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Background: Patients with Parkinson’s disease (PD) and Essential tremor (ET) who havebeen treated with Deep Brain Stimulation (DBS) generally experience a positive effect,particularly regarding the motor symptoms. However, the patients’ communication skillsare often negatively affected and the assessment instrument currently used withinneurological clinical care is not sufficiently sensitive to assess these patients’ speechclarity, voice and intelligibility satisfactorily.Aim: This study’s purpose was to develop a prototype assessment tool for speech clarity,intelligibility and voice, with speech and language pathology (SLP) validity, that isadaptable to a neurological clinical care setting.Method: The assessment tool was designed using general design methodology. Aprototype was constructed and tested on speech samples of read text for reliability. ThreeSLP’s, three DBS nurses and three naive listeners (NL) were represented in the test group.Levels of agreement were calculated using Percent Close Agreement, PCA.Results: The results indicate a relatively high level of agreement between the groups, inparticular the SLP group and the DBS group (μ: 0.82, 0.79, and 0.74).Conclusion: The results demonstrate the need for an assessment tool with SLPcompetence to assess speech clarity, intelligibility and voice within neurological clinicalcare. The assessment tool was shown to be a useful and adequate prototype that can easilyevolve into a truly useful and versatile perceptual speech assessment tool. The results ofthis study should be treated cautiously, considering the test groups’ modest size. / Bakgrund: Patienter med Parkinsons sjukdom (PD) och patienter med Essentiell tremor(ET) som behandlats med Deep Brain Stimulation (DBS) upplever i allmänhet en positiveffekt, framför allt gällande de motoriska symtomen. Emellertid påverkas oftapatienternas kommunikativa färdigheter negativt. De bedömingsmaterial som användsinom den kliniska nerurologiska vården; UPDRS/ETRS är alltför trubbiga för att kunna geen tillfredsställande bild av patientens tal, röst och förståelighet.Mål: Skapa ett bedömningsverktyg för tal, förståelighet och röst med logopedisk validitet,och som kan användas inom den kliniska neurologiska verksamheten i samband medDBS-behandling.Metod: Bedömningsverktyget designades enligt generell designmetodik. En prototypskapades och testades för reliabilitet på röstexempel av en läst text. Tre logopeder, treDBS-sköterskor och tre naiva lyssnare deltog i testningen. Grad av samstämmighetberäknades med Percent Close Agreement, PCA.Resultat: Resultaten indikerar en relativt hög grad av samstämmighet mellan grupperna(μ: 0.82, 0.79, respektive 0.74). Logopederna bedömde nästan alla röstexempel sompatienter i behov av logopedhjälp. DBS-gruppen och gruppen med naiva lyssnarebedömde ett mindre antal ha behov av logoped.Slutsats: Resultaten belyser behovet av ett bedömningsverktyg med logopedisk validitetför bedöming av tal, förståelighet och röst inom den kliniska neurologiska verksamheten.Bedömingsverktyget som framtagits i denna studie är en användbar och adekvat prototypsom enkelt skulle kunna utvecklas till ett verkligt användbart och mångsidigt perceptuelltbedömningsmaterial. Dock ska resultaten i denna studie tolkas en smula försiktigt medtanke på de låga antalet deltagare.

Our understanding of the pathophysiology Parkinson’s disease has transformed over the last decade as we have come to appreciate the importance of changes in neuronal firing pattern that occur within the motor network in the dopamine deficient state. These changes in firing pattern, particularly increased synchrony result in oscillations that can be recorded as local field potentials. This thesis concerns itself with the study of beta oscillations which are characteristic of Parkinson’s disease. Firstly, I investigate whether beta oscillations play a pathophysiological role in Parkinson’s disease or whether they are purely epiphenomenal by augmenting beta with low frequency deep brain stimulation. In this study I show that rigidity is increased by ~25% with low frequency stimulation providing significant further evidence for a patho-physiological role of beta in Parkinson’s disease. Next I investigate whether beta oscillations correlate with Parkinsonian severity at rest and could therefore potentially be used as a biomarker of clinical state. I demonstrate that the variability of beta amplitude recorded from the subthalamic nucleus strongly correlates with symptom severity at rest and also in response to levodopa administration. I then use beta amplitude as a biomarker for a trial of adaptive deep brain stimulation in Parkinson’s disease. I show that by using beta amplitude to control stimulation, time on stimulation is reduced by >50% but despite this, clinical outcome is improved by 25% relative to conventional continuous high frequency stimulation. Finally, I investigate the bilateral subcortical beta network and its response to levodopa. I report statistically significant bilateral functional connectivity in the beta range which is driven by phase locking and modulated by levodopa in the low beta range with implications for bilateral adaptive deep brain stimulation. These findings further our understanding of the pathophysiological role of beta oscillations in Parkinson’s disease and provide new avenues for treatment development.

Relatively little is known about the role of the basal ganglia and their pathways in human deglutition. Deep Brain Stimulation (DBS) is a treatment for Parkinson Disease (PD) that stimulates the subthalamic nuclei and affords us a model for examining deglutition in humans with known impairment of the basal ganglia. The purpose of this study was to examine the effects of DBS in the ON versus Off conditions on the oral and pharyngeal stages of deglutition in participants with PD. It was hypothesized that DBS in the ON condition would yield improvement in the following dependent variables: oral total composite score, pharyngeal total composite score, pharyngeal transit time, and maximal hyoid bone excursion. Statistically significant differences (improvement) were found for the pharyngeal composite score and pharyngeal transit time in the DBS ON condition. Findings of this study demonstrated that DBS in the ON condition helps to alleviate some of the bradykinesia and hypokinesia associated with PD on the pharyngeal stage of deglutition, but not the oral stage. These findings suggest that Parkinsonian swallowing dysfunction is not solely related to nigrostriatal dopamine deficiency which is purported to be the primary means of DBS alleviation of motor signs. Rather, it may be due to an additional non-dopamine related system of deglutition found in the brainstem.

Mental fatigue decreases motivation. I tested whether applying electricity to a self-control region of the brain would replenish some of the motivation normally lost during mental fatigue. 224 people participated in this study. Each person received real or placebo brain stimulation while undergoing activities that increased mental fatigue. The dependent variable was a task where participants had to perform work by clicking a computer mouse repeatedly. Before performing this task, participants indicated how hard they were planning to work on this motivation task. Participants who received real brain stimulation were able to perform more work, but only if they also indicated they planned to work hard on the task.

tDCS brain stimulation does not always work in the intended direction. It has been found to sometimes worsen behavior rather than improve it. A preliminary study shows that people high on sensation-seeking and lack of premeditation were prone to reverse effects of tDCS on performance on a Stop Signal Task. Both of these constructs are related to dopamine levels. Study 2 seeks to intentionally cause a reverse effect of tDCS by increasing participants’ dopamine levels via caffeine. There was not a significant interaction between tDCS and caffeine on errors on the Stop Signal Task in this study. However, other factors interacted with tDCS and caffeine including lack of premeditation. This two study package suggests the effects of tDCS are variable across individuals, with personality and neurochemistry both affecting behavioral outcomes of tDCS.

Healthy aging influences peripheral and central levels of the neuromotor system. These age-related changes contribute to the decline in dexterous manual behavior. Difficulty in performing activities of daily living increases reliance on external assistance. Understanding specific mechanisms leading to the decline in fine manual performance is crucial for their rehabilitation. In this thesis, we have attempted to increase our awareness of the causes underlying manual disability in old age. The first study investigated how old adults apply forces and moments on a freely-movable object using a precision grip (thumb and index finger) during functionally-relevant tasks. During the grasp-lift task old adults misaligned their thumb and finger contacts and produced greater grip force, greater external moments on the object around its roll axis, and oriented force vectors differently compared with young adults. During a precision-orientation task of inserting a slot on the object over a bar (`key-slot' task), old adults were more variable in digit-tip force directions and performed the key-slot task more slowly. With practice old adults aligned their digits, reduced their grip force, and minimized external moments on the object. We conclude that with old age comes with a reduced ability to control the forces and moments applied to objects during precision grasp and manipulation. This may contribute to the ubiquitous slowing and deteriorating manual dexterity in healthy aging. Another study investigated the effects of transcranial direct current stimulation (tDCS) to the contralateral M1 combined with motor training (MP) on changes in the forces applied to the object during grasp and manipulation. We also measured performances on functional tasks in healthy elderly individuals. Our results indicate that anodal tDCS+MP facilitates retention of learning on a skillful manual task in healthy old adults. Furthermore, improved retention on the pegboard test was associated with reduced force variability on the key-slot task that demanded similar precise control over the forces applied to the object. These findings suggest that the improvement in force steadiness is one of the potential mechanisms through which short-term anodal tDCS during motor training improved performance on a functional task that outlasted the intervention period. Furthermore, anodal tDCS over M1 in combination with motor practice also influenced motor response to tasks that critically depend on sensory signals in healthy old adults. Finally, we found that, in healthy elderly individuals, the memory representations scaling the lift force for the grip and lift task generalized, while the training-based learning on the ballistic task showed an incomplete transfer to the contralateral hand. These differences may indicate task-dependent interhemispheric transfer of learning in old age. Collectively, the work presented in this thesis demonstrates that the performance on dexterous manual tasks in healthy old adults may depend on how they configure their grasp, and control their finger forces (both linear and rotational) applied to the grasped object, specifically how smooth is the applied force.

Background The last decade has witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders, especially advanced Parkinson’s disease (PD), essential tremor (ET) and dystonia. Ablative lesions such as thalamotomy and pallidotomy have been gradually replaced by the technique of chronic deep brain stimulation (DBS) applied to targets in the basal ganglia and thalamus, and assumed to be more lenient to the brain than stereotactic radiofrequency lesions. Since the aim of functional neurosurgery is to alleviate symptoms of these chronic, progressive, non-fatal diseases, and to improve life quality of the patients, it is imperative that the surgical procedures remain safe and do not result in complications mitigating any anticipated positive effect of the surgery on the symptoms of the disease. Aim The aim of this thesis is to evaluate, compare and analyse the safety of various surgical procedures used to treat patients with movement disorders, and to document side effects and complications both peri operatively and in a long term follow-up. Further to compare the effects of pallidotomy and pallidal DBS, and to evaluate the longterm efficacy of Vim-DBS. Method 256 consecutive surgical procedures, 129 DBS and 127 stereotactic lesions, were reviewed with respect to complications in 197 treated patients. In a series of 119 patients operated on with DBS during a 10 year period, the occurrence of hardware related complications (infection, breakage, erosion etc) was documented and analysed. Additionally, the interference of external magnetic field with the stimulation was documented. In one patient operated on with subthalamic nucleus DBS, a highly unusual and unexpected psychiatric side effect was carefully analysed. In 5 patients operated on with both methods (lesion and DBS) on each hemisphere, respectively, the effect and side effects of each method were compared. The long term effect and side effects of thalamic DBS was analysed in a series of patients with ET followed for 7 years. Results There were no deaths and few severe neurological complications in this material. Unilateral ablative lesions in the pallidum were well tolerated by patients with advanced PD, while for tremor, thalamic DBS was much safer than thalamotomy, even if its effect on certain aspects of tremor could show some decrease of efficacy over time. Some of the side effects of lesioning are transient while most but not all side effects of DBS are reversible. Hardware-related complications were not uncommon especially in the early “learning curve” period, and the DBS technique, being a life-long therapy, will necessitate a life long follow up of patients. Provided safety protocols are followed and provided patient’s and carer’s education and awareness, external electromagnetic interference should not constitute a risk for patients with DBS. PD patients undergoing STN DBS should be carefully selected to avoid psychiatric or cognitive side effects, due to this brain target´s proximity to, and involvment in, non-motor associative and limbic circuitry. Conclusions In terms of mortality and morbidity, modern stereotactic neurosurgery for movement disorders, both ablation and DBS, is a safe procedure even in advanced stages of disease. Symptoms of PD, ET and dystonia can be alleviated mainly with DBS and even unilaterally with pallidal lesions, at the expense of, in most cases, minor side-effects.

Parkinson’s disease (PD) and dystonia are movement disorders related to dysfunctions of basal ganglia (BG). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) are treatments for PD and dystonia. Previous research indicated that abnormally elevated oscillatory activities at the theta (3-10 Hz) beta frequency bands (11-30 Hz) may be related to parkinsonian and dystonic motor symptoms but their precise roles are not well understood. Recently, DBS of the pedunculopontine nucleus region (PPNR) has been used to treat PD patients with postural and gait dysfunctions, but movement-related PPNR activities had not been explored. We aimed to investigate movement-related local field potentials (LFP) recorded from the BG and PPNR in PD and dystonia patients. We recorded STN LFP from PD patients and subsequently applied the intrinsic STN theta, beta, and gamma (31-100 Hz) frequencies through DBS to study their effects on PD motor signs. We also recorded movement-related PPNR LFP in PD patients and movement-related GPi activities in patients with primary dystonia. Finally, we simultaneously recorded movement-related activities from the GPi and the motor thalamus in a patient with secondary dystonia. We found that DBS at the dopamine-dependent and movement-related intrinsic STN gamma frequencies, were as effective as traditionally used high frequencies (130-185 Hz) in reducing PD motor signs, but theta and beta frequencies did not worsen motor symptoms. Voluntary movements modulated two discrete movement-related frequencies in the theta and beta bands in the PPNR and these two frequencies interacted with the sensorimotor and frontal cortices during movements. We showed that voluntary movements modulated beta and gamma frequencies in the GPi. A resting ~5-18 Hz coherence between the GPi bilaterally was attenuated during movements in patients, which may be related to dystonia because this 5-18Hz coherence was also present between the GPi and motor thalamus in the patient with secondary dystonia. Our findings indicated that intrinsic STN gamma frequency oscillations were likely prokinetic rhythms but theta and beta frequencies may not contribute to PD motor symptoms. Voluntary movements modulated theta and beta frequencies in the PPNR, which may explain why PPNR DBS uses lower frequencies than those of the BG. The 5-18 Hz oscillatory activities in the BG-thalamic circuit may be a feature of dystonia.