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.

<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.

Objective: In patients with Parkinson’s disease (PD), deep brainstimulation of the subthalamic nucleus (STN DBS) is well recognizedin improving limb function, but the outcome on swallowing functionhas rarely been studied. The aim of this work was to evaluate theeffect of STN DBS on pharyngeal swallowing function in patientswith PD using self-estimation and fiberoptic endoscopic evaluation ofswallowing. Methods: Eleven patients (aged 41–72, median 61 years)were evaluated preoperatively and at 6 and 12 months after STN DBSsurgery. All patients were evaluated with self-estimation on a visualanalogue scale, and eight of them with a fiberoptic endoscopicexamination with a predefined swallowing protocol includingRosenbek’s Penetration-Aspiration Scale, Secretion Severity Scale,preswallow spillage, pharyngeal residue, and pharyngeal clearance. Results: The self-assessments of swallowing function revealed asubjective improvement with STN DBS stimulation, whereas the datafrom the swallowing protocol did not show any significant effect ofthe STN DBS treatment itself. The prevalence of aspiration was notaffected by the surgery. Conclusions: The results show thatswallowing function was not negatively affected by STN DBS and therisk of aspiration did not increase. Self-estimation of swallowingfunction showed a subjective improvement due to stimulation / Speech, voice and swallowing outcomes after deep brain stimulation (DBS)

Diffusion tensor imaging (DTI) is a noninvasive MRI technique used to assess white matter (WM) integrity, fiber orientation, and structural connectivity (SC) using water diffusion properties. DTI techniques are rapidly evolving and are now having a dramatic effect on depression research. Major depressive disorder (MDD) is highly prevalent and a leading cause of worldwide disability. Despite decades of research, the neurobiology of MDD remains poorly understood. MDD is increasingly viewed as a disorder of neural circuitry in which a network of brain regions involved in mood regulation is dysfunctional. In an effort to better understand the neurobiology of MDD and develop more effective treatments, much research has focused on delineating the structure of this mood regulation network. Although many studies have focused on the structural connectivity of the mood regulation network, findings using DTI are highly variable, likely due to many technical and analytical limitations. Further, structural connectivity pattern analyses have not been adequately utilized in specific clinical contexts where they would likely have high relevance, e.g., the use of white matter deep brain stimulation (DBS) as an investigational treatment for depression. In this dissertation, we performed a comprehensive analysis of structural WM integrity in a large sample of depressed patients and demonstrated that disruption of WM does not play a major role in the neurobiology of MDD. Using graph theory analysis to assess organization of neural network, we elucidated the importance of the WM network in MDD. As an extension of this WM network analysis, we identified the necessary and sufficient WM tracts (circuit) that mediate the response of subcallosal cingulate cortex DBS treatment for depression; this work showed that such analyses may be useful in prospective target selection. Collectively, these findings contribute to better understanding of depression as a neural network disorder and possibly will improve efficacy of SCC DBS.

Deep brain stimulation (DBS) is currently being investigated as a therapy for treatment-resistant depression, with promising results. However, it is not clear whether or not DBS works via the same mechanisms as those induced by antidepressant medications. Processes currently implicated in antidepressant effects include neuroplastic changes and promotion of neurogenesis. We investigated the effects of chronic treatment with three different classes of antidepressants and DBS on markers of neuroplasticity (brain-derived neurotrophic factor, (BDNF), and phosphorylated cyclic-AMP regulatory element binding protein, (pCREB)) and neurogenesis (Ki-67, bromodeoxyuridine (BrdU) and doublecortin) in the rat hippocampus. No clear treatment effects were seen on BDNF, pCREB and Ki-67 levels. However all treatments caused increased levels of BrdU (range: 46%-96%) and doublecortin (8%-61%), although these effects were statistically significant only for DBS and amitriptyline, respectively. This overall pattern of results may suggest that diverse antidepressant treatments could possibly share common mechanisms involving cell survival and neuronal differentiation. Potentiated effects of DBS on cell survival may underlie its efficacy in treatment-resistant depression.

Deep brain stimulation (DBS) is currently being investigated as a therapy for treatment-resistant depression, with promising results. However, it is not clear whether or not DBS works via the same mechanisms as those induced by antidepressant medications. Processes currently implicated in antidepressant effects include neuroplastic changes and promotion of neurogenesis. We investigated the effects of chronic treatment with three different classes of antidepressants and DBS on markers of neuroplasticity (brain-derived neurotrophic factor, (BDNF), and phosphorylated cyclic-AMP regulatory element binding protein, (pCREB)) and neurogenesis (Ki-67, bromodeoxyuridine (BrdU) and doublecortin) in the rat hippocampus. No clear treatment effects were seen on BDNF, pCREB and Ki-67 levels. However all treatments caused increased levels of BrdU (range: 46%-96%) and doublecortin (8%-61%), although these effects were statistically significant only for DBS and amitriptyline, respectively. This overall pattern of results may suggest that diverse antidepressant treatments could possibly share common mechanisms involving cell survival and neuronal differentiation. Potentiated effects of DBS on cell survival may underlie its efficacy in treatment-resistant depression.

Background: Major depressive disorder is a debilitating psychiatric condition with high rates of treatment resistance that may be associated with working memory (WM) deficits. For treatment resistant depression (TRD) patients, deep brain stimulation (DBS) is emerging as an effective therapeutic option. Objective: To determine if electroencephalography signals recorded during DBS ON and OFF states while performing WM tasks can serve as biomarkers of therapeutic efficacy for DBS in TRD patients. Results: DBS stimulation suppressed frontal gamma oscillations (30–50Hz) during the ON state relative to the OFF state, an effect that was more pronounced with higher WM load. This suppression strongly correlated with depressive symptoms reduction. Conclusion: Suppression of gamma oscillations by DBS is likely mediated by indirect activation of inhibitory circuits in the frontal cortex. It represents a potential treatment biomarker for DBS in TRD and may lead to more tailored treatment parameters that can result in enhanced efficacy.

Background: Major depressive disorder is a debilitating psychiatric condition with high rates of treatment resistance that may be associated with working memory (WM) deficits. For treatment resistant depression (TRD) patients, deep brain stimulation (DBS) is emerging as an effective therapeutic option. Objective: To determine if electroencephalography signals recorded during DBS ON and OFF states while performing WM tasks can serve as biomarkers of therapeutic efficacy for DBS in TRD patients. Results: DBS stimulation suppressed frontal gamma oscillations (30–50Hz) during the ON state relative to the OFF state, an effect that was more pronounced with higher WM load. This suppression strongly correlated with depressive symptoms reduction. Conclusion: Suppression of gamma oscillations by DBS is likely mediated by indirect activation of inhibitory circuits in the frontal cortex. It represents a potential treatment biomarker for DBS in TRD and may lead to more tailored treatment parameters that can result in enhanced efficacy.

Multielectrode arrays may have several advantages compared to the traditional single macroelectrode brain electrical stimulation technique including less tissue damage due to implantation and the ability to deliver several spatio-temporal patterns of stimulation. Prior work on cell cultures has shown that multielectrode arrays are capable of completely stopping seizure-like spontaneous bursting events through a distributed asynchronous multi-site approach. In my studies, I used a similar approach for controlling seizures in a rat model of temporal lobe epilepsy. First, I developed a new method of electroplating in vivo microelectrode arrays for durably improving their impedance. I showed that microelectrode arrays electroplated through the new technique called sonicoplating, required the least amount of voltage in current controlled stimulation studies and also produced the least amplitude and duration of stimulation artifact compared to unplated, DC electroplated or pulse-plated microelectrodes. Second, using c-fos immunohistochemistry, I showed that 16-electrode sonicoplated microelectrode arrays can activate 5.9 times more neurons in the dorsal hippocampus compared to a single macroelectrodes while causing < 77% the tissue damage. Next, through open-loop multisite asynchronous microstimulation, I reduced seizure frequency by ~50% in the rodent model of temporal lobe epilepsy. Preliminary studies aimed at using the same stimulation protocol in closed-loop responsive and predictive seizure control did not stop seizures. Finally, through an internship at Medtronic Neuromodulation, I worked on developing and implementing a rapid algorithm prototyping research tool for closed-loop human deep brain stimulation applications.