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Background The cerebellum and primary motor cortex (M1) are crucial to coordinated and accurate movements of the upper limbs. There is also appreciable evidence that these two structures exert somewhat divergent influences upon proximal versus distal upper limb control. Here, we aimed to differentially regulate the contribution of the cerebellum and M1 to proximal and distal effectors during motor adaptation, with transcranial direct current stimulation (tDCS). For this, we employed tasks that promote similar motor demands, but isolate whole arm from hand/finger movements, in order to functionally segregate the hierarchy of upper limb control. Methods Both young and older adults took part in a visuomotor rotation task; where they adapted to a 60° visuomotor rotation using either a hand-held joystick (requiring finger/hand movements) or a 2D robotic manipulandum (requiring whole-arm reaching movements), while M1, cerebellar or sham tDCS was applied. Results We found that cerebellar stimulation improved adaptation performance when arm movements were required to complete the task, while in contrast stimulation of M1 enhanced adaptation during hand and finger movements only. This double-dissociation was replicated in an independent group of older adults, demonstrating that the behaviour remains intact in ageing. Conclusions These results suggest that stimulation of distinct motor areas can selectively improve motor adaptation in the proximal and distal upper limb. This also highlights new ways in which tDCS might be best applied to achieve reliable rehabilitation of upper limb motor deficits.

BackgroundThere is a current discord between the foundational theories underpinning motor learning and how we currently apply transcranial direct current stimulation (TDCS): the former is dependent on tight coupling of events while the latter is conducted with very low temporal resolution.ObjectiveHere we aimed to investigate the temporal specificity of stimulation by applying TDCS in short epochs, and coincidentally with movement, during a motor adaptation task.MethodsParticipants simultaneously adapted a reaching movement to two opposing velocity-dependent force-fields (clockwise and counter-clockwise), distinguished by a contextual leftward or rightward shift in the task display and cursor location respectively. Brief bouts (< 3 second) of event-related TDCS (er-TDCS) were applied over M1 or the cerebellum during movements for only one of these learning contexts.ResultsWe show that when short duration stimulation is applied to the cerebellum and yoked to movement, only those reaching movements performed simultaneously with stimulation are selectively enhanced, whilst similar and interleaved movements are left unaffected. We found no evidence of improved adaptation following M1 er-TDCS, as participants displayed equivalent levels of error during both stimulated and unstimulated movements. Similarly, participants in the sham stimulation group adapted comparably during left and right-shift trials.ConclusionsIt is proposed that the coupling of cerebellar stimulation and movement influences timing-dependent (i.e., Hebbian-like) mechanisms of plasticity to facilitate enhanced learning in the stimulated context.

Objective Respiratory abnormalities such as upper airway obstruction are common in Parkinson's disease (PD) and are an important cause of mortality and morbidity. We tested the effect of pedunculopontine region (PPNr) stimulation on respiratory maneuvers in human participants with PD, and separately recorded PPNr neural activity reflected in the local field potential (LFP) during these maneuvers. Methods Nine patients with deep brain stimulation electrodes in PPNr, and seven in globus pallidus interna (GPi) were studied during trials of maximal inspiration followed by forced expiration with stimulation OFF and ON. Local field potentials (LFPs) were recorded in the unstimulated condition. Results PEFR increased from 6.41 ± 0.63 L/sec in the OFF stimulation state to 7.5 L ± 0.65 L/sec in the ON stimulation state (z = −2.666, df = 8, P = 0.024). Percentage improvement in PEFR was strongly correlated with proximity of the stimulated electrode contact to the mesencephalic locomotor region in the rostral PPN (r = 0.814, n = 9, P = 0.008). Mean PPNr LFP power increased within the alpha band (7–11 Hz) during forced respiratory maneuvers (1.63 ± 0.16 μV2/Hz) compared to resting breathing (0.77 ± 0.16 μV2/Hz; z = −2.197, df = 6, P = 0.028). No changes in alpha activity or spirometric indices were seen with GPi recording or stimulation. Percentage improvement in PEFR was strongly positively correlated with increase in alpha power (r = 0.653, n = 14 (7 PPNr patients recorded bilaterally), P = 0.0096). Interpretation PPNr stimulation in PD improves indices of upper airway function. Increased alpha‐band activity is seen within the PPNr during forced respiratory maneuvers. Our findings suggest a link between the PPNr and respiratory performance in PD.

Adaptation of movements involving the proximal and distal upper-limb can be differentially facilitated by anodal transcranial direct current stimulation (TDCS) over the cerebellum and primary motor cortex (M1). Here, we build on this evidence by demonstrating that cathodal TDCS impairs motor adaptation with a differentiation of the proximal and distal upper-limbs, relative to the site of stimulation. Healthy young adults received M1 or cerebellar cathodal TDCS while making fast ‘shooting’ movements towards targets under 60° rotated visual feedback conditions, using either whole-arm reaching or fine hand and finger movements. As predicted, we found that cathodal cerebellar TDCS resulted in impairment of adaptation of movements with the whole arm compared to M1 and sham groups, which proved significantly different during late adaptation. However, cathodal cerebellar TDCS also significantly enhanced adaptation of hand movements, which may reflect changes in the excitability of the pathway between the cerebellum and M1. We found no evidence for change of adaptation rates using arm or finger movements following cathodal TDCS directly over M1. These results are further evidence to support movement specific effects of TDCS, and highlight how the connectivity and functional organisation of the cerebellum and M1 must be considered when designing TDCS-based therapies.

The multi-sensory nature of episodic memories indicates that communication between a multitude of brain areas is required for their effective creation and recollection. Previous studies have suggested that the effectiveness of memory processes depends on theta synchronization (4 Hz) of sensory areas relevant to the memory. This study aimed to manipulate theta synchronization between different sensory areas in order to further test this hypothesis. We intend to entrain visual cortex with 4 Hz alternating current stimulation (tACS), while simultaneously entraining auditory cortex with 4 Hz amplitude-modulated sounds. By entraining these different sensory areas, which pertain to learned audio–visual memory associations, we expect to find that when theta is synchronized across the different sensory areas, the memory performance would be enhanced compared to when theta is not synchronized across the sensory areas. We found no evidence for such an effect in this study. It is unclear whether this is due to an inability of 4 Hz tACS to entrain the visual cortex reliably, or whether sensory entrainment is not the underlying mechanism required for episodic memory.

[Background] There is an urgent need to identify individuals at risk of postural instability and gait difficulties, and the resulting propensity for falls, in Parkinson's disease., [Objectives] Given known relationships between posture and gait and degeneration of the cholinergic pedunculopontine nucleus, we investigated whether metrics of pedunculopontine nucleus microstructural integrity hold independent utility for predicting future postural instability and gait difficulties and whether they could be combined with other candidate biomarkers to improve prognostication of these symptoms., [Methods] We used stereotactic mapping of the pedunculopontine nucleus and diffusion tensor imaging to extract baseline pedunculopontine nucleus diffusivity metrics in 147 participants with Parkinson's disease and 65 controls enrolled in the Parkinson's Progression Markers Initiative. We also recorded known candidate markers of posture and gait changes: loss of caudate dopamine and CSF β‐amyloid 1‐42 levels at baseline; as well as longitudinal progression motor symptoms over 72‐months., [Results] Survival analyses revealed that reduced dopamine in the caudate and increased axial diffusivity in the pedunculopontine nucleus incurred independent risk of postural instability and gait difficulties. Binary logistic regression and receiver operating characteristics analysis in 117 participants with complete follow‐up data at 60 months revealed that only pedunculopontine nucleus microstructure provided more accurate discriminative ability for predicting future postural instability and gait difficulties than clinical and demographic variables alone., [Conclusion] Dopaminergic and cholinergic loss incur independent risk for future postural instability and gait difficulties, and pedunculopontine nucleus microstructure can be used to prognosticate these symptoms from early Parkinson's disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., The Parkinson's Progression Markers Initiative is sponsored and partially funded by the Michael J. Fox Foundation for Parkinson's Research. Other funding partners include a consortium of industry players, nonprofit organizations, and private individuals. Additional funding to support the current analysis was provided by the Wellcome Trust.

The dysregulation of endogenous rhythms within brain networks have been implicated in a broad range of motor and non-motor pathologies. Essential tremor (ET), classically the purview of a single aberrant pacemaker, has recently become associated with network-level dysfunction across multiple brain regions. Specifically, it has been suggested that motor cortex constitutes an important node in a tremor-generating network involving the cerebellum. Yet the mechanisms by which these regions relate to tremor remain a matter of considerable debate. We sought to discriminate the contributions of cerebral and cerebellar dysregulation by combining high-density electroencephalography with subject-specific structural MRI. For that, we contrasted ET with voluntary (mimicked) tremor before and after ingestion of alcohol to regulate the tremorgenic networks. Our results demonstrate distinct loci of cortical tremor coherence, most pronounced over the sensorimotor cortices in healthy controls, but more frontal motor areas in ET-patients consistent with a heightened involvement of the supplementary motor area. We further demonstrate that the reduction in tremor amplitude associated with alcohol intake is reflected in altered cerebellar - but not cerebral - coupling with movement. Taken together, these findings implicate tremor emergence as principally associated with increases in activity within frontal motor regions, whereas modulation of the amplitude of established tremor relates to changes in cerebellar activity. These findings progress a mechanistic understanding of ET and implicate network-level vulnerabilities in the rhythmic nature of communication throughout the brain.

People with Parkinson’s disease (PD) experience motor symptoms that are affected by sensory information in the environment. Sensory attenuation describes the modulation of sensory input caused by motor intent. This appears to be altered in PD and may index important sensorimotor processes underpinning PD symptoms. We review recent findings investigating sensory attenuation and reconcile seemingly disparate results with an emphasis on task-relevance in the modulation of sensory input. Sensory attenuation paradigms, across different sensory modalities, capture how two identical stimuli can elicit markedly different perceptual experiences depending on our predictions of the event, but also the context in which the event occurs. In particular, it appears as though contextual information may be used to suppress or facilitate a response to a stimulus on the basis of task-relevance. We support this viewpoint by considering the role of the basal ganglia in task-relevant sensory filtering and the use of contextual signals in complex environments to shape action and perception. This perspective highlights the dual effect of basal ganglia dysfunction in PD, whereby a reduced capacity to filter task-relevant signals harms the ability to integrate contextual cues, just when such cues are required to effectively navigate and interact with our environment. Finally, we suggest how this framework might be used to establish principles for effective rehabilitation in the treatment of PD.

There is a pressing need to better understand the mechanisms underpinning the increasingly recognised non-motor deficits in Parkinson’s disease. Brain activity during Parkinson’s disease is excessively synchronized within the beta range (12–30Hz). However, relatively little is known about how the abnormal beta rhythms impact on non-motor symptoms. In healthy adults, beta desynchronization is necessary for successful episodic memory formation. We investigated whether there was a direct relationship between decreased beta modulation and memory formation in Parkinson’s disease. Electroencephalography recordings were made during an established memory-encoding paradigm. Parkinson’s participants showed impaired memory strength (P = 0.023) and reduced beta desynchronization (P = 0.014) relative to controls. Longer disease duration was correlated with a larger reduction in beta desynchronization, and a concomitant reduction in memory performance. These novel results extend the notion that pathological beta activity is causally implicated in the motor and (lesser appreciated) non-motor deficits inherent to Parkinson’s disease.

Purpose of Review: This review aims to survey recent trends in electrical forms of neuromodulation, with a specific application to Parkinson’s disease (PD). Emerging trends are identified, highlighting synergies in state-of-the-art neuromodulation strategies, with directions for future improvements in stimulation efficacy suggested. Recent Findings: Deep brain stimulation remains the most common and effective form of electrical stimulation for the treatment of PD. Evidence suggests that transcranial direct current stimulation (tDCS) most likely impacts the motor symptoms of the disease, with the most prominent results relating to rehabilitation. However, utility is limited due to its weak effects and high variability, with medication state a key confound for efficacy level. Recent innovations in transcranial alternating current stimulation (tACS) offer new areas for investigation. Summary: Our understanding of the mechanistic foundations of electrical current stimulation is advancing and as it does so, trends emerge which steer future clinical trials towards greater efficacy.

Key points Healthy ageing in man is associated with a decline in motor adaptation. Transcranial direct current stimulation (TDCS) over the primary motor cortex (M1) or the lateral cerebellum can improve motor adaptation in young and older adults, but as yet no direct comparisons of TDCS effects exist between the two age groups and the two stimulation sites. TDCS over M1 enhanced the motor adaptation in both age groups by ∼30% relative to their respective non-stimulated groups and improved the performance of older adults to the extent that it compared with that of young adults without stimulation. The study suggests that the plastic mechanisms activated by TDCS that underpin improvements in motor behaviour in young adults remain available in older adults. The results indicate that TDCS may be a useful tool to help combat the normal decline in motor performance seen in normal healthy ageing. Abstract Healthy ageing is characterised by deterioration of motor performance. In normal circumstances motor adaptation corrects for movements’ inaccuracies and as such, it is critical in maintaining optimal motor control. However, motor adaptation performance is also known to decline with age. Anodal transcranial direct current stimulation (TDCS) of the cerebellum and the primary motor cortex (M1) have been found to improve visuomotor adaptation in healthy young and older adults. However, no study has directly compared the effect of TDCS on motor adaptation between the two age populations. The aim of our study was to investigate whether the application of anodal TDCS over the lateral cerebellum and M1 affected motor adaptation in young and older adults similarly. Young and older participants performed a visuomotor rotation task and concurrently received TDCS over the left M1, the right cerebellum or received sham stimulation. Our results replicated the finding that older adults are impaired compared to the young adults in visuomotor adaptation. At the end of the adaptation session, older adults displayed a larger error (−17 deg) than the young adults (−10 deg). The stimulation of the lateral cerebellum did not change the adaptation in both age groups. In contrast, anodal TDCS over M1 improved initial adaptation in both age groups by around 30% compared to sham and this improvement lasted up to 40 min after the end of the stimulation. These results demonstrate that TDCS of M1 can enhance visuomotor adaptation, via mechanisms that remain available in the ageing population.

Non-invasive transcranial brain stimulation (NTBS) techniques have a wide range of applications but also suffer from a number of limitations mainly related to poor specificity of intervention and variable effect size. These limitations motivated recent efforts to focus on the temporal dimension of NTBS with respect to the ongoing brain activity. Temporal patterns of ongoing neuronal activity, in particular brain oscillations and their fluctuations, can be traced with electro- or magnetoencephalography (EEG/MEG), to guide the timing as well as the stimulation settings of NTBS. These novel, online and offline EEG/MEG-guided NTBS-approaches are tailored to specifically interact with the underlying brain activity. Online EEG/MEG has been used to guide the timing of NTBS (i.e., when to stimulate): by taking into account instantaneous phase or power of oscillatory brain activity, NTBS can be aligned to fluctuations in excitability states. Moreover, offline EEG/MEG recordings prior to interventions can inform researchers and clinicians how to stimulate: by frequency-tuning NTBS to the oscillation of interest, intrinsic brain oscillations can be up- or down-regulated. In this paper, we provide an overview of existing approaches and ideas of EEG/MEG-guided interventions, and their promises and caveats. We point out potential future lines of research to address challenges.

Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. Both have been associated with similar patterns of network activation leading to the suggestion that they may result from similar network dysfunction, specifically involving the cerebellum. Here, we demonstrate that parkinsonian tremors and ETs result from distinct patterns of interactions between neural oscillators. These patterns are reflected in the tremors' derived frequency tolerance, a novel measure readily attainable from bedside accelerometry. Frequency tolerance characterizes the temporal evolution of tremor by quantifying the range of frequencies over which the tremor may be considered stable. We found that patients with PD (N= 24) and ET (N= 21) were separable based on their frequency tolerance, with PD associated with a broad range of stable frequencies whereas ET displayed characteristics consistent with a more finely tuned oscillatory drive. Furthermore, tremor was selectively entrained by transcranial alternating current stimulation applied over cerebellum. Narrow frequency tolerances predicted stronger entrainment of tremor by stimulation, providing good evidence that the cerebellum plays an important role in pacing those tremors. The different patterns of frequency tolerance could be captured with a simple model based on a broadly coupled set of neural oscillators for PD, but a more finely tuned set of oscillators in ET. Together, these results reveal a potential organizational principle of the human motor system, whose disruption in PD and ET dictates how patients respond to empirical, and potentially therapeutic, interventions that interact with their underlying pathophysiology.

Tremor is a debilitating comorbidity which can develop following acquired brain injury (ABI). There is well-established evidence for the efficacy of thalamic deep brain stimulation (DBS) in the treatment of tremor, particularly in PD and ET3. The standard electrode target is the ventralis intermedius (Vim) thalamic nucleus. DBS is also effective for treating more complex tremor syndromes such as those associated with MS. For complex tremor syndromes, often with proximal and distal components, DBS targeted to the ventro-oralis posterior (Vop)/zona incerta (ZI) has shown good efficacy. This is explained by the fact that in Vop/ZI DBS, the electrode is sited in such a way that it traverses both areas, and stimulation can be adjusted to blend the effects of Vop stimulation, which tends to target proximal tremor, and ZI stimulation, effective for distal tremor. Like MS tremor, post-ABI tremor is a highly variable syndrome, with heterogenous patterns of neural damage producing complex movements composed of distal and proximal components. Positive results have been reported from trials of DBS for post-ABI tremor, but mostly in the form of case reports and small series. Here we report surgical experience and follow-up of a series of 8 patients diagnosed with post-ABI tremor resulting from acquired brain injury (ABI) and treated with DBS to the contralateral Vop/ZI. To the authors' knowledge this is the largest cohort study reported to date.

Tremor represents one of the most prominent examples of aberrant synchronisation within the human motor system, and Essential Tremor (ET) is by far the most common tremor disorder. Yet, even within ET there is considerable variation, and patients may have contrasting amounts of postural and intention tremor. Recently, Pedrosa et al. (2013) challenged tremor circuits in a cohort of patients presenting with ET, by applying low-frequency deep brain stimulation within thalamus. This interventional approach provided strong evidence that distinct (yet possibly overlapping) neural substrates are responsible for postural and intention tremor in ET. Intention tremor, and not postural tremor, was exacerbated by low frequency stimulation, and the effect was localised in the region of the ventrolateral thalamus in such a way as to implicate cerebello-thalamic pathways. These results, taken in conjunction with the contemporary literature, reveal that pathological changes exaggerate oscillatory synchrony in selective components of an extensive and distributed motor network, and that synchronisation within these networks is further regulated according to motor state. Through a combination of pathological and more dynamic physiological factors, activity then spills out into the periphery in the form of tremor. The findings of Pedrosa et al. (2013) are timely as they coincide with an emerging notion that tremor may result through selective dysregulation within a broader tremorgenic network.

Oscillatory activity in the beta (13-30 Hz) frequency band is widespread in cortico-basal ganglia circuits, and becomes prominent in Parkinson's disease (PD). Here we develop the hypothesis that the degree of synchronization in this frequency band is a critical factor in gating computation across a population of neurons, with increases in beta band synchrony entailing a loss of information-coding space and hence computational capacity. Task and context drive this dynamic gating, so that for each state there will be an optimal level of network synchrony, and levels lower or higher than this will impair behavioural performance. Thus, both the pathological exaggeration of synchrony, as observed in PD, and the ability of interventions like deep brain stimulation (DBS) to excessively suppress synchrony can potentially lead to impairments in behavioural performance. Indeed, under physiological conditions, the manipulation of computational capacity by beta activity may itself present a mechanism of action selection and maintenance. © 2014 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley and Sons Ltd.

Oscillations form a ubiquitous feature of the central nervous system. Evidence is accruing from cortical and sub-cortical recordings that these rhythms may be functionally important, although the precise details of their roles remain unclear. The basal ganglia share this predilection for rhythmic activity which, as we see in Parkinson's disease, becomes further enhanced in the dopamine depleted state. While certain cortical rhythms appear to penetrate the basal ganglia, others are transformed or blocked. Here, we discuss the functional association of oscillations in the basal ganglia and their relationship with cortical activity. We further explore the neural underpinnings of such oscillatory activity, including the important balance to be struck between facilitating information transmission and limiting information coding capacity. Finally, we introduce the notion that synchronised oscillatory activity can be broadly categorised as immutability promoting rhythms that reinforce incumbent processes, and mutability promoting rhythms that favour novel processing. © 2013 Elsevier Inc.

Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral. © 2012 The Author.

The mechanisms by which neural signals are encoded to produce conscious sensations remain a central question in neuroscience. Invasive recordings from human brain structures in vivo give us the opportunity to study neural correlates of these sensations. Pain is a sensation fundamental to survival and its subjective nature in the clinical setting makes it difficult to quantify. It remains without direct objective neuronal correlates. Here we describe an 8–14 Hz, spindle-shaped neural signal present in both the sensory thalamus and periaqueductal gray area (PAG) in humans that directly correlates to the subjective reporting of pain intensity. Local field potentials (LFPs) recorded by deep brain macroelectrodes reveal the ensemble activity of neuronal groups in particular brain regions.1 The oscillatory amplitude of such ensembles is proportionate to the degree of synchrony with which they oscillate.2 Properties of oscillations including their synchrony, frequency, and corresponding power spectra vary both between brain structures and dynamically, depending upon the activity performed.3 ### Methods. Twelve patients (11 male, 1 female) underwent deep brain stimulation for treatment of chronic neuropathic pain. Etiology was as follows; poststroke pain (4), phantom limb pain (3), facial pain of various causes (4), and brachial plexus injury (1). Nuclei targeted were periaqueductal gray (PAG) alone in 3 patients, ventroposterolateral/medial nucleus of the thalamus (VPL/VPM) in 6 patients, and both in 3 patients. This was decided upon based on clinical grounds (in general, sensory thalamus was avoided if the patient had had a thalamic stroke). Three patients …

Surprising events markedly affect behaviour and cognition, yet the underlying mechanism is unclear. Surprise recruits a brain mechanism that globally suppresses motor activity, ostensibly via the subthalamic nucleus (STN) of the basal ganglia. Here, we tested whether this suppressive mechanism extends beyond skeletomotor suppression and also affects cognition (here, verbal working memory, WM). We recorded scalp-EEG (electrophysiology) in healthy participants and STN local field potentials in Parkinson's patients during a task in which surprise disrupted WM. For scalp-EEG, surprising events engage the same independent neural signal component that indexes action stopping in a stop-signal task. Importantly, the degree of this recruitment mediates surprise-related WM decrements. Intracranially, STN activity is also increased post surprise, especially when WM is interrupted. These results suggest that surprise interrupts cognition via the same fronto-basal ganglia mechanism that interrupts action. This motivates a new neural theory of how cognition is interrupted, and how distraction arises after surprising events., Surprising events affect ongoing behaviour and cognitive processing, yet the underlying neural mechanisms remain unclear. Wessel and colleagues show that surprise recruits a motor suppression mechanism which may be implemented via the sub-thalamic nucleus and interrupts working memory performance.

Groups III and IV afferents carry sensory information regarding the muscle exercise pressor reflex, although the central integrating circuits of the reflex in humans are still poorly defined. Emerging evidence reports that the periaqueductal gray (PAG) could be a major site for integrating the “central command” component that initiates the cardiovascular response to exercise, since this area is activated during exercise and direct stimulation of the dorsal PAG causes an increase in arterial blood pressure (ABP) in humans. Here we recorded local field potentials (LFPs) from various “deep” brain nuclei during exercise tasks designed to elicit the muscle pressor reflex. The patients studied had undergone neurosurgery for the treatment of movement or pain disorders, thus had electrodes implanted stereotactically either in the PAG, subthalamic nucleus, globus pallidus interna, thalamus, hypothalamus, or anterior cingulate cortex. Fast Fourier transform analysis was applied to the neurograms to identify the power of fundamental spectral frequencies. Our PAG patients showed significant increases in LFP power at frequencies from 4 to 8 Hz ( P < 0.01), 8 to 12 Hz ( P < 0.001), and 12 to 25 Hz ( P < 0.001). These periods were associated with maintained elevated ABP during muscle occlusion following exercise. Further increases in exercise intensity resulted in corresponding increases in PAG activity and ABP. No significant changes were seen in the activity of other nuclei during occlusion. These electrophysiological data provide direct evidence for a role of the PAG in the integrating neurocircuitry of the exercise pressor reflex in humans.

We measured reaction times during a stop-signal task while patients with Parkinson's disease were on and off unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). While reaction times to a “go” stimulus improved, there was no change in reaction times to the “stop” stimulus (SSRTs). However, changes in SSRTs induced by DBS were highly dependent on baseline SSRTs (measured off stimulation), with the greatest improvements being achieved by those with particularly slow reaction times. We therefore selected only those patients whose baseline SSRTs were within the limits of a control sample (N = 10). In this group, SSRTs became slower when DBS was on. This finding suggests a role for the STN in response inhibition, which can be interrupted by DBS, observable only when more general improvements in Parkinson's function are minimised. We also compared the effects of unilateral left and right sided stimulation. We found a greater increase in SSRTs after DBS of the left STN.

Objective The objective of this study was to use motor unit coupling in the time and frequency domains to obtain evidence of changes in motoneuronal drive during walking in subjects with stroke. Methods Paired tibialis anterior (TA) EMG activity was sampled during the swing phase of treadmill walking in eight subjects with unilateral stroke. Results On the unaffected side, short-term synchronization was evident from the presence of a narrow central peak in cumulant densities and from the presence of significant coherence between these signals in the 10–25 Hz band. Such indicators of short-term synchrony were either absent or very small on the affected side. Instead, pronounced 10 Hz coupling was observed. Conclusions It is suggested that reduced corticospinal drive to the spinal motoneurones is responsible for the reduced short-term synchrony and coherence in the 10–25 Hz frequency band on the affected side in hemiplegic patients during walking. Significance This is of importance for understanding the mechanisms responsible for reduced gait ability and development of new strategies for gait restoration.

The physician is often seeking more efficient ways of performing patient assessments. Currently, measuring tremor frequency requires expensive and bulky equipment. We propose the use of the in-built accelerometer of the iPhone via the iSeismo application for rapid measurement of tremor frequency. We use this device in a series of 7 different tremor cases, and show that the frequency measurements on the iSeismo graph closely match the more sophisticated EMG analysis during tremor. This is a preliminary confirmation of the usefulness of this device in the clinical setting for quick assessment of the dominant frequency component in a variety of tremors.

The subthalamic nucleus (STN) is thought to play a central role in modulating responses during conflict. Computational models have suggested that the location of the STN in the basal ganglia, as well as its numerous connections to conflict-related cortical structures, allows it to be ideally situated to act as a global inhibitor during conflict. Additionally, recent behavioral experiments have shown that deep brain stimulation to the STN results in impulsivity during high-conflict situations. However, the precise mechanisms that mediate the “hold-your-horses” function of the STN remain unclear. We recorded from deep brain stimulation electrodes implanted bilaterally in the STN of 13 human subjects with Parkinson's disease while they performed a flanker task. The incongruent trials with the shortest reaction times showed no behavioral or electrophysiological differences from congruent trials, suggesting that the distracter stimuli were successfully ignored. In these trials, cue-locked STN theta band activity demonstrated phase alignment across trials and was followed by a periresponse increase in theta power. In contrast, incongruent trials with longer reaction times demonstrated a relative reduction in theta phase alignment followed by higher theta power. Theta phase alignment negatively correlated with subject reaction time, and theta power positively correlated with trial reaction time. Thus, when conflicting stimuli are not properly ignored, disruption of STN theta phase alignment may help operationalize the hold-your-horses role of the nucleus, whereas later increases in the amplitude of theta oscillations may help overcome this function.

Background Gain-of-function mutations in the ATP-sensitive potassium channel can cause permanent neonatal diabetes mellitus (PNDM) or neonatal diabetes accompanied by a constellation of neurological symptoms (iDEND syndrome). Studies of a mouse model of iDEND syndrome revealed that cerebellar Purkinje cell electrical activity was impaired and that the mice exhibited poor motor coordination. In this study, we probed the hand-eye coordination of PNDM and iDEND patients using visual tracking tasks to see if poor motor coordination is also a feature of the human disease. Methods Control participants (n = 14), patients with iDEND syndrome (n = 6 or 7), and patients with PNDM (n = 7) completed three computer-based tasks in which a moving target was tracked with a joystick-controlled cursor. Patients with PNDM and iDEND were being treated with sulphonylurea drugs at the time of testing. Results No differences were seen between PNDM patients and controls. Patients with iDEND syndrome were significantly less accurate than controls in two of the three tasks. The greatest differences were seen when iDEND patients tracked blanked targets, i.e. when predictive tracking was required. In this task, iDEND patients incurred more discrepancy errors (p = 0.009) and more velocity errors (p = 0.009) than controls. Conclusions These results identify impaired hand-eye coordination as a new clinical feature of iDEND. The aetiology of this feature is likely to involve cerebellar dysfunction. The data further suggest that sulphonylurea doses that control the diabetes of these patients may be insufficient to fully correct their neurological symptoms.

Brain-derived neurotrophic factor (BDNF) plays an important role in learning, memory, and brain plasticity. Humans with a val66met polymorphism in the BDNF gene have reduced levels of BDNF and alterations in motor learning and short-term cortical plasticity. In the current study, we sought to further explore the role of BDNF in motor learning by testing human subjects on a visuomotor adaptation task. In experiment 1, 21 subjects with the polymorphism (val/met) and 21 matched controls (val/val) were tested during learning, short-term retention (45 min), long-term retention (24 h), and de-adaptation of a 60° visuomotor deviation. We measured both mean error as well as rate of adaptation during each session. There was no difference in mean error between groups; however, val/met subjects had a reduced rate of adaptation during learning as well as during long-term retention, but not short-term retention or de-adaptation. In experiment 2, 12 val/met and 12 val/val subjects were tested on a larger 80° deviation, revealing a more pronounced difference in mean error during adaptation than the 60° deviation. These results suggest that BDNF may play an important role in visuomotor adaptive processes in the human. © 2012 Springer-Verlag.

The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or whether higher cognitive centers are alone responsible. We show stimulus-driven desychronization in the beta band (15–35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials—in which response times were elongated due to the Stroop effect—a resynchronization was seen in the beta band before response. Crucially, in the incongruent trials during which the participant was unable to withhold the prepotent response, this resynchronization occurred after response onset. We suggest that this beta-band resynchronization pauses the motor system until conflict can be resolved.

Oscillatory activities in the brain within the beta (15–30 Hz) and gamma (70–90 Hz) ranges have been implicated in the generation of voluntary movement. However, their roles remain unclear. Here, we record local field potential activity from the region of the subthalamic nucleus during movement of the contralateral limb in 11 patients with Parkinson's disease. Patients were on their normal dopaminergic medication and were cued to perform arm-reaching movements after a delay period at three different speeds: ‘slow’, ‘normal’, and ‘fast’. Beta activity desynchronized earlier in response to the cue indicating an upcoming fast reach than to the cues for slow or normal speed movement. There was no difference in the degree of beta desynchronization between reaching speeds and beta desynchronization was established prior to movement onset in all cases. In contrast, synchronization in the gamma range developed during the reaching movement, and was especially pronounced during fast reaching. Thus the timing of suppression in the beta band depended on task demands, whereas the degree of increase in gamma oscillations depended on movement speed. These findings point to functionally segregated roles for different oscillatory frequencies in motor preparation and performance.

Timing is central to all motor behavior, especially repetitive or rhythmic movements. Such complex programs are underpinned by a network of motor structures, including the cerebellum, motor cortex, and basal ganglia. Patients with Parkinson's disease (PD) are impaired in some aspects of timing behavior, presumably as a result of the disruption to basal ganglia function. However, direct evidence that this deficit is specifically due to basal ganglia dysfunction is limited. Here, we sought to further understand the role of the basal ganglia in motor timing by studying PD patients with implanted subthalamic nucleus (STN) electrodes. Patients performed a synchronization-continuation tapping task at 500 ms and 2000 ms intervals both off and on therapeutic high frequency stimulation of the STN. Our results show that the mean tap interval was not affected by STN stimulation. However, in the un-stimulated state variability of tapping was abnormally high relative to controls, and this deficit was significantly improved, even normalized, with stimulation. Moreover, when partitioning the variance into central and peripheral motor components according to the Wing and Kristofferson model (1973), a selective reduction of central, but not motor, variance was revealed. The effect of stimulation on central variance was dependent on off-stimulation performance. These results demonstrate that STN stimulation can improve rhythmic movement performance in PD through an effect on central timing. Our experimental approach strongly implicates the STN, and more generally the basal ganglia, in the control of timing stability.

Response inhibition as measured during a stop-signal task refers to the ability to halt an action that has already been set in motion. Cortical and sub-cortical structures, such as the subthalamic nucleus (STN), that are active during attempts to inhibit action are thought to contribute to a ‘stop-process’ that must gain dominance over a ‘go-process’ if inhibition is to be successful. We recorded local field potential activity from the STN of Parkinson's disease patients with implanted deep brain stimulation electrodes during a stop-signal task. In particular we measured activity in the STN that has traditionally been associated with motor action (gamma-band, 60–100 Hz) and inhibition (beta-band, 10–30 Hz). Our data support the idea that beta activity in the STN is related to the inhibition of motor action. Further, we report that gamma oscillatory activity responds robustly to stop-signals as well as go-signals. This unexpected finding might suggest that gamma activity supports a go-process that not only responds to go-signals, but is also sensitive to stimuli that signal stopping.

We report a case of induced oscillopsia caused by deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN). Recent reports have described involuntary oscillopsia during DBS of the PPN that patients have described as trembling vision. Here we substantiate this observation using infra-red eye tracking. It has been suggested that this phenomenon might be used as an indicator of accurate targeting of the PPN with DBS. Our observations suggest that this phenomenon may not be related to a constricted anatomical structure and therefore such practise may be unwise. Scrutiny has led us to believe that the oscillopsia in our patient is not caused by direct stimulation of the oculomotor nerve as suggested in a previous report, but by stimulation of fibres in the uncinate fasciculus of the cerebellum and the superior cerebellar peduncle, which in turn stimulate the saccadic pre-motor neurones in the brainstem.

Local field potential (LFP) and Electromyographic (EMG) signals were recorded from 12 Parkinsonian patients with tremor-dominant symptoms as they performed passive and voluntary movements. The LFP signals were categorised into episodes of tremorous and atremorous activity (identified through EMG power spectra), then divided into delta (2–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), and beta (13–30 Hz) frequency bands. Modulation of LFP oscillatory activity in these frequency bands were compared between the subthalamic nucleus (STN) and the globus pallidus internus (GPi) to determine if differential tremor-related characteristics were identifiable for either target. Our results suggest that such local characteristic activity is identifiable in the STN, and thus could be a target for initial development of a closed-loop demand driven stimulator device which capitalises on such activity to trigger stimulation, even during voluntary movement activity.

Surface electromyograms (EMGs) are valuable in the pathophysiological study and clinical treatment for dystonia. These recordings are critically often contaminated by cardiac artefact. Our objective of this study was to evaluate the performance of an adaptive noise cancellation filter in removing electrocardiogram (ECG) interference from surface EMGs recorded from the trapezius muscles of patients with cervical dystonia. Performance of the proposed recursive-least-square adaptive filter was first quantified by coherence and signal-to-noise ratio measures in simulated noisy EMG signals. The influence of parameters such as the signal-to-noise ratio, forgetting factor, filter order and regularization factor were assessed. Fast convergence of the recursive-least-square algorithm enabled the filter to track complex dystonic EMGs and effectively remove ECG noise. This adaptive filter procedure proved a reliable and efficient tool to remove ECG artefact from surface EMGs with mixed and varied patterns of transient, short and long lasting dystonic contractions.

Cluster headache is a severely debilitating disorder that can remain unrelieved by current pharmacotherapy. Alongside ablative neurosurgical procedures, neuromodulatory treatments of deep brain stimulation (DBS) and occipital nerve simulation have emerged in the last few years as effective treatments for medically refractory cluster headaches. Pioneers in the field have sought to publish guidelines for neurosurgical treatment; however, only small case series with limited long-term follow-up have been published. Controversy remains over which surgical treatments are best and in which circumstances to intervene. Here we review current data on neurosurgical interventions for chronic cluster headache focusing upon DBS and occipital nerve stimulation, and discuss the indications for and putative mechanisms of DBS including translational insights from functional neuroimaging, diffusion weighted tractography, magnetoencephalography and invasive neurophysiology.

Parkinson's disease is treated pharmacologically with dopamine replacement medication and, more recently, by stimulating basal-ganglia nuclei such as the subthalamic nucleus (STN). Depth recordings after this procedure have revealed excessive activity at frequencies between 8 and 35 Hz (Brown et al., 2001; Kuhn et al., 2004; Priori et al., 2004) that are reduced by dopamine therapy in tandem with improvements in bradykinesia/rigidity, but not tremor (Kuhn et al., 2006). It has also been shown that improvements in motor symptoms after dopamine correlate with single unit activity in the beta range (Weinberger et al., 2006). We recorded local field potentials (LFPs) from the subthalamic nucleus of patients with Parkinson's disease (PD) after surgery to implant deep brain stimulating electrodes while they were on and off dopaminergic medication. As well as replicating Kuhn et al., using the same patients we were able to extend Weinberger et al. to show that LFP beta oscillatory activity correlated with the degree of improvement in bradykinesia/rigidity, but not tremor, after dopamine medication. We also found that the power of beta oscillatory activity uniquely predicted improvements in bradykinesia/rigidity, but again not tremor, after stimulation of the STN in a regression analysis. However improvements after STN stimulation related inversely to beta power, possibly reflecting the accuracy of the electrode placement and/or the limits of STN stimulation in patients with the greatest levels of beta oscillatory activity.

Udgivelsesdato: 2009-Jan Deep brain stimulation (DBS) is used to alleviate chronic pain. Using magnetoencephalography (MEG) to study the mechanisms of DBS for pain is difficult because of the artefact caused by the stimulator. We were able to record activity over the occipital lobe of a patient using DBS for phantom limb pain during presentation of a visual stimulus. This demonstrates that MEG can be used to study patients undergoing DBS provided control stimuli are used to check the reliability of the data. We then asked the patient to rate his pain during and off DBS. Correlations were found between these ratings and power in theta (6-9) and beta bands (12-30). Further, there was a tendency for frequencies under 25 Hz to correlate with each other after a period off stimulation compared with immediately after DBS. The results are interpreted as reflecting abnormal thalamocortical dynamics, previously implicated in painful syndromes.

Summary Voluntary movement is accompanied by changes in the degree to which neurons in the brain synchronize their activity within discrete frequency ranges. Two patterns of movement-related oscillatory activity stand out in human cortical motor areas. Activity in the beta frequency (15–30 Hz) band is prominent during tonic contractions but is attenuated prior to and during voluntary movement [1]. Without such attenuation, movement may be slowed, leading to the suggestion that beta activity promotes postural and tonic contraction, possibly at a cost to the generation of new movements [2, 3]. In contrast, activity in the gamma (60–90 Hz) band increases during movement [4]. The direction of change suggests that gamma activity might facilitate motor processing. In correspondence with this, increased frontal gamma activity is related with reduced reaction times [5]. Yet the possibility remains that these functional correlations reflect an epiphenomenal rather than causal relationship. Here we provide strong evidence that oscillatory activities at the cortical level are mechanistically involved in determining motor behavior and can even improve performance. By driving cortical oscillations using noninvasive electrical stimulation, we show opposing effects at beta and gamma frequencies and interactions with motor task that reveal the potential quantitative importance of oscillations in motor behavior., Highlights ► Cortical driving at 20 and 70 Hz slows and speeds voluntary force generation ► Performance can be enhanced even during contractions made as fast as possible ► Scale of effects of cortical driving depend on the nature of the cued motor task

Deep brain stimulation is an increasingly prevalent surgical option in the treatment of a multitude of neurological conditions, most notably Parkinson's disease. The development of a neurofeedback device is driven primarily by stimulator habituation, surgical risk factors, the cost of battery replacement, and reported neuropsychiatric side-effects under prolonged chronic administration. Here we present two distinct regimes for stimulation delivery in chronic and acute symptomatic conditions, presented in the context of Parkinsonian bradykinesias and tremor. Implementation strategies are discussed with a focus on vector-autoregressive hidden Markov models for tremor prediction. Detection of simple motor actions versus tremor are compared in a preliminary performance analysis.

High frequency deep brain stimulation of the thalamus can help ameliorate severe essential tremor. Here we explore how the efficacy, efficiency and selectivity of thalamic deep brain stimulation might be improved in this condition. We started from the hypothesis that the effects of electrical stimulation on essential tremor may be phase dependent, and that, in particular, there are tremor phases at which stimuli preferentially lead to a reduction in the amplitude of tremor. The latter could be exploited to improve deep brain stimulation, particularly if tremor suppression could be reinforced by cumulative effects. Accordingly, we stimulated 10 patients with essential tremor and thalamic electrodes, while recording tremor amplitude and phase. Stimulation near the postural tremor frequency entrained tremor. Tremor amplitude was also modulated depending on the phase at which stimulation pulses were delivered in the tremor cycle. Stimuli in one half of the tremor cycle reduced median tremor amplitude by ∼10%, while those in the opposite half of the tremor cycle increased tremor amplitude by a similar amount. At optimal phase alignment tremor suppression reached 27%. Moreover, tremor amplitude showed a non-linear increase in the degree of suppression with successive stimuli; tremor suppression was increased threefold if a stimulus was preceded by four stimuli with a similar phase relationship with respect to the tremor, suggesting cumulative, possibly plastic, effects. The present results pave the way for a stimulation system that tracks tremor phase to control when deep brain stimulation pulses are delivered to treat essential tremor. This would allow treatment effects to be maximized by focussing stimulation on the optimal phase for suppression and by ensuring that this is repeated over many cycles so as to harness cumulative effects. Such a system might potentially achieve tremor control with far less power demand and greater specificity than current high frequency stimulation approaches, and may lower the risk for tolerance and rebound.

BACKGROUND: Deep brain stimulation (DBS) of subcortical brain areas such as the periaqueductal grey and subthalamic nucleus has been shown to alter cardiovascular autonomic performance. The supramedullary circuitry controlling respiratory airways is not well defined and has not been tested in humans. OBJECTIVE: To use direct electric stimulation via DBS macroelectrodes to test whether airway resistance could be manipulated by these areas in awake humans. METHODS: Thirty-seven patients with in-dwelling deep brain electrodes for movement disorders or chronic pain underwent spirometry according to the European Respiratory Society guidelines. Testing was performed randomly 3 times on stimulation and 3 times off stimulation; patients were blinded to the test. Thoracic diameter changes were measured by a circumferential pressure-sensitive thoracic band. Ten periaqueductal grey and 10 subthalamic nucleus patients were tested. To control for confounding pain and movement disorder relief, the sensory thalamus in 7 patients and globus pallidus interna in 10 patients, respectively, were also tested. RESULTS: Peak expiratory flow rate (PEFR) increased significantly with periaqueductal grey and subthalamic nucleus stimulation by up to 14% (P = .02 and .005, respectively, paired-samples Student t tests). Stimulation of control nuclei produced no significant PEFR change. Similarly, changes in thoracic diameter reflecting skeletal activity rather than airway caliber did not correlate with the improvement in PEFR. Forced expiratory volume in 1 second was unchanged by stimulation. CONCLUSION: DBS can improve PEFR in chronic pain and movement disorder patients. This finding provides insights into the neural modulation of respiratory performance and may explain some of the subjective benefits of DBS.