Motor symptoms in Parkinson's disease: A unified framework

Parkinson’s disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement

Imaging the subthalamic nucleus in Parkinson’s disease

This thesis is comprised of a set of work that aims to visualize and quantify the anatomy, structural variability, and connectivity of the subthalamic nucleus (STN) with optimized neuroimaging methods. The study populations include both healthy cohorts and individuals living with Parkinson's disease (PD). PD was chosen specifically due to the involvement of the STN in the pathophysiology of the disease. Optimized neuroimaging methods were primarily obtained using ultra-high field (UHF) magnetic resonance imaging (MRI). An additional component of this thesis was to determine to what extent UHF-MRI can be used in a clinical setting, specifically for pre-operative planning of deep brain stimulation (DBS) of the STN for patients with advanced PD. The thesis collectively demonstrates that i, MRI research, and clinical applications must account for the different anatomical and structural changes that occur in the STN with both age and PD. ii, Anatomical connections involved in preparatory motor control, response inhibition, and decision-making may be compromised in PD. iii. The accuracy of visualizing and quantifying the STN strongly depends on the type of MR contrast and voxel size. iv, MRI at a field strength of 3 Tesla (T) can under certain circumstances be optimized to produce results similar to that of 7 T at the expense of increased acquisition time

Understanding Autonomic Control via Human Deep Brain Stimulation

The Central Autonomic Network (CAN) consists of higher cortical areas, basal ganglia, and brainstem areas that are important in the control of the autonomic nervous system (ANS). This thesis concentrates on the control of the respiratory and cardiovascular systems both alone and in combination in the context of exercise. Deep Brain Stimulation (DBS) is a type of therapy in patients in which electrodes are inserted into the brain to treat neurological disorders such as Parkinson’s disease. The presence of electrodes allows the study of the effects of stimulation of components of the CAN, as well as measurement of electrical activity (local field potentials (LFPs)) to assess whether a nucleus is integral to a specific change in autonomic output. The sum of my work outlined in this thesis demonstrates that common DBS targets such as subthalamic nucleus (STN) and pedunculopontine nucleus (PPN) alter both cardiovascular and respiratory control. Furthermore, these changes have clinical implications not previously highlighted. This includes the relief of breathlessness for some nuclei (such as the motor thalamus) and induction of breathlessness for others (such as STN). In addition to clinical implications, insights are provided into the ‘central command’ system of autonomic control in the brain, such as the role of the anterior cingulate cortex (ACC) in the cardiovascular response to intermittent exercise. Besides advancing understanding of the regulation of these autonomic processes, this work has also directly resulted in first in-human clinical trials of DBS for the treatment of autonomic symptoms of multiple systems atrophy

Neural Preparation For Step Initiation In Unpredictable Conditions With Age And Parkinson\u27s Disease

Mobility is essential for the independent lifestyle. However, as the US population ages, challenges to mobility start to arise, among them just the aging itself which leads to decreased postural stability, falls and the second most common neurodegenerative disease, that is Parkinson’s disease (PD). We decided to investigate step initiation as it is crucial to mobility: walking is not possible without the first step. Step initiation is impaired in PD. However, the impact of PD on the neural mechanisms of step initiation when some of the step parameters are unpredictable remains unexplored. Cortical preparation for step initiation can be assessed by beta event-related desynchronization (ERD) derived from electroencephalography (EEG) recordings. We hypothesized that subjects with PD would exhibit less cortical modulation between conditions of forward step initiation with and without prior knowledge of limb choice. Further, we hypothesized that decreased cortical modulation in PD would associate with a higher impairment of motor performance. Results identified that the group with PD exhibited decreased beta ERD amplitudes that were similar regardless of condition, whereas control subjects modulated beta ERD amplitudes between conditions, particularly in early stages of pre-movement processing in areas overlying sensory cortex. Subjects with PD presented with delayed and reduced postural preparation with increased step target error across both conditions and exhibited a greater incidence of multiple anticipatory postural adjustments (APAs) in the predictable relative to the unpredictable condition. Delayed postural preparation significantly correlated with lower amplitudes of beta ERD. We concluded that diminished early pre-movement processing over sensory cortex was concomitant with poor pre-selection of the stepping limb in predictable conditions and that a generally diminished amplitude of cortical pre-movement processing relates to delayed step initiation in people with PD. Furthermore, impaired mobility accompanies healthy aging, but there is a need for deeper understanding of how aging changes central control of motor behavior. Using previous study’s method, we compared cortical preparation for step initiation using beta ERD in young and older healthy subjects performing forward steps with and without prior knowledge of limb choice. Our results show that older subjects exhibited increased beta ERD amplitudes before the step regardless of whether they were informed of limb choice or not. Moreover, older subjects exhibited early increases in beta ERD in the “sensory” cluster of electrodes, but only when full limb-choice information was available. Behaviorally, the older subjects also exhibited shortened and increased anticipatory postural adjustments which led to earlier step initiation and similar swing-foot velocities but was also accompanied by greater target step placement errors and decreased postural stability. For the older group, condition-related increases in beta ERD amplitudes and stability correlated with condition-related prolongation of APA durations. We conclude that older subjects exhibited a spectrum across two strategies: (1) a “fast” strategy associated with decreased neural preparation that trades shortened step preparation and higher swing-foot velocity for target step errors and lowered postural stability; and (2) an “accurate” strategy associated with greater neural preparation, longer step-preparation time, and higher stability during step execution. In conclusion, this thesis provides more support for beta ERD as a useful tool for studying cortical preparation non-invasively. We have also established the importance of the signals recorded by “sensory” clusters: in subjects with PD the absence of beta ERD similar to the control group was associated with impaired motor behavior even when conditions were predictable. Similarly, a part of the older group seemed to pre-potentiate its cortex lying beneath the cluster of “sensory” electrodes which was associated with more safe and accurate steps. Further investigations should focus on the importance of sensorimotor integration and its’ changes due to PD or healthy aging and beta ERD may be an excellent tool for this task

Neural Modeling and Imaging of the Cortical Interactions Underlying Syllable Production

This paper describes a neural model of speech acquisition and production that accounts for a wide range of acoustic, kinematic, and neuroimaging data concerning the control of speech movements. The model is a neural network whose components correspond to regions of the cerebral cortex and cerebellum, including premotor, motor, auditory, and somatosensory cortical areas. Computer simulations of the model verify its ability to account for compensation to lip and jaw perturbations during speech. Specific anatomical locations of the model's components are estimated, and these estimates are used to simulate fMRI experiments of simple syllable production with and without jaw perturbations.National Institute on Deafness and Other Communication Disorders (R01 DC02852, RO1 DC01925

Application of MRI Connectivity in Stereotactic Functional Neurosurgery

This thesis examines potential applications of advanced MRI-connectivity studies in stereotactic functional neurosurgery. Several new analysis methodologies are employed to: (1) build predictive models of DBS surgery outcome; (2) refine the surgical target and (3) help build a better understanding of the pathogenesis of the treated conditions and the mechanism of action of DBS therapy. The experimental component is divided into three main parts focusing on the following pathologies: (1) Parkinson’s disease (PD), (2) tremor and (3) trigeminal autonomic cephalalgias (TAC). Section I: In the first experiment (chapter 3), resting state fMRI was used to find radiological biomarkers predictive of response to L-DOPA in 19 patients undergoing subthalamic nucleus (STN) DBS for PD. A greater improvement in UPDRS-III scores following L-DOPA administration was characterized by higher resting state functional connectivity (fcMRI) between the prefrontal cortex and the striatum (p=0.001) and lower fcMRI between the pallidum (p=0.001), subthalamic nucleus (p=0.003) and the paracentral lobule. In the second experiment (chapter 4), structural (diffusion) connectivity was used to map out the influence of the hyperdirect pathways on outcome and identify the therapeutic ‘sweet spots’ in twenty PD patients undergoing STN-DBS. Clusters corresponding to maximum improvement in symptoms were in the posterior, superior and lateral portion of the STN. Greater connectivity to the primary motor area, supplementary motor area and prefrontal cortex was predictive of higher improvement in tremor, bradykinesia and rigidity, and rigidity respectively. The third experiment (chapter 5) examined pyramidal tract (PT) activation in 20 PD patients with STN-DBS. Volume of tissue activation (VTA) around DBS contacts were modelled in relation to the PT. VTA/ PT overlap predicted EMG activation thresholds. Sections II: Pilot data suggest that probabilistic tractography techniques can be used to segment the ventrolateral (VL) and ventroposterior (VP) thalamus based on cortical and cerebellar connectivity in nine patients who underwent thalamic DBS for tremor (chapter 6). The thalamic area, best representing the ventrointermedialis nucleus (VIM), was connected to the contralateral dentate cerebellar nucleus. Streamlines corresponding to the dentato-rubro-thalamic tract (DRT) connected M1 to the contralateral dentate nucleus via the dentato-thalamic area. Good response was seen when the active contact’s VTA was in the thalamic area with the highest connectivity to the contralateral dentate nucleus. Section III: The efficacy and safety of DBS in the ventral tegmental area (VTa) in the treatment of chronic cluster headache (CH) and short lasting unilateral neuralgiform headache attacks (SUNA) were examined (chapters 7 and 8). The optimum stimulation site within the VTa that best controls symptoms was explored (chapter 9). The average responders’ deep brain stimulation activation volume lay on the trigemino-hypothalamic tract, connecting the trigeminal system and other nociceptive brainstem nuclei, with the hypothalamus, and the prefrontal and mesial temporal areas

Single neuron computations of cognition in the human brain

Understanding how information is encoded, processed, and decoded to produce behavior is a fundamental goal of neuroscience. In this dissertation, we aim to expand our understanding of our human decision-making processes at the single-neuronal level. We describe three studies exploring the neural substrate of decision-making in three separate brain regions. First, we describe a method for recording the activity of individual neurons in human subjects. The unique combination of behavioral and neurophysiological data will allow us to better understand the neural substrate of cognitive functions in humans. Second, we explored how decisions are represented in the brain. We recorded single neuronal responses in the human nucleus accumbens while subjects engaged in a financial decision-making task. We found that neurons in the nucleus accumbens predicted upcoming decisions well before the behavior was manifested. In addition, these neurons encoded a positive and negative prediction error signal, signaling the difference between expected and realized outcome. Third, we explored how the brain represents decision conflict and how it adapts to prime future decisions allowing tradeoff between speed and accuracy. We found that individual neurons in the human dorsal anterior cingulate cortex encode the level of decision conflict in a dose-dependent manner. In addition, these neurons encode historical conflict information, priming the neural circuit to future trials of the same or varying conflict levels. Following selective ablation of the dorsal anterior cingulate cortex, we found this signal was selectively abolished. Lastly, we explored how the brain represents decisions under conflict and if these decisions are malleable to external intervention. We found that neurons in the human subthalamic nucleus are selectively activated and encode the upcoming decision during situations of high decision conflict. Based on the physiological findings, we then applied intermittent stimulation through the implanted deep brain stimulation electrode during the same task, to demonstrate a causal interaction between the physiology and behavior. In conclusion, we describe a set of experiments that systematically explore human decision-making processes at the single-neuronal level