巴金森氏症（Parkinson's disease，PD）是一種常見的退化性神經疾病，巴金森氏模式大鼠的運動皮質中有兩種不正常信號。第一為運動皮質的區域電場出現了Beta頻帶的共振，先前有研究說明其與運動缺陷的關係。我們發現到以6-OHDA誘導的大鼠其Beta震盪並不是立即形成的。而是部分多巴胺神經元失去功能後神經迴路漸漸改變而造成的，震盪的能量隨著時間而漸漸提高，最後在六周後會達到尖峰值。有趣的是給予Beta震盪達尖峰值之大鼠深層腦刺激於STN後，Beta震盪能量會降低，大鼠的運動障礙也會消失。而另一種不正常訊號稱為High Voltage Spindle（HVS），HVS發生區域較Beta震盪廣泛，很多腦區都會出現此一訊號，這種訊號通常發生於大鼠發呆時。在巴金森氏模式大鼠中出現率及強度都遠遠大於正常老鼠。
在本實驗中，我們首先以Beta震盪生成模式為指標。餵食稱為「精神益生菌」的PS128，由於此益生菌有抗發炎及調控腦內多巴胺濃度以改善憂鬱的功效，因此我們根據此背景探究其對6-OHDA誘導半巴金森氏鼠是否能改善其症狀。在不同時間點開始持續餵食PS128的條件下，我們發現PS128有部分改善誘導後Beta震盪已達顛峰之老鼠震盪能量。且提早在誘導前餵食的大鼠也可以減緩其Beta震盪的生成。
深層腦刺激雖已是良好且完善的巴金森氏症治療方式，但其仍有改善空間，而閉循環控制就是其一。其不但能節省電力，更能讓刺激的副作用減少。在本實驗中，我們利用了另一種不正常訊號HVS作為回饋信號，開發出了針對HVS偵側並給予刺激的閉循環刺激控制器並進行雙向研究，證明其中的演算法可以準確偵測HVS並給予誘發信號，同時受到閉循環刺激的HVS也能夠被誘發產生的刺激降低其能量。證明我們的控制器的效果。未來我們將會將針對Beta能量的閉循環加入控制器中，使其成為多功能的刺激控制器並縮小其體積以利更方便使用。

Parkinson's disease (PD) is a common neuron degeneration disease. While recording the local field potential (LFP) of primary motor cortex (M1) in hemi-parkinsonian rats, there are two abnormal signals, which are synchronized at 20-45 Hz and 5-13Hz were respectively called beta oscillation and HVS, were observed. We found the power of beta oscillations gradually increase as the time of dopamine depletion. Besides, it will decrease the power of beta oscillation and improve the movement deficits of the hemi-PD rat while the high frequency stimulation were applied into the STN. Interestingly, HVS could be detected from many brains regions of the rat in the idle state and the occurrence frequency of HVS was more frequently in hemi-PD than control rat.
In our study, we utilize the power of beta oscillation as a marker to figure out the effect of PS128, one of the Prochobiotics, on the abnormal synchronization of hemi-parkinsonian rats. Since the functions of anti-inflammatory and regulation of dopamine concentrations in the brain of PS128 had been report, we wonder whether administration of PS128 could also alleviate the abnormal beta oscillation in M1 of hemi-PD rats. Our result indicated that the power of beta oscillation in M1 were decreased after administrating PS128 to 6 weeks post-surgery hemi-PD rat. Moreover, the formation and the power of beta oscillation of M1 will be postponed and decrease after administrating PS128 before the surgery of 6-OHDA injection.
Closed-loop controller which can save the power consumption and reduce side effects of traditional DBS is one of another options to improve traditional DBS. In another part of this study, we used a closed-loop controller which was made by our team to detect signals of HVS from M1 as triggers to deliver output signals into the STN and by mean of this method to achieve a closed-loop stimulation model. Our result show that the controller adopt the algorithm designed by our team to accurately detect HVS and send out a trigger signal by using. Additionally, the occurrence frequency and the power of HVS recorded from M1 of hemi-PD rat were actually suppressed by the stimuli were delivered into STN immediately.

第1章 緒論……………………………….…………………………1
第2章 實驗目的…………………………………….………………8
第3章 材料與方法……………………………….…………………9
3.1. 實驗材料………………………………………………….……………9
3.1.1. 實驗動物……………………………………….……………9
3.1.2. 實驗藥品……………………………………….……………9
3.1.3. 實驗儀器………………………………………….…………10
3.2. 手術及分析實驗方法…………………………………………….……10
3.2.1. 巴金森氏症動物模式建立…………………………….……10
1. 誘導單側巴金森氏症大鼠模式…………………….………11
2. 旋轉行為測試……………………………………….………11
3.2.2. 電極植入……………………………………………….……11
1. 利用立體定位植入記錄電極……………………….………11
2. 利用細胞外電生理訊號記錄方法定位STN……………....12
3. 利用組織學方法判斷電極位置……………………….……13
4. 刺激與記錄電極…………………………………….………13
3.2.3. 刺激、紀錄方法及數據分析……………………….………13
1. 刺激與記錄方法……………………………………….……13
2. 譜密度（Power spectral density）分析……………….……15
3. 快速傅立葉轉換分析（Fast Fourier Transform, FFT）...…15
4. 時頻分析……………………………………………….……18
3.2.4. 免疫染色…………………………………………….………19
1. 大鼠犧牲及灌流取腦…………………………….…………19
2. 冷凍切片…………………………………………….………19
3.2.5. 量化及統計………………………………………….………20
1. 貝塔能量的計算…………………………………….………20
2. HVS能量的計算……………………………………………21
3. 貝塔及HVS峰值頻率的計算………………..……….……21
3.3. 不正常腦波的生成與刺激降低Beta震盪實驗方法...………………21
3.3.1. 實驗動物準備………………………………………………21
3.3.2. 刺激及記錄方法……………………………………………22
3.4. 精神益生菌實驗方法……………………………….…………22
3.4.1. 精神益生菌實驗的老鼠準備………………………………22
3.4.2. 精神益生菌實驗餵食與紀錄………………………………23
3.5. 閉循環控制器（closed-loop controller）刺激HVS實驗方法.........24
3.5.1. 實驗老鼠準備……………….………………………...……24
3.5.2. 閉循環刺激實驗方法………………………………………24
第4章 實驗結果……………………………………………………26
4.1. Beta震盪的發生及受到刺激下降之模式建立實驗結果…...………26
4.1.1. 巴金森氏症動物模式的誘導與判定………………………26
4.1.2. 不同腦區Beta頻帶共振訊號的強度及峰值頻率的變化…27
4.1.3. 以133Hz刺激STN會降低Beta震盪訊號能量與頻率…27
4.2. 精神益生菌實驗結果……………………………………………...….27
4.2.1. PS128 對誘導成熟大鼠之Beta震盪能量有抑制效果......28
4.2.2. PS128早期投藥能夠提前抑制Beta震盪能量………..….28
4.2.3. 誘導前兩周餵食可以有效控制Beta震盪的生成……...…29
4.3. 閉循環控制器實驗結果…………………………………………...….29
4.3.1. HVS平均時間分布……………………………………...…30
4.3.2. 閉循環系統能準確的偵測HVS的出現並給予誘發….….30
4.3.3. Closed-loop刺激能有效地使HVS出現時間變短…….…30
4.3.4. 刺激強度的不同影響HVS能量的抑制程度………….….31
4.3.5. 改變刺激開始時間點可以控制HVS被抑制的時間……..32
第5章 結果討論………………………………………………...….33
5.1. Beta 震盪在巴金森氏模式鼠中的生成與其影響………...……...…33
5.1.1. 大鼠的行為及狀態能改變Beta震盪的峰值頻率與能量...33
5.1.2. 在對側無誘導腦半球運動皮質也會有beta能量聚集……33
5.2. PS128對於巴金森氏模式大鼠的效果….………………………...…33
5.3. 閉循環系統對於HVS刺激的效果及效率………………………..…34
5.4. 未來展望………………………………………………………………35
第6章 圖表…..……………………………………………..………37
第7章 參考文獻……………………………………………………48

1 Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354-359, doi:10.1126/science.1167093 (2009).
2 He, Z. et al. High frequency stimulation of subthalamic nucleus results in behavioral recovery by increasing striatal dopamine release in 6-hydroxydopamine lesioned rat. Behav Brain Res 263, 108-114, doi:10.1016/j.bbr.2014.01.014 (2014).
3 Bjorklund, A. & Dunnett, S. B. Dopamine neuron systems in the brain: an update. Trends Neurosci 30, 194-202, doi:10.1016/j.tins.2007.03.006 (2007).
4 Kim, S. W., Jang, Y. J., Chang, J. W. & Hwang, O. Degeneration of the nigrostriatal pathway and induction of motor deficit by tetrahydrobiopterin: an in vivo model relevant to Parkinson's disease. Neurobiol Dis 13, 167-176 (2003).
5 Jankovic, J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79, 368-376, doi:10.1136/jnnp.2007.131045 (2008).
6 Olanow, C. W. & Tatton, W. G. Etiology and pathogenesis of Parkinson's disease. Annu Rev Neurosci 22, 123-144, doi:10.1146/annurev.neuro.22.1.123 (1999).
7 Hauser, R. A., McDermott, M. P. & Messing, S. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch Neurol 63, 1756-1760, doi:10.1001/archneur.63.12.1756 (2006).
8 Finlay, C. J., Duty, S. & Vernon, A. C. Brain morphometry and the neurobiology of levodopa-induced dyskinesias: current knowledge and future potential for translational pre-clinical neuroimaging studies. Front Neurol 5, 95, doi:10.3389/fneur.2014.00095 (2014).
9 Iravani, M. M. & Jenner, P. Mechanisms underlying the onset and expression of levodopa-induced dyskinesia and their pharmacological manipulation. J Neural Transm (Vienna) 118, 1661-1690, doi:10.1007/s00702-011-0698-2 (2011).
10 Benabid, A. L., Chabardes, S., Mitrofanis, J. & Pollak, P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease. Lancet Neurol 8, 67-81, doi:10.1016/S1474-4422(08)70291-6 (2009).
11 Deuschl, G. et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 355, 896-908, doi:10.1056/NEJMoa060281 (2006).
12 Okun, M. S. & Foote, K. D. Parkinson's disease DBS: what, when, who and why? The time has come to tailor DBS targets. Expert Rev Neurother 10, 1847-1857 (2010).
13 Benabid, A. L. Deep brain stimulation for Parkinson's disease. Curr Opin Neurobiol 13, 696-706 (2003).
14 Rezai, A. R. et al. Surgery for movement disorders. Neurosurgery 62 Suppl 2, 809-838; discussion 838-809, doi:10.1227/01.neu.0000316285.52865.53 (2008).
15 Shehab, S., D'Souza, C., Ljubisavljevic, M. & Redgrave, P. High-frequency electrical stimulation of the subthalamic nucleus excites target structures in a model using c-fos immunohistochemistry. Neuroscience 270, 212-225, doi:10.1016/j.neuroscience.2014.04.016 (2014).
16 Limousin, P. et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 339, 1105-1111, doi:10.1056/NEJM199810153391603 (1998).
17 Okun, M. S. et al. Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol 65, 586-595, doi:10.1002/ana.21596 (2009).
18 Groenewegen, H. J. The basal ganglia and motor control. Neural Plast 10, 107-120, doi:10.1155/NP.2003.107 (2003).
19 Chakravarthy, V. S., Joseph, D. & Bapi, R. S. What do the basal ganglia do? A modeling perspective. Biol Cybern 103, 237-253, doi:10.1007/s00422-010-0401-y (2010).
20 Hamani, C., Saint-Cyr, J. A., Fraser, J., Kaplitt, M. & Lozano, A. M. The subthalamic nucleus in the context of movement disorders. Brain 127, 4-20, doi:10.1093/brain/awh029 (2004).
21 Qiu, M. H., Chen, M. C., Huang, Z. L. & Lu, J. Neuronal activity (c-Fos) delineating interactions of the cerebral cortex and basal ganglia. Front Neuroanat 8, 13, doi:10.3389/fnana.2014.00013 (2014).
22 Nambu, A., Takada, M., Inase, M. & Tokuno, H. Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area. J Neurosci 16, 2671-2683 (1996).
23 Nambu, A. et al. Excitatory cortical inputs to pallidal neurons via the subthalamic nucleus in the monkey. J Neurophysiol 84, 289-300 (2000).
24 Nambu, A., Tokuno, H. & Takada, M. Functional significance of the cortico-subthalamo-pallidal 'hyperdirect' pathway. Neurosci Res 43, 111-117 (2002).
25 Bosch, C., Mailly, P., Degos, B., Deniau, J. M. & Venance, L. Preservation of the hyperdirect pathway of basal ganglia in a rodent brain slice. Neuroscience 215, 31-41, doi:10.1016/j.neuroscience.2012.04.033 (2012).
26 Williams, D. et al. Dopamine-dependent changes in the functional connectivity between basal ganglia and cerebral cortex in humans. Brain 125, 1558-1569 (2002).
27 Fogelson, N. et al. Different functional loops between cerebral cortex and the subthalmic area in Parkinson's disease. Cereb Cortex 16, 64-75, doi:10.1093/cercor/bhi084 (2006).
28 Gaynor, L. M. et al. Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans. Eur J Neurosci 28, 1686-1695, doi:10.1111/j.1460-9568.2008.06363.x (2008).
29 Kuhn, A. A. et al. High-frequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance. J Neurosci 28, 6165-6173, doi:10.1523/JNEUROSCI.0282-08.2008 (2008).
30 de Solages, C., Hill, B. C., Koop, M. M., Henderson, J. M. & Bronte-Stewart, H. Bilateral symmetry and coherence of subthalamic nuclei beta band activity in Parkinson's disease. Exp Neurol 221, 260-266, doi:10.1016/j.expneurol.2009.11.012 (2010).
31 Giannicola, G. et al. The effects of levodopa and ongoing deep brain stimulation on subthalamic beta oscillations in Parkinson's disease. Exp Neurol 226, 120-127, doi:10.1016/j.expneurol.2010.08.011 (2010).
32 Litvak, V. et al. Movement-related changes in local and long-range synchronization in Parkinson's disease revealed by simultaneous magnetoencephalography and intracranial recordings. J Neurosci 32, 10541-10553, doi:10.1523/JNEUROSCI.0767-12.2012 (2012).
33 Litvak, V. et al. Resting oscillatory cortico-subthalamic connectivity in patients with Parkinson's disease. Brain 134, 359-374, doi:10.1093/brain/awq332 (2011).
34 Hirschmann, J. et al. Differential modulation of STN-cortical and cortico-muscular coherence by movement and levodopa in Parkinson's disease. Neuroimage 68, 203-213, doi:10.1016/j.neuroimage.2012.11.036 (2013).
35 Kato, K. et al. Bilateral coherence between motor cortices and subthalamic nuclei in patients with Parkinson's disease. Clin Neurophysiol 126, 1941-1950, doi:10.1016/j.clinph.2014.12.007 (2015).
36 Quinn, E. J. et al. Beta oscillations in freely moving Parkinson's subjects are attenuated during deep brain stimulation. Mov Disord 30, 1750-1758, doi:10.1002/mds.26376 (2015).
37 Weiss, D. et al. Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease. Brain 138, 679-693, doi:10.1093/brain/awu380 (2015).
38 Oswal, A. et al. Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson's disease. Brain 139, 1482-1496, doi:10.1093/brain/aww048 (2016).
39 Marsden, J. F., Limousin-Dowsey, P., Ashby, P., Pollak, P. & Brown, P. Subthalamic nucleus, sensorimotor cortex and muscle interrelationships in Parkinson's disease. Brain 124, 378-388 (2001).
40 Cassidy, M. et al. Movement-related changes in synchronization in the human basal ganglia. Brain 125, 1235-1246 (2002).
41 Lalo, E. et al. Patterns of bidirectional communication between cortex and basal ganglia during movement in patients with Parkinson disease. J Neurosci 28, 3008-3016, doi:10.1523/JNEUROSCI.5295-07.2008 (2008).
42 Garcia, L., D'Alessandro, G., Bioulac, B. & Hammond, C. High-frequency stimulation in Parkinson's disease: more or less? Trends Neurosci 28, 209-216, doi:10.1016/j.tins.2005.02.005 (2005).
43 Quiroga-Varela, A., Walters, J. R., Brazhnik, E., Marin, C. & Obeso, J. A. What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity. Neurobiol Dis 58, 242-248, doi:10.1016/j.nbd.2013.05.010 (2013).
44 Weinberger, M. et al. Beta oscillatory activity in the subthalamic nucleus and its relation to dopaminergic response in Parkinson's disease. J Neurophysiol 96, 3248-3256, doi:10.1152/jn.00697.2006 (2006).
45 Kuhn, A. A. et al. Modulation of beta oscillations in the subthalamic area during motor imagery in Parkinson's disease. Brain 129, 695-706, doi:10.1093/brain/awh715 (2006).
46 Kuhn, A. A. et al. Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity. Exp Neurol 215, 380-387, doi:10.1016/j.expneurol.2008.11.008 (2009).
47 Ray, N. J. et al. Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation. Exp Neurol 213, 108-113, doi:10.1016/j.expneurol.2008.05.008 (2008).
48 Eusebio, A. et al. Effects of low-frequency stimulation of the subthalamic nucleus on movement in Parkinson's disease. Exp Neurol 209, 125-130, doi:10.1016/j.expneurol.2007.09.007 (2008).
49 Chen, C. C. et al. Stimulation of the subthalamic region at 20 Hz slows the development of grip force in Parkinson's disease. Exp Neurol 231, 91-96, doi:10.1016/j.expneurol.2011.05.018 (2011).
50 Brown, P. Abnormal oscillatory synchronisation in the motor system leads to impaired movement. Curr Opin Neurobiol 17, 656-664, doi:10.1016/j.conb.2007.12.001 (2007).
51 Oswal, A., Brown, P. & Litvak, V. Synchronized neural oscillations and the pathophysiology of Parkinson's disease. Curr Opin Neurol 26, 662-670, doi:10.1097/WCO.0000000000000034 (2013).
52 Stein, E. & Bar-Gad, I. beta oscillations in the cortico-basal ganglia loop during parkinsonism. Exp Neurol 245, 52-59, doi:10.1016/j.expneurol.2012.07.023 (2013).
53 Little, S. et al. Adaptive deep brain stimulation in advanced Parkinson disease. Ann Neurol 74, 449-457, doi:10.1002/ana.23951 (2013).
54 Little, S. et al. Bilateral adaptive deep brain stimulation is effective in Parkinson's disease. J Neurol Neurosurg Psychiatry 87, 717-721, doi:10.1136/jnnp-2015-310972 (2016).
55 Priori, A., Foffani, G., Rossi, L. & Marceglia, S. Adaptive deep brain stimulation (aDBS) controlled by local field potential oscillations. Exp Neurol 245, 77-86, doi:10.1016/j.expneurol.2012.09.013 (2013).
56 Costa, R. M. et al. Rapid alterations in corticostriatal ensemble coordination during acute dopamine-dependent motor dysfunction. Neuron 52, 359-369, doi:10.1016/j.neuron.2006.07.030 (2006).
57 Dejean, C. et al. Power fluctuations in beta and gamma frequencies in rat globus pallidus: association with specific phases of slow oscillations and differential modulation by dopamine D1 and D2 receptors. J Neurosci 31, 6098-6107, doi:10.1523/JNEUROSCI.3311-09.2011 (2011).
58 Degos, B. et al. Neuroleptic-induced catalepsy: electrophysiological mechanisms of functional recovery induced by high-frequency stimulation of the subthalamic nucleus. J Neurosci 25, 7687-7696, doi:10.1523/JNEUROSCI.1056-05.2005 (2005).
59 Mallet, N. et al. Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex. J Neurosci 28, 4795-4806, doi:10.1523/JNEUROSCI.0123-08.2008 (2008).
60 Brazhnik, E., Novikov, N., McCoy, A. J., Cruz, A. V. & Walters, J. R. Functional correlates of exaggerated oscillatory activity in basal ganglia output in hemiparkinsonian rats. Exp Neurol 261, 563-577, doi:10.1016/j.expneurol.2014.07.010 (2014).
61 Delaville, C., McCoy, A. J., Gerber, C. M., Cruz, A. V. & Walters, J. R. Subthalamic nucleus activity in the awake hemiparkinsonian rat: relationships with motor and cognitive networks. J Neurosci 35, 6918-6930, doi:10.1523/JNEUROSCI.0587-15.2015 (2015).
62 Sacchettini, J. C. & Kelly, J. W. Therapeutic strategies for human amyloid diseases. Nat Rev Drug Discov 1, 267-275, doi:10.1038/nrd769 (2002).
63 Brettschneider, J., Del Tredici, K., Lee, V. M. & Trojanowski, J. Q. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci 16, 109-120, doi:10.1038/nrn3887 (2015).
64 Jenner, P. Molecular mechanisms of L-DOPA-induced dyskinesia. Nat Rev Neurosci 9, 665-677, doi:10.1038/nrn2471 (2008).
65 Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18, 965-977, doi:10.1038/nn.4030 (2015).
66 Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670, doi:10.1126/science.aad8670 (2016).
67 Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16, 341-352, doi:10.1038/nri.2016.42 (2016).
68 Devos, D. et al. Colonic inflammation in Parkinson's disease. Neurobiol Dis 50, 42-48, doi:10.1016/j.nbd.2012.09.007 (2013).
69 Braak, H., Rub, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna) 110, 517-536, doi:10.1007/s00702-002-0808-2 (2003).
70 Verbaan, D. et al. Patient-reported autonomic symptoms in Parkinson disease. Neurology 69, 333-341, doi:10.1212/01.wnl.0000266593.50534.e8 (2007).
71 Del Tredici, K. & Braak, H. A not entirely benign procedure: progression of Parkinson's disease. Acta Neuropathol 115, 379-384, doi:10.1007/s00401-008-0355-5 (2008).
72 Sampson, T. R. et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell 167, 1469-1480 e1412, doi:10.1016/j.cell.2016.11.018 (2016).
73 Zhou, L. & Foster, J. A. Psychobiotics and the gut-brain axis: in the pursuit of happiness. Neuropsychiatr Dis Treat 11, 715-723, doi:10.2147/NDT.S61997 (2015).
74 Dinan, T. G., Stanton, C. & Cryan, J. F. Psychobiotics: a novel class of psychotropic. Biol Psychiatry 74, 720-726, doi:10.1016/j.biopsych.2013.05.001 (2013).
75 Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451-1463, doi:10.1016/j.cell.2013.11.024 (2013).
76 Liu, Y. W. et al. Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naive adult mice. Brain Res 1631, 1-12, doi:10.1016/j.brainres.2015.11.018 (2016).
77 Liu, W. H. et al. Genome architecture of Lactobacillus plantarum PS128, a probiotic strain with potential immunomodulatory activity. Gut Pathog 7, 22, doi:10.1186/s13099-015-0068-y (2015).
78 Hariz, M. Twenty-five years of deep brain stimulation: celebrations and apprehensions. Mov Disord 27, 930-933, doi:10.1002/mds.25007 (2012).
79 Moro, E. et al. The impact on Parkinson's disease of electrical parameter settings in STN stimulation. Neurology 59, 706-713 (2002).
80 Reich, M. M. et al. Short pulse width widens the therapeutic window of subthalamic neurostimulation. Ann Clin Transl Neurol 2, 427-432, doi:10.1002/acn3.168 (2015).
81 Timmermann, L. et al. Multiple-source current steering in subthalamic nucleus deep brain stimulation for Parkinson's disease (the VANTAGE study): a non-randomised, prospective, multicentre, open-label study. Lancet Neurol 14, 693-701, doi:10.1016/S1474-4422(15)00087-3 (2015).
82 Abosch, A. et al. Long-term recordings of local field potentials from implanted deep brain stimulation electrodes. Neurosurgery 71, 804-814, doi:10.1227/NEU.0b013e3182676b91 (2012).
83 Little, S. & Brown, P. What brain signals are suitable for feedback control of deep brain stimulation in Parkinson's disease? Ann N Y Acad Sci 1265, 9-24, doi:10.1111/j.1749-6632.2012.06650.x (2012).
84 Rosa, M. et al. Adaptive deep brain stimulation in a freely moving Parkinsonian patient. Mov Disord 30, 1003-1005, doi:10.1002/mds.26241 (2015).
85 Little, S. et al. Adaptive deep brain stimulation for Parkinson's disease demonstrates reduced speech side effects compared to conventional stimulation in the acute setting. J Neurol Neurosurg Psychiatry 87, 1388-1389, doi:10.1136/jnnp-2016-313518 (2016).
86 Dejean, C. et al. Evolution of the dynamic properties of the cortex-basal ganglia network after dopaminergic depletion in rats. Neurobiol Dis 46, 402-413, doi:10.1016/j.nbd.2012.02.004 (2012).
87 Dejean, C., Gross, C. E., Bioulac, B. & Boraud, T. Synchronous high-voltage spindles in the cortex-basal ganglia network of awake and unrestrained rats. Eur J Neurosci 25, 772-784, doi:10.1111/j.1460-9568.2007.05305.x (2007).
88 Buzsaki, G. & Silva, F. L. High frequency oscillations in the intact brain. Prog Neurobiol 98, 241-249, doi:10.1016/j.pneurobio.2012.02.004 (2012).
89 Ge, S. et al. Dopamine depletion increases the power and coherence of high-voltage spindles in the globus pallidus and motor cortex of freely moving rats. Brain Res 1465, 66-79, doi:10.1016/j.brainres.2012.05.002 (2012).
90 Magill, P. J. et al. Coherent spike-wave oscillations in the cortex and subthalamic nucleus of the freely moving rat. Neuroscience 132, 659-664, doi:10.1016/j.neuroscience.2005.01.006 (2005).
91 Dejean, C., Gross, C. E., Bioulac, B. & Boraud, T. Dynamic changes in the cortex-basal ganglia network after dopamine depletion in the rat. J Neurophysiol 100, 385-396, doi:10.1152/jn.90466.2008 (2008).
92 Li, Q. et al. Therapeutic deep brain stimulation in Parkinsonian rats directly influences motor cortex. Neuron 76, 1030-1041, doi:10.1016/j.neuron.2012.09.032 (2012).
93 Yang, C. et al. High frequency stimulation of the STN restored the abnormal high-voltage spindles in the cortex and the globus pallidus of 6-OHDA lesioned rats. Neurosci Lett 595, 122-127, doi:10.1016/j.neulet.2015.04.011 (2015).
94 Shinko, A. et al. Spinal cord stimulation exerts neuroprotective effects against experimental Parkinson's disease. PLoS One 9, e101468, doi:10.1371/journal.pone.0101468 (2014).
95 Johnson, S. G. & Frigo, M. A modified split-radix FFT with fewer arithmetic operations. Ieee T Signal Proces 55, 111-119, doi:10.1109/Tsp.2006.882087 (2007).
96 Frigo, M. & Johnson, S. G. The design and implementation of FFTW3. P Ieee 93, 216-231, doi:10.1109/Jproc.2004.840301 (2005).
97 Sharott, A. et al. Dopamine depletion increases the power and coherence of beta-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat. Eur J Neurosci 21, 1413-1422, doi:10.1111/j.1460-9568.2005.03973.x (2005).
98 Pan, M. K. et al. Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control. J Clin Invest 126, 4516-4526, doi:10.1172/JCI88170 (2016).