Parkinson’s disease is a common neurological disease which will progressively damagedopaminergic neurons in the brain. Later stages of the disease will result in death of theneurons. The diagnosis is often made with respect to the motor symptoms, which includetremors, bradykinesia, and rigidity. In addition to motor symptoms, non-motor symptomsappear in many patients, such as cognitive changes and mood disorders. One method used totreat Parkinson’s disease is deep brain stimulation, where electric pulses are emitted to aspecific brain area. A common target is the subthalamic nucleus, which is part of the basalganglia. By using deep brain stimulation, the dose of other medications for Parkinson’sdisease can be lowered. However, the mechanisms of deep brain stimulation are not yetentirely known, and there have been many reports of adverse side-effects caused by thismethod, including depression and other types of mood changes. Even so, information of apossible sex distribution of these side-effects is still limited. Here, a qualitative essay wasmade where 16 articles describing reported side-effects in men and women were compared. Inaddition, unpublished data from optogenetic studies on male and female mice were analysedin order to examine putative sex-differences upon experimental brain stimulation strategies.The results from the optogenetics results did not show any statistically significant sexdifferences.In contrast, by comparing the selected articles in which results of deep brainstimulation treatment in patients were reported, some differences were found. First, it seemsthat women report more depressive-like symptoms than men. Second, while men also reportdepressions, they also report more aggressive behaviour upon the treatment. A preliminaryconclusion of this essay is therefore that certain sex-differences can be observed among theadverse side-effects reported upon deep brain stimulation in Parkinson´s disease. However,since the studied material was limited, more research is required to make firmer conclusions.

Ziel: Diese retrospektive Analyse sollte die Besserung nach tiefer Hirnstimulation in Abhängigkeit der verwendeten Medikamente zur Sedierung während der Elektrodenplatzierung vergleichen. Einführung: Deep brain stimulation (DBS) stellt eine effektive Therapieoption für Patienten mit fortgeschrittenem Morbus Parkinson dar. Sowohl die intraoperative Aktivität der subcortikalen Neurone als auch die intraoperative klinische Testung ist wichtig, um die exakte Elektrodenplatzierung zu kontrollieren. Beides könnte durch die Gabe von Sedativa, die intraoperativ zur Gewährleistung des Patientenkomforts und zur Optimierung der Operationsbedingungen verabreicht werden, beeinflußt werden. Material und Methoden: Wir analysierten retrospektiv die Daten von 47 Patienten, die Elektroden zur DBS implantiert bekamen. 7 Patienten erhielten während des Eingriffes keinerlei sedierende Medikation, 40 Patienten wurden Sedativa und/oder Analgetika verabreicht.( Propofol allein: n=13, Propofol und Remifentanyl: n=9, Propofol und Alfentanil: n=1, Remifentanil allein: n=13, Alfentanil und Midazolam: n=4) Ergebnisse: Es ergaben sich keine signifikanten Unterschiede zwischen den 5 Patientengruppen bezüglich der Besserung der Parkinson Symptome, gemessen an Hand der Unified Parkinson`s Disease Rating Scale Part III (UPDRS III) oder der Reduktion der Parkinson Medikamentendosis, analysiert als Levodopa Äquivalent Units (LEU). Untersuchten wir die Daten der Patienten, die Propofol während der Platzierung erhielten, zeigte sich ein signifikant schlechteres Ergebnis sowohl determiniert in der UPDRS III als auch in der LEU, verglichen mit den Patienten, die kein Propofol erhielten. Bei Einteilung der Patienten in Gruppen, die ein Opioid während der Platzierung erhielten, und Patienten die kein Opioid erhielten fielen keine signifikanten Unterschiede auf. Ergebnisse: Diese Daten könnten ein erster Hinweis sein, Propofol vorsichtig bei der Platzierung der Elektroden zur tiefen Hirnstimulation einzusetzen. Ein möglicher negativer Effekt des Propofols auf den klinischen Effekt der tiefen Hirnstimulation des Nucleus subthalamicus sollte aber in prospektiven Studien analysiert werden.

The subthalamic nucleus (STN) is a key structure for motor, limbic and associative function. Parkinson's disease (PD) and Obsessive compulsive disorder (OCD) have been connected to abnormal firing activity of STN neurons. Subthalamotomy and deep brain stimulation (DBS) of the STN have been shown to be effective treatment methods for previous suggested diagnosis, however, the mechanism behind the treatment and the reason for adverse side-effects remains unsolved. The aim of this study was to establish if it is possible to distinguish specific gene expressions in structures of transgenic mouse brains as well as gaining more knowledge about the medial part of STN, which is hypothesized to be the limbic part of the structure. Here, immunofluorescence and PCR was performed on Cre-driven transgenic mice followed by histological analysis in order to identify the distribution of tachykinin 1 (Tac1) and paired-like homeodomain 2 (Pitx2) in these transgenic mice brains. The results demonstrate that STN and pSTN were positive structures in Pitx2-CreSunGFP and Tac1-CreSunGFP mice. Tac1-CreSunGFP mice further contained GFP positive cells in striatum, nucleus accumbens, amygdala, thalamus, hypothalamus, submedial nucleus of thalamus and the septal area, proposing the gene expression of Tac1 to be present in several limbic structures. Today, we lack knowledge of the internal organization of the STN, and solving the structural-functional organization of the STN would be helpful to distinguish distinct roles of STN neurons and develop effective STN-DBS-targeting treatment without side-effects.

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Abstract Background Deep brain stimulation (DBS) is a viable surgical treatment method for Parkinson’s disease (PD). It has positive effects on the classical motor symptoms, but effects on speech and voice are not equally beneficial. The speech disorder related to PD is hypokinetic dysarthria, with impaired articulatory precision as a prominent symptom. Studies have shown effects on different aspects of speech due to DBS of the subthalamic nucleus (STN) but the effects of stimulation of the caudal zona incerta (cZi) are less explored. Aims The aim of the current study was to investigate the effect of STN-DBS and cZi-DBS on perceptually measured articulatory precision in PD patients. Method Read speech productions were collected from 19 DBS-treated PD patients, ten STN and nine cZi. The recordings were made before surgery and 12 months postoperatively with stimulator on and off. Levodopa medication was always on. From the reading passage, three-syllable words were selected and isolated. Articulatory precision of the words was rated in two different assessments; an overall rating of articulatory precision and an identification of occurring misarticulations. Results The results from the perceptual assessment showed a decrease in articulatory precision after surgery for both groups. The decrease was significant for the cZi group, but not for the STN group. There was no significant difference between the groups. The frequency of observed misarticulations increased as an effect of DBS for both patient groups, with significant increase for the STN group but not for the cZi group. There was no significant difference between the groups. The most commonly observed misarticulation categories were stop-plosive reduced in quality, fricative realized as other fricative and stop-plosive realized as fricative . Conclusions The results obtained in the current study show that STN-DBS and cZi-DBS may have adverse effects on articulatory precision in PD patients. Keywords Articulatory precision, Parkinson’s disease, DBS, STN, cZi

<p>Deep brain stimulation (DBS) is used to treat the motor symptoms of advanced Parkinson's disease (PD). Although this therapy has been widely applied, the mechanisms of action underlying its effectiveness remain unclear. The goal of this dissertation was to investigate the mechanisms underlying the effectiveness of subthalamic nucleus (STN) DBS by quantifying changes in neuronal activity in the basal ganglia during both effective and ineffective DBS.</p><p>Two different approaches were adopted in this study. The first approach was the unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model. Using this animal model, we developed behavioral tests that were used to quantify the effectiveness of DBS with various frequencies and temporal patterns. These changes in behavior were correlated with changes in the activity of multiple single neurons recorded from the globus pallidus externa (GPe) and substantia nigra reticulata (SNr). The second approach was a computational model of the basal ganglia-thalamic network. The output of the model was quantified using an error index that measured the fidelity of transmission of information in model thalamic neurons. We quantified changes in error index as well as neural activity within the model GPe and globus pallidus interna (GPi, equivalent to the SNr in rats).</p><p>Using these two approaches, we first quantified the effects of different frequencies of STN DBS. High frequency stimulation was more effective than low frequency stimulation at reducing motor symptoms in the rat, as well as improving the error index of the computational model. In both the GPe and SNr/GPi from the rat and computational model, pathological low frequency oscillations were present. These low frequency oscillations were suppressed during effective high frequency DBS but not low frequency DBS. Furthermore, effective high frequency DBS generated oscillations in neural firing at the same frequency of stimulation. Such changes in neuronal firing patterns were independent of changes in firing rates.</p><p>Next, we investigated the effects of different temporal patterns of high frequency stimulation. Stimulus trains with the same number of pulses per second but different coefficients of variation (CVs) were delivered to the PD rat as well as PD model. 130 Hz regular DBS was more effective than irregular DBS at alleviating motor symptoms of the PD rat and improving error index in the computational model. However, the most irregular stimulation pattern was still more effective than low frequency stimulation. All patterns of DBS were able to suppress the pathological low frequency oscillations present in the GPe and SNr/GPi, but only 130 Hz stimulation increased high frequency 130 Hz oscillations. Therefore, the suppression of pathological low frequency neural oscillations was necessary but not sufficient to produce the maximum benefits of DBS.</p><p>The effectiveness of regular high frequency STN DBS was associated with a decrease in pathological low frequency oscillations and an increase in high frequency oscillations. These observations indicate that the effects of DBS are not only mediated by changes in firing rate, but also involve changes in neuronal firing patterns within the basal ganglia. The shift in neural oscillations from low to high frequency during effective STN DBS suggests that high frequency regular DBS suppresses pathological firing by entraining neurons to the stimulus pulses. </p><p>Therefore, results from this dissertation support the hypothesis that the underlying mechanism of effective DBS is its ability to entrain and regularize neuronal firing, therefore disrupting pathological patterns of activity within the basal ganglia.</p> / Dissertation

Quantification of blood fraction (fblood), blood oxygenation (S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-2.gif?v=1&amp;t=h70man4a&amp;s=4a6d004ec608a2a6ec8e8597f73bdb6be30286e8" />), melanin, lipofuscin and oxidised and reduced Cytochrome aa 3 and c was done from diffuse reflectance spectra captured in cortex, white matter, globus pallidus internus (GPi) and subthalamus during stereotactic implantations of 29 deep brain stimulation (DBS) electrodes with the aim of investigating whether the chromophores can give physiological information about the targets for DBS. Double-sided Mann-Whitney U -tests showed more lipofuscin in GPi compared to white matter and subthalamus (p &lt; 0.05). Compared to the other structures, fbloodwas significantly higher in cortex (p &lt; 0.05) and S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-4.gif?v=1&amp;t=h70man4c&amp;s=855c70105e88a292de25618487573dfc7d30e08a" /> lower in GPi (p &lt; 0.05). Median values and range for fblood were 1.0 [0.2–6.0]% in the cortex, 0.3 [0.1–8.2]% in white matter, 0.2 [0.1–0.8]% in the GPi and 0.2 [0.1–11.7]% in the subthalamus. Corresponding values for S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-6.gif?v=1&amp;t=h70man4e&amp;s=151ec25bee7270bcfc2292e70d6f4aea18348dbc" /> was 20 [0–81]% in the cortex, 29 [0–78]% in white matter, 0 [0–0]% in the GPi and 0 [0–92]% in the subthalamus. In conclusion, the measurements indicate very low oxygenation and blood volume for DBS patients, especially in the GPi. It would be of great interest to investigate whether this is due to the disease, the normal situation or an artefact of doing invasive measurements.

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