{"id":6822,"date":"2026-04-01T12:38:01","date_gmt":"2026-04-01T12:38:01","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/faisal-alosaimi\/"},"modified":"2026-04-01T12:38:08","modified_gmt":"2026-04-01T12:38:08","slug":"faisal-alosaimi","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/faisal-alosaimi\/","title":{"rendered":"Faisal Alosaimi"},"content":{"rendered":"","protected":false},"excerpt":{"rendered":"","protected":false},"author":8,"featured_media":6825,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-6822","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"Monoaminergic neurotransmitter systems underlie therapeutic and side effects of deep brain stimulation","samenvatting":"Er is geen Nederlandse samenvatting beschikbaar. De Engelse samenvatting vind je <a href=\"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/faisal-alosaimi\/\">hier<\/a>.","summary":"Parkinson\u2019s disease (PD) is a neurogenerative disease affecting over ten million people worldwide. PD\nwas first described in 1817 by a British physician named James Parkinson. Its key motor symptoms\ninclude tremors, rigidity, bradykinesia, and postural instability. In addition, PD patients suffer from non-\nmotor symptoms such as cognitive impairments and mood disorders. The disease is caused by the\ndeath of dopamine cells in the substantia nigra pars compacta. The exact cause of this cell death is not\nwell understood. While there is no cure for PD, dopamine replacement therapy can only treat motor\nsymptoms in the early stages but have side effect and fluctuation in medical treatment, especially in\nadvanced stages.\n\nDeep brain stimulation (DBS) is a surgical procedure involving implanting electrodes in specific\nbrain regions to apply an electrical impulse that can improve motor symptoms in PD patients. In the past,\ntraditional surgical approaches were used to treat these conditions. However, they were abandoned\ndue to their irreversible nature and the availability of more effective drug treatments. Advancements\nin neurosurgery have led to improvements in stimulation equipment and neuroimaging techniques,\nmaking targeting brain structures more precise. Furthermore, intraoperative electrophysiology\ntechniques have also improved the targeting of brain regions, particularly the subthalamic nucleus\n(STN). High-frequency stimulation (HFS) of the STN, discovered in 1993, is now a standard treatment for\nPD.\n\nMonoaminergic neurotransmitter systems are essential for regulating various functions of\nthe central nervous system, such as mood, behavior, and movement. The primary monoaminergic\nneurotransmitters involved are dopamine, noradrenaline and serotonin. Dopaminergic neurons primarily\nproject to the basal ganglia, which are involved in movement regulation, while serotonergic neurons\nproject to several brain areas, including the basal ganglia and prefrontal cortex. In addition, noradrenergic\nneurons projects to cortical, subcortical, and spinal structures. Dysregulation of these systems can lead\nto neurological like PD. The cholinergic system may also interact with the monoaminergic systems,\nparticularly in movement regulation. Understanding the involvement of these systems in neurological 9 A\nwill help optimize treatment options to improve patient healthcare.\n\nMonoaminergic neurotransmitters, such as dopamine, noradrenaline and serotonin, play an\nessential role in DBS\u2019s therapeutic and side effects. In\u00a0Chapter 2, the literature review the DBS effects\non the activity of the striatal and mesolimbic dopaminergic systems, locus coeruleus (LC) noradrenergic,\ndorsal raphe nucleus (DRN) serotoninergic system, and the pedunculopontine nucleus (PPN) cholinergic\nsystem. DBS has been shown to improve motor symptoms and increase dopamine release in the\nstriatum. However, it can also cause non-motor side effects such as mood disorders, which might be\nrelated to its impact on the DRN serotonergic and LC noradrenergic systems. Recent research has shown\nthat external stimuli can drive neurotransmitter switching in the mature brain, providing evidence for\n\nADDENDUM\n\nDBS-induced neurotransmitter respecification. Understanding the effects of DBS on the monoaminergic\nsystems is essential for optimizing its benefits and minimizing its side effects.\n\nRecent approaches such as optogenetic, chemogenetic, and transgenic animal lines can address\nthe limitations of detecting real-time transmitter release and neurotransmitter-related changes in\ndistant neural locations. In addition, these approaches make it possible to target specific cell types.\nTherefore, in\u00a0Chapter 3, we have conducted optogenetic experiments to examine the precise effects of\nneuromodulation on neurotransmitter release and evaluate the cumulative and chronic impact of DBS\non local and distant neural components. While using a genetically encoded calcium indicator protein\nusing a viral vector, we could assess the neuronal activity and phenotype of serotonergic neurons in the\nDRN. Our findings suggest that long-term STN-DBS may have a negative impact on the serotonergic\nsystem, specifically by inhibiting the activity of DRN serotonergic neurons, which may contribute to\nmood-related side effects such as depression. The use of a specific cell-type approach using transgenic\nmice allowed for the assessment of the effects of STN-DBS on DRN serotonergic neurons with greater\nspecificity. The observed reduction in calcium signaling in the DRN is consistent with previous studies\nthat have demonstrated the inhibitory effect of STN-DBS on serotonergic neurons in the DRN.\n\nAdditionally, the behavioral despair observed in mice treated with STN-DBS suggests the negative\nimpact of STN-DBS on the serotonergic system. The findings highlight the importance of investigating\nthe long-term effects of DBS on the brain\u2019s neuromodulatory systems, particularly those implicated\nin mood regulation. Post-mortem immunohistochemistry analysis reveals that the STN-DBS may\ncause a change in the phenotype of DRN serotonergic neurons. This is supported by previous studies\nshowing that STN-DBS can lead to changes in neurotransmitter release and the expression of specific\nneurotransmitter-related proteins in various brain regions.\u00a0\n\nNeuroplasticity refers to the ability of the brain to adapt and reorganize in response to\nenvironmental stimuli or experiences. There is increasing evidence that neuroplasticity also occurs with\nDBS, including STN-DBS. As previously mentioned, STN-DBS can affect local neural circuits and distant\nbrain areas, leading to changes in neurotransmitter release and behavioral outcomes. The stimulation-\ninduced changes in neurotransmitter release may cause neuroplastic changes in the target neurons,\nresulting in the respecification of neurotransmitter phenotypes. This may contribute to the long-term\neffects of STN-DBS on both motor and non-motor symptoms in PD.\n\nThere is no direct connection between STN and DRN, and STN-DBS could bypass through other\nrelay nuclei such as lateral habenula and prefrontal cortex. Nevertheless, a novel link between globus\npallidus externus (GPe) and DRN has been discovered. In addition, the known connection of the GPe to\nSTN. As a result, in\u00a0Chapter 4,\u00a0we assessed the effect of GPe on DRN using a chemogentic approach in\nmice treated with STN-DBS. Our findings suggest that the GPe does not directly mediate the effect of\nSTN-DBS on DRN serotonergic neurons. Further studies are needed to investigate the precise pathways\ninvolved in STN-DBS. In\u00a0Chapter 5, our findings suggest that STN-DBS has no significant effect on the\n\nPPN cholinergic system. These findings indicate that STN-DBS may improve gait in PD through other\npathways, including the STN projection and modulation of cortical connectivity.\u00a0\n\nDBS requires invasive surgery and can lead to complications. In\u00a0Chapter 6, we have reviewed\nthe use of nanomaterial for neuromodulation. Novel approaches are being explored, such as using\nmagnetoelectric nanoparticles (MENPs) to deliver DBS wirelessly. MENPs generate an electric field in\nresponse to a magnetic field, which can stimulate the brain without genetic modification. In Chapter 7,\nour findings suggest that magnetoelectric stimulation of the STN may have similar effects as conventional\nSTN-DBS, particularly concerning enhancing locomotion and an increase in the neuronal activity in the\nmotor cortex and paraventricular thalamus. Notably, magnetoelectric stimulation of the STN decreases the\nactivity of the ventral tegmental area (VTA) dopaminergic and DRN serotoninergic neurons, respectively.\nHowever, it\u2019s important to note that magnetoelectric stimulation did not affect neuron activity in the\nPPN cholinergic and SNc dopaminergic neurons. These results suggest that the principal monoaminergic\nneurotransmitter systems may play a role in the mechanisms of magnetoelectric stimulation of the STN.\nThese findings may have implications for developing noninvasive neuromodulation approaches for\ntreating PD. In addition, the increased activity in the PV following magnetoelectric stimulation of the\nSTN may lead to hyperlocomotion due to the relay of information from the subthalamic and brainstem\nregions to the nucleus accumbens and the amygdala, which are associated with cortical areas.\u00a0\n\nThese findings suggest that magnetoelectric stimulation of the STN may modulate dopaminergic\nactivity in the VTA, which could lead to the observed hyper locomotion. The potential involvement of\nGABAergic cells in the VTA in this mechanism warrants further investigation. In addition, it is possible\nthat the lack of observed effects on the nigrostriatal network in na\u00efve animals could be due to\ncompensatory mechanisms within the system. Future studies could investigate the long-term effects\nof magnetoelectric stimulation of the STN on both the mesolimbic and nigrostriatal pathways, as well\nas potential downstream effects on behavior and cognition. Overall, these findings provide insight\ninto the neural mechanisms underlying the therapeutic effects of magnetoelectric stimulation of the\nSTN and could inform the development of new neuromodulatory approaches for PD. In addition,\nmagnetoelectric stimulation of the STN did not significantly impact the activity of cholinergic neurons 9 A\nin the PPN. This is consistent with previous research on conventional STN-DBS, which also suggests\nthat the therapeutic effect of STN-DBS may be related to other pathways, such as the direct projection\nto the cortex and the mesolimbic dopaminergic system, despite a known dopaminergic-cholinergic\nimbalance that exists in axial movement disorder symptoms, especially in PD. However, it appears that\nmagnetoelectric stimulation of the STN did not affect this particular pathway.\n\nNevertheless, this technology is still new and needs more research to optimize it, including designing\na powering device and less invasive delivery routes to the brain. In addition, several challenges must be\naddressed before nanomaterials can be used in clinical applications. It needs to be explored whether\nmultiple MENPs can be used simultaneously. Delivering nanomaterials to the brain requires noninvasive\nmethods that do not damage neural tissue. Moreover, studying the optimal stimulation parameters and\n\nADDENDUM\n\npatterns of MENPs would be essential to optimize their therapeutic effects while minimizing side effects.\nOverall, further research is needed to understand the potential of MENPs technology for PD treatment.\nIn\n, These findings provide valuable insight into the mechanisms of action of STN-DBS and\nits effects on the monoaminergic neurotransmitter system. The role of the serotonergic system in mood\nregulation and its relationship with STN-DBS-induced adverse mood effects highlight the importance of\nmonitoring and managing the serotonergic system in PD patients. The lack of effect on the cholinergic\nsystem suggests that other pathways may be responsible for the therapeutic effects. STN-DBS surgery\nfor PD has overall had a beneficial impact. It must, however, be taken with caution, monitored closely,\nand individually assessed for each patient while considering possible harmful effects. Future studies\nmust fully detail how to enhance this process, reduce the negative impacts of these procedures, and\nuncover the precise neurotransmitters mechanism. 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