: The posterior subthalamic area (PSA) is essentially composed of the caudal Zona incerta and the prelemniscal radiation. Subthalamotomy in the PSA was renowned for its effectiveness in alleviating movement disorders and particularly tremor. The modern literature on DBS of this area is limited, but promising results have been presented for Parkinson’s disease (PD), essential tremor (ET) and other movement disorders.   Aim: To evaluate the safety of PSA DBS with emphasis on the panorama of side effects, the distribution of stimulation-induced side effects and the effects of PSA DBS on verbal fluency. To evaluate the therapeutic effect of PSA DBS on less common forms of tremor, tremor-dominant PD, and concerning the long-term results in ET. Method: 40 patients were evaluated regarding side effects of the procedure. 28 patients with ET were analyzed for stimulation-induced side effects in a standardized manner. The locations of the contacts that caused stimulation-induced side effects were plotted on atlas slides. A 3-D model of the area was created based on these slides. Verbal fluency was analyzed in 17 patients with ET before surgery, after 3 days and finally after 1 year. Five patients with less common forms of tremor and 18 with ET were evaluated according to the ETRS at baseline and one year or 3-5 years after surgery, respectively. 14 patients with mainly unilateral tremor-dominant PD were evaluated a mean of 18 months after surgery according to the motor part of UPDRS. Results: PSA DBS was associated with few serious side-effects, but a transient and mild postoperative dysphasia was found in 22.5% of the patients. There was a slight transient decline in the performance on verbal fluency tests immediately after surgery. Visualization of the contacts causing stimulation-induced side effects showed that identical responses can be elicited from various points in the PSA and its vicinity. The effect on the less common forms of tremor was excellent except for neuropathic tremor where the effect was moderate. A pronounced and sustained microlesional effect was seen for some of the patients. After a mean of 4 years with unilateral PSA DBS the total ETRS score was improved by 52.4%, tremor by 91.8% and hand function by 78.0% in the patients with ET. There was no increase in the stimulation strength over time. In PD, the scores improved 47.7% for contralateral UPDRS III. Contralateral tremor, rigidity, and bradykinesia improved by 82.2%, 34.3%, and 26.7%, respectively. Conclusions: PSA DBS generally seem to be a safe procedure, but it may be associated with transient declines of verbal fluency. There was no clear somatotopic pattern with regard to stimulation-induced side effects in the PSA. PSA DBS can alleviate tremor regardless of the etiology. The long-term effects in ET were favorable when compared to our previous results of Vim DBS. The effect on Parkinsonian tremor was satisfying, however, the reductions of rigidity and bradykinesia were less compared to previous studies of PSA DBS for PD.

No description available.

Parkinson's Disease affects more than 1 million people in the United States with 60,000 new cases being diagnosed each year. Currently, there is no cure for Parkinson's Disease, but there are several treatment options available. Currently the most popular surgical option is Deep Brain Stimulation. Microelectrode recording helps identify nuclei as the microelectrode passes through them. While the firing frequencies of the target nuclei are well defined, other nuclei are not. This study will attempt to characterize the Zona Incerta, which is the structure directly above the Subthalamic Nucleus, a target nucleus. Characterization of the firing frequency of the Zona Incerta will help aid Deep Brain Stimulation procedures. Looking at the Interspike Intervals for 25 files showed that the average firing frequency is 11.6Hz. A file recorded in the STN was used for comparison and to validate the methods used. This yielded an average firing frequency of 37.5Hz.