This report will review critically the available research on deep brain stimulation and levodopa as a means of treatment for Parkinson’s disease in an attempt to determine why neither of these treatments improves speech. / text

With approximately 7% of the adult population reporting to have taken illicit substances over the course of a year and the chronically relapsing nature of substance use disorders there is a great need for effective forms of treatment and therapies to reduce relapse. Deep brain stimulation (DBS) is a process of neuromodulation where electrodes are implanted in a target region to modulate the electrophysiological activity of the target region. DBS has been postulated as a potential therapy for treatment-refractory addiction, with a great deal of focus on the nucleus accumbens (NAc). Forty male Long Evans rats were implanted with unilateral stimulating electrodes within the right NAc prior to exposure to chronic cocaine self-administration (0.5 mg/kg/infusion). Following self administration, the animals were withdrawn from cocaine and treated with 14 consecutive days of sham, low frequency (LF, 20 Hz) or high frequency (HF, 160 Hz) stimulation sessions (30 min/day). The animals underwent drug seeking tests on days 1, 15 and 30 of the withdrawal phase with context-induced relapse paired with a drug challenge (5 mg/kg i.p). Relapse rates were highest on day 15 after withdrawal, with both LF and HF attenuating cocaine during this drug-seeking test, however this was not the case for tests on days 1 and 30. Motivation to respond for saccharin solution (0.1 %) remained intact following both LF and HF stimulation intake sessions. These results demonstrate that unilateral DBS of the NAc effectively attenuated cocaine-seeking following chronic exposure to stimulation although these beneficial effects appeared to diminish following cessation of daily treatment with stimulation. The results obtained in this experiment provide support for DBS as a potential therapy for patients with treatment-resistant cases of substance use disorders.

Deep brain stimulation (DBS) improves the quality of life for patients suffering from neurological disorders such as Parkinson’s disease and, more recently, psychiatric/cognitive disorders such as depression and addiction. This treatment option involves the implantation of an implantable pulse generator (or neurostimulator) and leads (or electrodes) implanted deep within the human brain. Magnetic resonance imaging (MRI) is a powerful diagnostic tool that offers superior soft tissue contrast and is routinely used in clinics for neuroimaging applications. MRI is advantageous in DBS pre-surgical planning as precise lead placement within the brain is essential for optimal treatment outcomes. DBS patients can also benefit from post-surgery MRI, and studies have shown that DBS patients are more likely to require MRI within 5-10 years post-surgery. However, imaging DBS patients is restricted by substantial safety concerns that arise from localized electric charge accumulation along the implanted device during resonant radiofrequency (RF) excitation, which can potentially lead to tissue heating and bodily damage. With the technological advancement of ultra-high field (UHF) MRI systems and a growing DBS patient population, DBS MRI safety will become increasingly problematic in the future and needs to be addressed. Parallel RF transmission (pTx) is a promising technology that utilizes multiple transmit channels to generate a desired electromagnetic profile during MRI RF excitation. Several proof-of-concept studies successfully demonstrated its efficacy in creating a "safe mode" of imaging that minimizes the localized RF heating effects. However, pTx MRI systems are not easily accessible and are often custom-built and integrated onto existing MRI systems. Consequently, it adds system characterization and verification complexity to the DBS MRI safety problem. System channel count is also an important consideration as implementation costs can be very high, and the impact of system transmit channel count remains unexplored. Furthermore, in practice, DBS patients with motor-related disorders will impact the pTx MRI system’s ability to precisely generate these safe mode electromagnetic profiles. Commercial DBS devices (i.e., the neurostimulator and leads) are manufactured with fixed dimensions, and the caring surgeon typically manages the surgical orientation of the implanted DBS device and leads. Therefore, lead trajectories can vary hospital-to-hospital. As a result, standard phantoms, i.e., the ASTM International Standard, used in safety verification experiments may not be suitable for DBS MRI applications. To advance DBS patient safety in MRI, this thesis studied the implant heating effects of pTx system uncertainty, system channel count, patient motion on a novel pTx MRI research platform and its associated safe mode of imaging. It developed a new anthropomorphic heterogeneous phantom to improve safety verification experiments. / Dissertation / Doctor of Philosophy (PhD)

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<p>Modulation of neural activity with electrical stimulation is a widespread therapy for treating neurological disorders and diseases. Two notable applications that have had striking clinical success are deep brain stimulation (DBS) for the treatment of movement disorders (e.g., Parkinson's disease) and spinal cord stimulation (SCS) for the treatment of chronic low back and limb pain. In these therapies, the battery life of the stimulators is much less than the required duration of treatment, requiring patients to undergo repeated battery replacement surgeries, which are costly and obligate them to incur repeatedly the risks associated with surgery. Further, deviations in lead position of 2-3 mm can preclude some or all potential clinical benefits, and in some cases, generate side-effects by stimulation of non-target regions. Therefore, despite the success of DBS and SCS, their efficiency and ability to activate target neural elements over non-target elements, termed selectivity, are inadequate and need improvement.</p><p>We combined computational models of volume conduction in the brain and spine with cable models of neurons to design novel electrode configurations for efficient and selective electrical stimulation of nervous tissue. We measured the efficiency and selectivity of prototype electrode designs in vitro and in vivo. Stimulation efficiency was increased by increasing electrode area and/or perimeter, but the effect of increasing perimeter was not as pronounced as increasing area. Cylindrical electrodes with aspect (height to diameter) ratios of > 5 were the most efficient for stimulating neural elements oriented perpendicular to the axis of the electrode, whereas electrodes with aspect ratios of < 2 were the most efficient for stimulating parallel neural elements.</p><p>Stimulation selectivity was increased by combining two or more electrodes in multipolar configurations. Asymmetric bipolar configurations were optimal for activating parallel axons over perpendicular axons; arrays of cathodes with short interelectrode spacing were optimal for activating perpendicular axons over parallel axons; anodes displaced from the center of the target region were optimal for selectively activating terminating axons over passing axons; and symmetric tripolar configurations were optimal for activating neural elements based on their proximity to the electrode. The performance of the efficient and selective designs was not be explained solely by differences in their electrical properties, suggesting that field-shaping effects from changing electrode geometry and polarity can be as large as or larger than the effects of decreasing electrode impedance.</p><p>Advancing our understanding of the features of electrode geometry that are important for increasing stimulation efficiency and selectivity facilitates the design of the next generation of stimulation electrodes for the brain and spinal cord. Increased stimulation efficiency will increase the battery life of IPGs, increase the recharge interval of rechargeable IPGs, and potentially reduce stimulator volume. Greater selectivity may improve the success rate of DBS and SCS by mitigating the sensitivity of clinical outcomes to malpositioning of the electrode.</p> / Dissertation

Background Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in Europe. Besides motor dysfunction, PD is characterized by several non-motor and secondary motor features, such as weight change, sialorrhea, constipation and swallowing problems. Of these, swallowing is one of the most critical, as it is associated with aspiration pneumonia and consequently is the comorbidity with the highest mortality rate. Swallowing problems affect four of every five patients with PD, and even mild swallowing problems have notable psychosocial effects for patients and their caregivers. Consequently, it is essential to find treatment strategies for PD that may alleviate symptoms for patients with swallowing problems and their potential consequences. Deep Brain Stimulation (DBS) is a surgical treatment option for PD, which improves overall motor function and quality of life, but its effect on swallowing function is not clear. The purpose of this thesis was to contribute to the understanding of the effect of deep brain stimulation in the subthalamic nucleus (STN DBS) and the caudal zona incerta (cZI DBS) on pharyngeal swallowing function and on swallow-specific quality of life in patients with PD. The specific aims were to assess longitudinally the effect of STN DBS and cZI DBS on swallowing at 6 and 12 months postoperatively, in order to identify possible effects of the DBS on swallowing function. In addition, the effects of cZI DBS on ratings of swallowing-related non-motor and secondary motor features such as body weight changes, sialorrhea and speech problems were to be assessed. Methods Eleven PD patients with STN DBS (Paper I) and seventeen patients with cZI DBS (Paper II-IV) were included in this thesis. All patients were evaluated preoperatively and 6 and 12 months postoperatively. The effect of STN DBS and cZI DBS on swallowing was assessed with Fibreoptic-Endoscopic Evaluation of Swallowing (FEES) according to a predefined protocol including Penetration-Aspiration scale, Secretion Severity scale, preswallow spillage, pharyngeal residue, and pharyngeal clearance. Self-assessments were addressed using a visual analogue scale. The cZI DBS patients also completed the Swallowing Quality of Life (SWAL-QOL) questionnaire. Weight changes measured by Body Mass Index, and specific items from the Unified Parkinson’s Disease Rating Scale were also examined. Nine controls without PD were included in Paper IV, by answering the SWAL-QOL questionnaire. Results No clear effect of DBS on swallowing function or swallow-specific quality of life could be observed. There was no effect of DBS on the occurrence of aspiration, secretion, pharyngeal residue or clearance in the study groups with STN DBS or cZI DBS. Patients with STN DBS reported a subjective improvement in swallowing function with DBS stimulation turned on at 6 and 12 months after surgery. In patients with cZI DBS, the median body mass index was postoperatively increased with 1.1kg/m2 and the median increase in weight were +3.0 kg after 12 months with cZI DBS. The scores from the SWAL-QOL questionnaire were high overall in the group with cZI DBS, and the scores were unaffected by the cZI DBS surgery and stimulation. The SWAL-QOL total score was not significantly different between the PD patients and the controls, but the scores from the ‘burden’ and the ‘symptom’ subscales were worse in PD patients. Conclusions STN DBS or cZI DBS did not have a negative effect on swallowing function or ratings of swallow-specific ‘quality of life’ aspects in this cohort. Patients with STN DBS reported a self-perceived improvement in swallowing function when DBS was turned on. With regard to swallowing, patients with cZI DBS had an overall good quality of life throughout the conduct of the study and their swallow-specific quality of life was not negatively affected by cZI DBS. There seems to be no increased risk for aspiration or penetration due to surgery or stimulation for either the STN DBS or the cZI DBS groups. cZI DBS caused weight gain postoperatively. Since the sample sizes in these cohorts are small, the findings need to be confirmed in larger studies.

The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of midbrain and pons. The PPN in animal models appears topographically organised and functionally related to locomotion and arousal. In Parkinson’s disease, the PPN degenerates and is susceptible to abnormal basal ganglia output. In patients with Parkinson’s disease, low frequency PPN stimulation is proposed to improve gait freezing and postural instability. However, the therapeutic mechanisms, optimal clinical application and precise effects on gait and posture of PPN stimulation are unclear. Here, a topographic arrangement of the PPN was supported by local field potential recordings in parkinsonian patients. In the PPN region, beta oscillations were recorded rostrally and alpha oscillations caudally. Alpha oscillations, consistent with their putative role in allocating attention, correlated with gait performance and attenuated with gait freezing. Thus the caudal PPN subregion may be the most relevant target for gait disorders. Accordingly, an unblinded clinical study suggested that stimulation of the caudal PPN subregion was beneficial for gait freezing, postural instability and falls. In a double-blinded study using spatiotemporal gait analysis, caudal PPN stimulation reduced triggered gait freezing, with bilateral stimulation more effective than unilateral. However, akinesia including akinetic gait did not improve with PPN stimulation. Accordingly, dopaminergic medication requirements did not change. Mechanisms underlying gait freezing and PPN stimulation were explored with reaction time experiments. Parkinsonian patients with severe gait freezing and postural instability demonstrated a ‘block’ to pre-programmed movement. This was evidenced by prolonged simple reaction times and the absence of ‘StartReact’, whereby pre-prepared responses are normally accelerated by loud acoustic stimuli. PPN stimulation improved simple reaction time and restored Startreact. The relief of this ‘motor block’ with PPN stimulation may therefore explain the associated improvement in gait freezing and postural instability, as these tend to occur in circumstances requiring triggered, pre-prepared adjustments.

Parkinson's disease (PD) is characterized by debilitating impairments in motor control arising from pathophysiological alterations in basal ganglia circuitry and function. In this research thesis two main approaches, namely electrical recording and stimulation, are combined in order to better understand motor performance in Parkinson's disease and ways it might be improved. Three main types of motor behaviors are studied: discrete ballistic movement, repetitive movement, and motor adaptation. <ul><li>First, deep brain stimulation (DBS) of the subthalamic nucleus (STN) was shown to improve the velocity of discrete, ballistic movements in PD. The neural correlates of ballistic movements were then studied by recording from the STN of PD patients, revealing onset of beta-range desynchronization prior to, and gamma-range frequency synchronization during, performance of fast arm reaches. To determine a causal role for these oscillatory frequencies in motor behavior, the motor cortex of healthy humans was stimulated at either beta or gamma frequency during a 'go/no-go' grip force task. Beta stimulation resulted in slower force generation on 'go' trials but enhanced inhibition during 'no-go' trials, whereas gamma stimulation resulted in faster force generation on 'go' trials.</li> <li>Second, STN DBS resulted in improved repetitive tapping performance in PD patients through a reduction in variability. Recordings from the STN demonstrated that repetitive movement was accompanied by a substantial and persistent suppression of beta oscillatory activity.</li> <li>Third, Parkinson's patients were tested on a motor adaptation task, revealing intact learning but impaired retention of a visuomotor rotation. Application of direct current stimulation of the motor cortex resulted in enhanced adaptation during both learning and retention in PD patients and healthy controls.</li> <li>These results causally implicate the basal ganglia and oscillatory activity in motor control, provide insight into the neuronal mechanisms of motor performance and adaptation, and demonstrate promising new avenues for enhancing motor control in Parkinson's disease.</li></ul>

The subthalamic nucleus (STN), which is the most common target for deep brain stimulation for Parkinson's disease, is known to be crucially involved in motor control. Recent appreciation of the potential non-motor side effects of STN deep brain stimulation, however, has led to speculation that the importance of this nucleus may also relate to processes involved in decision- making, particularly during high conflict scenarios. This thesis concerns itself with investigating the STN's role in action selection during conflict. I begin by recording local field potentials directly from the STN of Parkinson's disease patients while they perform a flanker task that has been shown to elicit theta (4-8 Hz) band activity in areas of the prefrontal cortex involved in cognitive control. I report that like the prefrontal cortex, the STN demonstrates elevated theta activity during conflict. I then test whether STN theta activity is related to that of the prefrontal cortex by recording from both sites simultaneously while patients perform a novel task that temporally separates conflict from stimulus onset or movement. This reveals that theta activity indeed becomes synchronized during conflict, with cortical oscillations driving those of the STN. Thirdly, I investigate how STN oscillations may affect firing rate dynamics by intra-operatively recording local field potentials and single unit activity from patients performing the flanker task. I report that both theta and beta (15-30 Hz) oscillations entrain STN neurons, but only during conflict. Finally, I record cortical and STN activity while a fourth group of patients performs the flanker task. This experiment confirms that cortico-STN theta synchrony is elevated during conflict and may also relate to across-trial adaptations to conflict and errors. Taken together these studies shed light on the mechanisms by which cortical structures may influence the STN during conflict and why STN deep brain stimulation may result in impulsivity.

avitsir@ccf.org / Hypertension is common in deep brain stimulator (DBS) placement predisposing to intracranial hemorrhage. This retrospective review evaluates factors predicting incremental antihypertensive use intraoperatively. Medical records of Parkinson’s disease (PD) patients undergoing DBS procedure between 2008–2011 were reviewed after Institutional Review Board approval. Anesthesia medication, preoperative levodopa dose, age, preoperative use of antihypertensive medications, diabetes mellitus, anxiety, motor part of the Unified Parkinson’s Disease Rating Scale score and PD duration were collected. Univariate and multivariate analysis was done between each patient characteristic and the number of antihypertensive boluses. From the 136 patients included 60 were hypertensive, of whom 32 were on angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), told to hold on the morning of surgery. Antihypertensive medications were given to 130 patients intraoperatively. Age (relative risk [RR] 1.01; 95% confidence interval [CI] 1.00–1.02; p = 0.005), high Joint National Committee (JNC) class (p < 0.0001), diabetes mellitus (RR 1.4; 95%CI 1.2–17; p < 0.0001) and duration of PD >10 years (RR 1.2; 95%CI 1.1–1.3; p = 0.001) were independent predictors for antihypertensive use. No difference was noted in the mean dose of levodopa (p = 0.1) and levodopa equivalent dose (p = 0.4) between the low (I/II) and high severity (III/IV) JNC groups. Addition of dexmedetomidine to propofol did not influence antihypertensive boluses required (p = 0.38). Intraoperative hypertension during DBS surgery is associated with higher age group, hypertensive, diabetic patients and longer duration of PD. Withholding ACEI or ARB is an independent predictor of hypertension requiring more aggressive therapy. Levodopa withdrawal and choice of anesthetic agent is not associated with higher intraoperative antihypertensive medications. / Revisión por pares