Tremor, which is defined as an oscillatory and rhythmic movement of a body part, is the most common movement disorder worldwide. The most frequent tremor syndromes are tremor in Parkinson’s disease, essential tremor, and dystonic tremor syndromes, whereas Holmes tremor, orthostatic tremor, and palatal tremor are less common in clinical practice. The pathophysiology of tremor consists of enhanced oscillatory activity in brain circuits, which are ofen modulated by tremor-related afferent signals from the periphery. The cerebello-thalamo-cortical circuit and the basal ganglia play a key role in most neurologic tremor disorders, but with different roles in each disorder. Here we review the pathophysiology of tremor, focusing both on neuronal mechanisms that promote oscillations (automaticity and synchrony) and circuit-level mechanisms that drive and maintain pathologic oscillations.

Clinical evaluation of motor dysfunction is crucial to make a correct diagnosis. The gold standard is clinical evaluation by a movement disorder specialist, relying on subjective measures and patient report. Regular clinical assessments are needed to provide long-term measures that monitor motor progression over time and therapy response, not only in clinical settings but also during daily activities at home. Wearable sensors have been developed to assess objective and quantifiable measures of motor dysfunction. Such sensors are small, light, cheap and portable, containing built-in accelerometers and gyroscopes and data storage. These new technologies are revolutionizing the field of movement disorders to improve clinical diagnosis and evaluation, treatment monitoring at home, and progression of symptoms over time. They are also of interest for adaptive therapy options, e.g. closed-loop deep brain stimulation, and are successful in quantifying and measuring tremor, showing promise in assessing bradykinesia, dyskinesia, gait impairments and prediction of therapy response. Despite device development, there is no validated clinical application yet; further research is needed.

This chapter summarizes the functional–anatomic organization of the connectivity of the basal ganglia with the thalamocortical systems and the brainstem. This connectional organization substantiates the neural basis for the wide array of functions in which the basal ganglia are involved, ranging from pure sensorimotor to cognitive–executive and emotional–motivational behaviors. Across this broad array of motor and behavioral functions, the mechanism by which the basal ganglia contribute to these functions is through “response selection.” This mechanism fits well with the arrangement of the intrinsic connections between the individual basal ganglia nuclei, supporting the selection of appropriate responses in a particular context and, at the same time, the suppression of inadequate responses. A variety of symptoms as part of neurologic movement disorders, such as Parkinson’s disease, Huntington’s disease and dystonia, or neuropsychiatric diseases like obsessive-compulsive disorder, mood disorders, and drug addiction, might be interpreted as an inadequate selection of motor, cognitive, or affective responses to internal or external stimuli.

Although movement is largely generated from the primary motor cortex, what movement to make and how to make it is influenced from the entire brain. External influences from the environment come from sensory systems in the posterior part of the brain, and internal influences, such as homeostatic drive and reward, from the anterior part. A movement is voluntary when a person’s consciousness recognizes it to be so because of proper activation of the agency network. Behavioral movement disorders can be understood as dysfunction of these mechanisms. Apraxia and task specific dystonia arise from disruption of parietal–premotor connections. Tics arise from a hyperactive limbic system. Functional movement disorders may also have an origin in abnormal limbic function and are believed to be involuntary due to dysfunction of the agency network. In Parkinson’s disease, bradykinesia comes from insufficient basal ganglia support to the anterior part of the brain.

Physical rehabilitation in people with Parkinson’s disease (PD) aims to restore everyday functioning and mobility through a multidisciplinary approach. We present and discuss the current evidence on efficacy of key rehabilitation specialties and therapies that contribute to improving everyday (motor and non-motor) functioning in PD. Rehabilitative therapies aiming to improve posture and balance, transfers, gait, and physical condition have been shown effective. Evidence that physical therapy interventions using for example external or internal cues is effective for improving gait and gait-related mobility is strong, although the evidence for improving upper limb function, speech, and swallowing deficits is still limited. Optimal intensity of rehabilitation services offered by physical therapists, occupational therapists, and speech therapists, as well as their active ingredients and long-term impact, need further underpinning to help continuing development and updating of clinical guidelines.

Parkinson’s disease (PD), a typical Parkinson syndrome, is seen as a progressive multisystem neurodegenerative disease with α-synuclein–containing Lewy bodies and neurites, affecting 1–2 per 1000 of the global population. The prevailing view of PD etiology is that it is the result of cell-autonomous and non-autonomous processes, starting in the olfactory nerve and the autonomous nervous system of the gut, spreading retrogradely through synaptically coupled networks in a topographically predictable sequence to postsynaptic brainstem neurons, affecting the nuclear grays of the basal midbrain and forebrain and finally the neocortex. Cell-autonomous processes (e.g., mitochondrial damage and a defective autophagy by lysosomal and ubiquitin proteasome systems) result in pathologic accumulation of intracellular α-synuclein oligomers and aggregates. Non–cell-autonomous processes comprise the spread of synucleinic pathology in dying neurons to neighboring dopaminergic, cholinergic, serotinergic, and adrenergic neurons and/or to astrocytes, microglia, and lymphocytes across brain regions, plus decreased brain-derived neurotrophic factors and/or microglial-induced inflammatory responses.

In Parkinson’s disease, parkinsonism occurs due to the loss of dopaminergic neurons of the substantia nigra. Existing treatments can enhance dopaminergic activity in the brain, but cause adverse effects due to the non-targeted, non-physiologic dopamine delivery, so there is interest in developing regenerative therapies to restore dopaminergic tone in the striatum in a targeted, physiologic manner. Experimental approaches include using viral vectors to deliver genes encoding growth factors or enzymes involved in dopamine synthesis, or to target nucleic acids and gene expression. A number of cell types have been considered potential sources of cell-based therapies for PD and have been trialled in humans and animals, but all have been limited by either poor efficacy, poor graft survival, or logistical barriers. However, stem cells offer a renewable source of dopaminergic cells and hold great promise as potential regenerative treatments, and human trials have begun. Although these treatments remain experimental, some are entering clinical trials and there is hope that they will become available for clinical use in the future.

The exact mechanisms underlying dysfunction of the basal ganglia that lead to Parkinson’s disease (PD) remain unclear. According to the standard model of PD, motor symptoms result from abnormal neuronal activity in dysfunctional basal ganglia, which can be recorded in human basal ganglia structures as functional neurosurgery for PD provides a unique opportunity to record from these regions. Microelectrode and local field potential recordings studies show alterations exist in basal ganglia nuclei as well as in the motor thalamus. Lesioning or stimulation of the basal ganglia results in significant improvement of PD symptoms, supporting the view that basal ganglia–thalamocortical circuits abnormality is important in parkinsonism generation. Different patterns of oscillatory neuronal activity plus changes in firing rate are associated with different parkinsonian motor subtypes. We present recordings of basal ganglia activity obtained with microelectrode recordings in parkinsonian patients, providing pathophysiology insight.

People with Parkinson’s disease (PD) often suffer from various non-motor symptoms, including manifestations of autonomic dysfunction. The latter encompass cardiovascular, urogenital, gastrointestinal manifestations, sexual dysfunction and thermoregulatory disturbances. Autonomic manifestations can be an intrinsic aspect of PD, resulting from degeneration of parasympathetic and sympathetic pathways, or can be secondary to comorbidity or medication intake. As autonomic dysfunction is prevalent and often troublesome, identification and appropriate treatment are relevant steps in the management of people with Parkinson’s disease. Some manifestations of this autonomic dysfunction may precede the onset of PD motor features by many years, and might be considered biomarkers of this disease. A variety of non-pharmacologic and pharmacologic treatments have been investigated for the treatment of autonomic dysfunction in PD, but a limited evidence base is available so far.

The clinical and pathologic hallmarks of Parkinson’s disease (PD) are motor parkinsonism due to underlying progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta accompanied by an accumulation of intracytoplasmic protein inclusions known as Lewy bodies and Lewy neurites. The diagnostic criteria/guidelines based on the UK Parkinson’s Disease Society Brain Bank clinical diagnostic criteria have guided clinicians and researchers in the diagnosis of PD for many decades. This chapter discusses whether this description represents our current understanding of PD, and why it is time to integrate new research findings and accommodate our definition and diagnostic criteria of PD, such as Parkinson-associated non-motor symptoms, genetics, biomarkers, imaging findings, or heterogeneity of phenotypes and underlying molecular mechanisms. In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson’s disease, which were designed specifically for use in research but also as a general guide to clinical diagnosis of PD. These criteria and some of their limitations are also discussed.

Many drugs are available to treat Parkinson’s disease (PD), but are limited to alleviating symptoms; no disease-modifying treatment (DMT) has been approved by any authority. There is much effort to develop remedies capable of altering the underlying neurodegenerative processes in PD. Current concepts target the deposition of pathologic α-synuclein oligomers either by immunization strategies or by small molecules that interact with the protein aggregation. Further DMT approaches modulate pathologically active intracellular processes such as the c-Abl kinase or LRRK2 pathway or aim to activate signaling pathways involved in neuroprotection, such as the GLP-1 receptor pathway (with GLP1-agonist exenatide being the most advanced DMT in the PD drug pipeline). Replacement of enzymes such as β-glucocerebrosidase, modification of the microbiome, or targeting energy metabolism or inflammation are further approaches proposed to slow down neurodegeneration. Novel symptomatic treatment approaches envisage improvement of pharmacologic properties of levodopa or dopamine agonists or target non-dopaminergic neurotransmitter systems, e.g., the glutamatergic, serotoninergic or cholinergic system.

Epilepsy is one of the most common neurological disorders, affecting people of all ages. This chapter focusses on what has been learnt about the microRNA system in this important disease. Starting with an overview of epilepsy, it addresses what causes seizures to occur and some of the underlying mechanisms, including gene mutations and brain injuries. It explores how and which microRNAs drive complex gene changes that underpin but also oppose the enduring hyperexcitability of the epileptic brain. This includes by regulating amounts of neurotransmitter receptors, structural components of synapses, metabolic processes and inflammation. It also covers some of the earliest studies linking microRNAs to epilepsy as well as recent large-scale efforts to map every microRNA and its target in the epileptic brain. Finally, it highlights ways to model epilepsies and use of experimental tools such as antisense oligonucleotides to understand the contributions of individual microRNAs. Collectively, these studies reveal how microRNAs contribute to the molecular landscape that underlies this disease and offer the exciting possibility of targeting microRNAs to treat genetic and acquired epilepsies.