Andrea A Kühn

• Prof. Dr. med.
• Consultant at Charité Universitätsmedizin Berlin

Parkinson's disease is linked to increased beta oscillations in the subthalamic nucleus, which correlate with motor symptoms. However, findings across studies have varied. Our standardized analysis of multicenter datasets reveals that insufficient sample sizes contributed to these discrepancies - a challenge we address by pooling datasets into one...

Background Parkinson’s disease (PD) is characterized by hypokinetic motor symptoms, tremor, and various non-motor symptoms with frequent fluctuations of symptoms in advanced disease stages. Invasive therapies, such as deep brain stimulation (DBS), ablative therapies, and continuous subcutaneous or intrajejunal delivery of dopaminergic drugs via pum...

Elevated beta (β; 13-30 Hz) synchronization within the subthalamic nucleus (STN) characterizes bradykinesia in Parkinson’s disease (PD). β oscillations may serve as biomarkers for off-period motor symptoms and control signals for adaptive, closed-loop deep brain stimulation (DBS) in PD. However, their relation to striatal dopaminergic denervation a...

Background Pallidal neurostimulation is an effective treatment for severe isolated dystonia, but long‐term data from clinical trials are lacking. Objectives To evaluate long‐term efficacy and safety of pallidal neurostimulation in patients with isolated generalized or segmental dystonia. Methods Extension study of the prospective multicenter tria...

Background Comprehensive clinical data regarding factors influencing the individual disease course of patients with movement disorders treated with deep brain stimulation might help to better understand disease progression and to develop individualized treatment approaches. Methods The clinical core data set was developed by a multidisciplinary wo...

Background Patients with Progressive Supranuclear Palsy (PSP) suffer from several neuropsychological impairments. These mainly affect the frontal lobe and subcortical brain structures. However, a scale for the assessment of cognitive and neuropsychiatric disability in PSP is still missing. Objectives To create and validate a new scale for cognitiv...

Comparatively high excitability of myelinated fibers suggests that they represent a major mediator of deep brain stimulation effects. Such effects can be modeled using different levels of abstraction, ranging from simple electric field estimates to complex multicompartment axon models. In this study, we explore three approaches to estimate axonal a...

Subthalamic (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients not only improves kinematic parameters of movement but also modulates cognitive control in the motor and non‐motor domain, especially in situations of high conflict. The objective of this study was to investigate the relationship between DBS‐induced changes in funct...

Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%) and the identification of several disease-linked genes, the etiology in most patients remains elusive. Moreover, understanding the correlations between clinical manifestation and gen...

Dystonia is a hyperkinetic movement disorder that has been associated with an imbalance towards the direct pathway between striatum and internal pallidum, but the neuronal underpinnings of this abnormal basal ganglia pathway activity remain unknown. Here, we report invasive recordings from ten dystonia patients via deep brain stimulation electrodes...

Background Comprehensive characterization of the metabolome in cerebrospinal fluid (CSF) and serum by Nuclear Magnetic Resonance (NMR) spectroscopy may identify biomarkers and contribute to the understanding of the pathophysiology of neurological diseases. Methods Metabolites were determined by NMR spectroscopy in stored CSF/serum samples of 20 pa...

Although deep brain stimulation of the subthalamic nucleus (STN-DBS) induces motor benefits in people with Parkinson’s disease (PwPD), the size and duration of the effects of STN-DBS on motor axial (e.g., postural instability, trunk posture alterations) and gait impairments (e.g., freezing of gait – FOG) are still ambiguous. Physical therapy (PT) e...

Background Despite considerable heritability, previous smaller genome‐wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. Objective The objective of this study was to perform a large‐scale GWAS in a well‐characterized, multicenter sample of >6000 individuals to identify genetic risk factors f...

Background Segmented electrodes for deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson’s disease (PD) enable directional current steering leading to expanded programming options. Objective This retrospective study covering a longitudinal period of up to 7 years compares the efficacy of segmented and non-segmented leads in m...

Objective: Dyskinetic cerebral palsy (DCP) encompasses a group of predominantly perinatally acquired complex motor disorders that present with dystonia and/or choreoathetosis and are frequently associated with brain lesions in neuroimaging. Recently, lesion network mapping provided a tool to redefine neurological disorders as circuitopathies. In th...

Background The dichotomy between the hypo- versus hyperkinetic nature of Parkinson’s disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology. In this study, we investigated differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathwa...

Magnetoencephalography (MEG) allows the non-invasive measurement of brain activity at millisecond precision combined with localization of the underlying generators. So far, MEG-systems consisted of superconducting quantum interference devices (SQUIDS), which suffer from several limitations. Recent technological advances, however, have enabled the d...

Estimates of the spectrum and frequency of pathogenic variants in Parkinson’s disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of t...

The dichotomy between the hypo-versus hyperkinetic nature of Parkinson’s disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology.Investigate differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections.GPi neurons were s...

Objective The Progressive Supranuclear Palsy quality of life scale (PSP‐QoL) has been shown to be a useful tool for capturing health‐related quality of life of patients in “everyday life” and in progressive supranuclear palsy (PSP) research. However, at 45 items in length, the questionnaire can take a long time, exhausting PSP patients, in particul...

Background Recent imaging studies identified a brain network associated with clinical improvement following deep brain stimulation (DBS) in Parkinson's disease (PD), the PD response network. Objectives This study aimed to assess the impact of neuromodulation on PD motor symptoms by targeting this network noninvasively using multifocal transcranial...

Background and objective Impulse control disorders (ICD), psychosis and delirium are part of the spectrum of behavioural changes associated with Parkinson’s disease (PD). The diagnostic and therapeutic management of these rather complex neuropsychiatric conditions has been updated in the clinical guideline by the German Society of Neurology (DGN)....

The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is w...

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. P...

Dystonia is a neurological movement disorder characterised by abnormal involuntary movements and postures, particularly affecting the head and neck. However, current clinical assessment methods for dystonia rely on simplified rating scales which lack the ability to capture the intricate spatiotemporal features of dystonic phenomena, hindering clini...

Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson’s disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the...

Excessive stride variability is a characteristic feature of cerebellar ataxias, even in pre-ataxic or prodromal disease stages. This study explores the relation of variability of arm swing and trunk deflection in relationship to stride length and gait speed in previously described cohorts of cerebellar disease and healthy elderly: we examined 10 pa...

Finely tuned gamma oscillations have been recorded from the subthalamic nucleus and cortex in Parkinson's disease patients undergoing deep brain stimulation and are often associated with dyskinesia. More recently, it was shown that deep brain stimulation entrains finely tuned gamma to 1/2 of the stimulation frequency; however, the functional role o...

These multi-modal findings suggest that ERNA is produced by synaptic effects of indirect pathway fiber activations and represents a spatially defined neuronal circuit signature linked to the therapeutic potential of subthalamic DBS.

italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Goal: Parkinson's disease (PD) can lead to gait impairment and Freezing of Gait (FoG). Recent advances in cueing technologies have enhanced mobility in PD patients. While sensor technology and machine learning offer real-time detection for on-demand cu...

Deep brain stimulation (DBS) is a brain circuit intervention that can modulate distinct neural pathways for the alleviation of neurological symptoms in patients with brain disorders. In Parkinson's disease, subthalamic DBS clinically mimics the effect of dopaminergic drug treatment, but the shared pathway mechanisms on cortex-basal ganglia networks...

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) produces an electrophysiological signature called evoked resonant neural activity (ERNA); a high-frequency oscillation that has been linked to treatment efficacy. However, the single-neuron and synaptic bases of ERNA are unsubstantiated. This study proposes that ERNA is a subcortical neu...

Subthalamic beta band activity (13–35 Hz) is known as a real-time correlate of motor symptom severity in Parkinson’s disease (PD) and is currently explored as a feedback signal for closed-loop deep brain stimulation (DBS). Here, we investigate the interaction of movement, dopaminergic medication, and deep brain stimulation on subthalamic beta activ...

Oculogyric crises are acute episodes of sustained, typically upward, conjugate deviation of the eyes. Oculogyric crises usually occur as the result of acute D2-dopamine receptor blockade, but the brain areas causally involved in generating this symptom remain elusive. Here, we used data from 14 previously reported cases of lesion-induced oculogyric...

Mapping circuits for DBS. Within the enigmatic depths of an aquatic universe, divers use flashlights to reveal the hidden contours of an uncharted seabed that teems with wondrous vegetation. In an analogous exploration, Hollunder et al. describe how invasive brain stimulation delivered to deep-seated brain nuclei may act as a beacon. Using deep br...

Background Additional stimulation of the substantia nigra (SNr) has been proposed to target axial symptoms and gait impairment in patients with Parkinson’s disease (PD). Objective This study aimed to characterize effects of combined deep brain stimulation (DBS) of the subthalamic nucleus (STN) and SNr on gait performance in PD and to map stimulati...

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By anal...

Background Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients’ safety and management. Objectives To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. Methods Cross-sectional data of MSA patients a...

Background: Deep brain stimulation (DBS) has strong beneficial effects for treating movement disorders. The related cortical mechanisms can be studied with magnetoencephalography (MEG) during active DBS. However, MEG is prone to artefacts induced by the electrical stimulation and the movement of ferromagnetic DBS components. Although artefacts migh...

Background Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co‐occurring movement disorders such as Parkin...

Introduction The clinical implementation of chronic electrophysiology-driven adaptive deep brain stimulation (DBS) algorithms in movement disorders requires reliable representation of motor and non-motor symptoms in electrophysiological biomarkers, throughout normal life (naturalistic). To achieve this, there is the need for high-resolution and -qu...

Zusammenfassung Ziel der Studie Es wird eine Studie im Prä-Post-Design mit einer Befragung von Patient*innen vorgestellt, bei denen zur Therapie einer neurologischen Bewegungsstörung die Indikation für eine Tiefe Hirnstimulation (THS) gegeben war. Die Patient*innen wurden vor und nach der THS-Operation zu ihren präoperativen Assoziationen bzw. post...

The dichotomy between the hypo-versus hyperkinetic nature of Parkinson’s disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology. Investigate differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections. GPi neurons were...

The dichotomy between the hypo-versus hyperkinetic nature of Parkinson’s disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology. Investigate differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections. GPi neurons were...

Obesity is an enormous health problem, and many patients do not respond to any of the available therapies. Deep brain stimulation (DBS) is currently investigated as a potential treatment for morbid obesity. In this study, we tested the hypothesis that high-frequency DBS targeting the nucleus accumbens (NAc) shell region reduces food intake and weig...

The ability to initiate movement is fundamental to human behavior. Loss of dopaminergic neurons in Parkinson’s disease (PD) is associated with impaired movement initiation, also termed akinesia. Dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. We recorded invasive neural activi...

Subthalamic beta band activity (13-35 Hz) is known as a real-time correlate of motor symptom severity in Parkinson’s disease (PD) and is currently explored as a feedback signal for closed-loop deep brain stimulation (DBS). Here, we investigate the interaction of movement, dopaminergic medication, and deep brain stimulation on subthalamic beta activ...

Background Deep brain stimulation ( DBS ) is an effective treatment option for patients with Parkinson's disease ( PD ). However, clinical programming remains challenging with segmented electrodes. Objective Using novel sensing‐enabled neurostimulators, we investigated local field potentials ( LFPs ) and their modulation by DBS to assess whether e...

Background Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. Objectives To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegene...

Parkinson’s disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the inves...

Parkinson’s disease (PD) is associated with excessive beta activity in the basal ganglia. Brain sensing implants aim to leverage this biomarker for demand-dependent adaptive stimulation. Sleep disturbance is among the most common non-motor symptoms in PD, but its relationship with beta activity is unknown. To investigate the clinical potential of b...

Objective In the fourth year of the COVID-19 pandemic, mortality rates decreased, but the risk of neuropsychiatric disorders remained the same, with a prevalence of 3.8% of pediatric cases, including movement disorders (MD) and ataxia. Methods In this study, we report on a 10-year-old girl with hemichorea after SARS-CoV-2 infection and immunostain...

Background: Protein synthesis is a tightly controlled process, involving a host of translation-initiation factors and microRNA-associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental-delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding euk...

Background Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective and evidence-based treatment for idiopathic Parkinson's disease (iPD). A minority of patients does not sufficiently benefit from STN-DBS. Objective The predictive validity of the levodopa challenge for individual patients is analyzed. Methods Data from patients...

Background: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. Objectives: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. Methods: The STIM-CP trial was a prospective, single-arm, multicente...

In patients with Parkinson’s disease (PD), suppression of beta and increase in gamma oscillations in the subthalamic nucleus (STN) have been associated with both levodopa treatment and motor functions. Recent results suggest that modulation of the temporal dynamics of theses oscillations (bursting activity) might contain more information about path...

Introduction: Deep brain stimulation (DBS) is an established treatment in patients of various ages with pharmaco-resistant neurological disorders. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures, and on electrode connectivity t...

Bradykinesia is a cardinal hallmark of Parkinson’s disease (PD). Improvement in bradykinesia is an important signature of effective treatment. Finger tapping is commonly used to index bradykinesia, albeit these approaches largely rely on subjective clinical evaluations. Moreover, recently developed automated bradykinesia scoring tools are proprieta...

Introduction: Dystonia is a movement disorder of variable etiology and clinical presentation and is accompanied by tremor in about 50% of cases. Monogenic causes in dystonia are rare, but also in the group of non-monogenic dystonias 10-30% of patients report a family history of dystonia. This points to a number of patients currently classified as...

Deep brain stimulation (DBS) is an effective treatment and has provided unique insights into the dynamic circuit architecture of brain disorders. This Review illus- trates our current understanding of the pathophysiology of movement disorders and their underlying brain circuits that are modulated with DBS. It proposes princi- ples of pathological n...

The frontal cortex is involved in motor, cognitive, and affective brain functions. In humans, however, neuroanatomy-function mappings are predominantly derived from correlative neuroimaging studies. Hence, exactly which frontal domains causally mediate which function remains largely elusive. Herein, we leverage a strategy that allows for causal inf...

Introduction Deep brain stimulation (DBS) is an established treatment in patients with pharmaco-resistant neurological disorders of different ages. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures and on electrode connectivity to...

Background: Pallidal deep brain stimulation (DBS) effectively alleviates symptoms in dystonia patients, but may induce movement slowness as a side-effect. In Parkinson's disease, hypokinetic symptoms have been associated with increased beta oscillations (13-30 Hz). We hypothesize that this pattern is symptom-specific, thus accompanying DBS-induced...

Every decision that we make involves a conflict between exploiting our current knowledge of an action's value or exploring alternative courses of action that might lead to a better, or worse outcome. The sub-cortical nuclei that make up the basal ganglia have been proposed as a neural circuit that may contribute to resolving this explore-exploit 'd...

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of cl...

Pathologically increased beta power has been described as a biomarker for Parkinson’s disease (PD) and related to prolonged bursts of subthalamic beta synchronization. Here, we investigate the association between subthalamic beta dynamics and motor impairment in a cohort of 106 Parkinson’s patients in the ON- and OFF-medication state, using two dif...

Introduction and goal: The investigation of gender differences in treatment response is crucial for effective personalized therapies. With only 30%, women are underrepresented in trials for deep brain stimulation (DBS) in Parkinson's disease (PD). It is therefore important to evaluate gender-specific outcomes of DBS in PD in order to improve thera...

Background: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. Objective: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility asse...

Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in controlling motor symptoms in patients with Parkinson's disease. However, correct selection of stimulation parameters is pivotal to treatment success and currently follows a time-consuming and demanding trial-and-error process. We aimed to assess treatme...

Introduction Subthalamic Deep Brain Stimulation (STN-DBS) is a safe and well-established therapy for the management of motor symptoms refractory to best medical treatment in patients with Parkinson's disease (PD). Early intervention is discussed especially for Early-onset PD (EOPD) patients that present with an age of onset ≤ 45–50 years and see th...