Research ArticleMotor Thalamic Deep Brain Stimulation Alters Cortical Activity and Shows Therapeutic Utility for Treatment of Parkinson’s Disease Symptoms in a Rat Model
Introduction
Parkinson’s Disease (PD) affects 1% of people age 60 or older (Tysnes and Storstein, 2017). Males are diagnosed with PD at rates 1.37 to 3.7 times that of females, making male sex the greatest risk factor after aging (Gillies et al., 2014). The two key pathophysiological correlates of PD are expression of protein aggregates known as Lewy bodies containing alpha synuclein and loss of 50–70% of substantia nigra pars compacta (SNc) dopamine (DA) neurons at diagnosis (Chen et al., 2013).
The motor symptoms of PD include bradykinesia, muscle rigidity, resting tremor, postural instability, gait dysfunction and reduced facial expression (Postuma et al., 2015). The non-motor symptoms of PD include mood disorders such as anxiety and depression, sleep disorders, orthostatic hypotension, constipation, hyposmia, fatigue, pain, urinary problems such as urgency and incontinence, sexual dysfunction, hallucinations, and delusions (Stacy, 2011). Related to our study, one fifth of PD patients experience cognitive impairment without dementia (CIND) at diagnosis and an increased likelihood of memory problems (Watson and Leverenz, 2010). These symptoms can progress to dementia and psychosis as the disease affects the cortex (Stacy, 2011). Impaired memory and cognitive decline in PD patients is associated with hippocampal atrophy (reviewed in Krajcovicova et al., 2019) and is more severe in patients with akinetic-rigid than tremor dominant PD (Wojtala et al., 2019). While deep brain stimulation (DBS) has been effective for patients with CIND, DBS is contraindicated for patients with a diagnosis of dementia (Hartmann et al., 2019).
Levodopa (L-DOPA) is a pharmacological replacement for the loss of SNc DA efferents to the basal ganglia (BG) and is the first-line treatment for PD motor symptoms. Levodopa-induced dyskinesia (LID) is experienced by 90% of PD patients after 10 years of treatment with the drug (Ahlskog and Muenter, 2001). These sometimes disabling abnormal movements can make it more difficult to manage drug titration and motor symptoms of PD, and diminish quality of life (Fabbrini et al., 2007). Interestingly, while subthalamic nucleus (STN) DBS allows for a greater reduction in levodopa equivalent dose (LED), globus pallidus pars interna (GPi) DBS produces a more pronounced improvement in dyskinesia than STN DBS (Ryu et al., 2017, Liu et al., 2019). Cognitive and memory decline is observed more frequently in PD patients receiving STN DBS than those receiving GPi DBS or those that did not undergo surgery (Hariz et al., 2008, Williams et al., 2011, Cernera et al., 2019), possibly owing to the associative and limbic connectivity of the STN (Parent and Hazrati, 1995, Temel et al., 2005, Arnold Anteraper et al., 2018). A meta-analysis found the adverse effects of STN DBS on human cognition included mildly significant declines in executive function and in verbal learning and memory, with moderately significant declines in verbal fluency (Parsons et al., 2006). Still, bilateral STN DBS remains the prevailing approach for treatment of PD motor symptoms (Williams et al., 2014).
In our previous study, we explored the efficacy of motor thalamic DBS for the treatment of akinesia, partially based on a report that optogenetic stimulation of the ventral anterior nucleus of the thalamus (VA) improved haloperidol-induced PD akinesia in rats [5]. We found that electrical stimulation at mode settings of 10 Hz, 100 µs. and 100 µA at the VA, ventrolateral (VL) and at the interface between the two (VA|VL) similarly improved forelimb akinesia in a 6-hydroxydopamine (6-OHDA) rat model of PD (Tucker et al., 2019). These three regions were collectively referred to as the VA-VL, due to their similar therapeutic effectiveness (Tucker et al., 2019). In vitro, VA|VL stimulation increased induced action potential frequencies in both VA and VL neurons and caused VL neurons to transition from bursting to single spike action potentials (Tucker et al., 2019). In vivo, VA|VL DBS reduced beta and gamma oscillations in the primary motor cortex (M1) (Tucker et al., 2019). Notably, the impact of VA-VL DBS on spike frequencies in the motor cortices was not explored, which could reveal mechanisms underlying its efficacy. Additionally, the translational viability of VA-VL DBS would be revealed by comparing its therapeutic window and cognitive effects to those of standard STN DBS.
We addressed these unanswered questions here by examining how VA-VL DBS affects average spike frequencies in the primary and secondary (M2) motor cortices of anesthetized hemiparkinsonian rats. We also compared therapeutic windows and onset rate of stimulation-induced dyskinesia in hemiparkinsonian rats, and cognitive effects in sham rats receiving VA-VL DBS to those receiving STN DBS.
Section snippets
Animals
All animal care and use complied with the National Institutes of Health and Albany Medical College (AMC) Institutional Animal Care and Use Committee (IACUC) guidelines. Animals were purchased from Taconic (Germantown, NY, USA) and all procedures were performed during the light phase of the light–dark cycle (7:00 AM to 7:00 PM, lights on). Animals had access to food and water ad libitum. The following described surgeries, behavioral testing and experiments in awake or anesthetized animals are
VA-VL DBS increases activity of pyramidal cells in the motor cortex
Rats underwent the LAT prior to single-unit recordings. PD rats (n = 27) touched 6% (IQR: 0–13) with their left impaired forepaw. This was less than sham rats (n = 9) that touched 45% (IQR: 32.5–51.5) with their left forepaw (Fig. 2B, p < 0.001). TH staining of the lesioned side was reduced 96.4% (IQR: 92.6–99.1) in the SNc and 92.4% (IQR: 89–95.2) in the striatum of PD rats (n = 25, two excluded due to staining quality). This was a greater reduction than the 0.4% (IQR: −2.8 to 1.8) in the SNc
Discussion
In this study, we found that VA-VL DBS increased spike frequencies in M1 and M2 pyramidal cells and interneurons in the M2, but not M1 cortices from anesthetized hemiparkinsonian rats. No change in spiking phenotype was noted with VA-VL DBS in any of the recorded neurons. Also, hemiparkinsonian rats had similar therapeutic windows and onset rates of stimulation-induced dyskinesia during VA-VL and STN DBS. Finally, DBS impaired memory in rats with normal cognitive function to mild cognitive
Declaration of disclosures
Dr. Pilitsis consults for Boston Scientific and Medtronic and has grant support from Boston Scientific, Medtronic, Abbott, Jazz Pharmaceuticals and NIH 1R01CA166379. She is also chief medical advisor for Centauri and has stock equity. Dr. Molho consults for Neurocrine Biosciences, is a promotional speaker for Neurocrine Biosciences and receives grant support from Cure Huntington Disease Initiative/Huntington Study Group, Civitas Therapeutics, Michael J. Fox Foundation/Parkinson Study Group,
Acknowledgements
We would like to thank Hope Soars and the Dinapoli Parkinson's Research Fund for funding this study.
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Equal effort contributed.