Volitional Control of Brain Motor Activity and Its Therapeutic Potential.

BACKGROUND: Neurofeedback training is a closed-loop neuromodulatory technique in which real-time feedback of brain activity and connectivity is provided to the participant for the purpose of volitional neural control. Through practice and reinforcement, such learning has been shown to facilitate measurable changes in brain function and behavior. OBJECTIVES: In this review, we examine how neurofeedback, coupled with motor imagery training, has the potential to improve or normalize motor function in neurological diseases such as Parkinson disease and chronic stroke. We will also explore neurofeedback in the context of brain-machine interfaces (BMIs), discussing both noninvasive and invasive methods which have been used to power external devices (eg, robot hand orthosis or exoskeleton) in the context of motor neurorehabilitation. CONCLUSIONS: The published literature provides mounting high-quality evidence that neurofeedback and BMI control may lead to clinically relevant changes in brain function and behavior.

Endurance of Short Pulse Width Thalamic Stimulation Efficacy in Intention Tremor.

The benefit of short pulse width stimulation in patients suffering from essential tremor (ET) refractory to thalamic deep brain stimulation remains controversial. Here, we add to the minimal body of evidence available by reporting the effect of this type of stimulation in 3 patients with a persistent and severe intention tremor component despite iterative DBS setting adjustments. While a reduction in pulse width to 30 µs initially showed promise in these patients by improving tremor control and mitigating cerebellar side effects arguably by widening the therapeutic window, these benefits seemed to dissipate during early follow-up. Our experience supports the need for measuring longer-term outcomes when reporting the usefulness of this mode of stimulation in ET.

Short Versus Conventional Pulse-Width Deep Brain Stimulation in Parkinson's Disease: A Randomized Crossover Comparison.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for selected Parkinson's disease patients with motor fluctuations, but can adversely affect speech and axial symptoms. The use of short pulse width (PW) has been shown to expand the therapeutic window acutely, but its utility in reducing side effects in chronic STN-DBS patients has not been evaluated. OBJECTIVE: To compare the effect of short PW settings using 30-µs with conventional 60-µs settings on stimulation-induced dysarthria in Parkinson's disease patients with previously implanted STN-DBS systems. METHODS: In this single-center, double-blind, randomized crossover trial, we assigned 16 Parkinson's disease patients who had been on STN-DBS for a mean of 6.5 years and exhibited moderate dysarthria to 30-µs or 60-µs settings for 4 weeks followed by the alternative PW setting for a further 4 weeks. The primary outcome was difference in dysarthric speech measured by the Sentence Intelligibility Test between study baseline and the 2 PW conditions. Secondary outcomes included motor, nonmotor, and quality of life measures. RESULTS: There was no difference in the Sentence Intelligibility Test scores between baseline and the 2 treatment conditions (P = 0.25). There were also no differences noted in motor, nonmotor, or quality of life scores. The 30-µs settings were well tolerated, and adverse event rates were similar to those at conventional PW settings. Post hoc analysis indicated that patients with dysarthria and a shorter duration of DBS may be improved by short PW stimulation. CONCLUSIONS: Short PW settings using 30 µs did not alter dysarthric speech in chronic STN-DBS patients. A future study should evaluate whether patients with shorter duration of DBS may be helped by short PW settings. © 2019 International Parkinson and Movement Disorder Society.

Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study.

BACKGROUND: Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting. METHODS: We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases. RESULTS: Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi. CONCLUSION: The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities.

Alternating Modulation of Subthalamic Nucleus Beta Oscillations during Stepping.

Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20-30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait.SIGNIFICANCE STATEMENT Gait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20-30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies.

Connectivity derived thalamic segmentation in deep brain stimulation for tremor.

The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing.

Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry.

Importance: Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome. Objective: To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome. Design, Setting, and Participants: The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide. Exposures: Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]). Main Outcomes and Measures: Scores on the Yale Global Tic Severity Scale and adverse events. Results: The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P < .001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P < .001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P < .001). The overall adverse event rate was 35.4% (56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Conclusions and Relevance: Deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.

Microvascular decompression or neuromodulation in patients with SUNCT and trigeminal neurovascular conflict?

Objectives To assess the effectiveness of neuromodulation and trigeminal microvascular decompression (MVD) in patients with medically-intractable short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). Methods Two patients with medically refractory SUNCT underwent MVD following beneficial but incomplete response to neuromodulation (occipital nerve stimulation and deep brain stimulation). MRI confirmed neurovascular conflict with the ipsilateral trigeminal nerve in both patients. Results Although neuromodulation provided significant benefit, it did not deliver complete relief from pain and management required numerous postoperative visits with adjustment of medication and stimulation parameters. Conversely, MVD was successful in eliminating symptoms of SUNCT in both patients with no need for further medical treatment or neuromodulation. Conclusion Neuromodulation requires expensive hardware and lifelong follow-up and maintenance. These case reports highlight that microvascular decompression may be preferable to neuromodulation in the subset of SUNCT patients with ipsilateral neurovascular conflict.

Stimulating at the right time: phase-specific deep brain stimulation.

SEE MOLL AND ENGEL DOI101093/AWW308 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Brain regions dynamically engage and disengage with one another to execute everyday actions from movement to decision making. Pathologies such as Parkinson's disease and tremor emerge when brain regions controlling movement cannot readily decouple, compromising motor function. Here, we propose a novel stimulation strategy that selectively regulates neural synchrony through phase-specific stimulation. We demonstrate for the first time the therapeutic potential of such a stimulation strategy for the treatment of patients with pathological tremor. Symptom suppression is achieved by delivering stimulation to the ventrolateral thalamus, timed according to the patient's tremor rhythm. Sustained locking of deep brain stimulation to a particular phase of tremor afforded clinically significant tremor relief (up to 87% tremor suppression) in selected patients with essential tremor despite delivering less than half the energy of conventional high frequency stimulation. Phase-specific stimulation efficacy depended on the resonant characteristics of the underlying tremor network. Selective regulation of neural synchrony through phase-locked stimulation has the potential to both increase the efficiency of therapy and to minimize stimulation-induced side effects.

Subcortical evoked activity and motor enhancement in Parkinson's disease.

Enhancements in motor performance have been demonstrated in response to intense stimuli both in healthy subjects and in the form of 'paradoxical kinesis' in patients with Parkinson's disease. Here we identify a mid-latency evoked potential in local field potential recordings from the region of the subthalamic nucleus, which scales in amplitude with both the intensity of the stimulus delivered and corresponding enhancements in biomechanical measures of maximal handgrips, independent of the dopaminergic state of our subjects with Parkinson's disease. Recordings of a similar evoked potential in the related pedunculopontine nucleus - a key component of the reticular activating system - provide support for this neural signature in the subthalmic nucleus being a novel correlate of ascending arousal, propagated from the reticular activating system to exert an 'energizing' influence on motor circuitry. Future manipulation of this system linking arousal and motor performance may provide a novel approach for the non-dopaminergic enhancement of motor performance in patients with hypokinetic disorders such as Parkinson's disease.

Deep brain stimulation versus anterior capsulotomy for obsessive-compulsive disorder: a review of the literature.

Obsessive-compulsive disorder (OCD) is a chronic and debilitating psychiatric condition. Traditionally, anterior capsulotomy (AC) was an established procedure for treatment of patients with refractory OCD. Over recent decades, deep brain stimulation (DBS) has gained popularity. In this paper the authors review the published literature and compare the outcome of AC and DBS targeting of the area of the ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (NAcc). Patients in published cases were grouped according to whether they received AC or DBS and according to their preoperative scores on the Yale-Brown Obsessive-Compulsive Scale (YBOCS), and then separated according to outcome measures: remission (YBOCS score < 8); response (≥ 35% improvement in YBOCS score); nonresponse (< 35% improvement in YBOCS score); and unfavorable (i.e., worsening of the baseline YBOCS score). Twenty studies were identified reporting on 170 patients; 62 patients underwent DBS of the VC/VS or the NAcc (mean age 38 years, follow-up 19 months, baseline YBOCS score of 33), and 108 patients underwent AC (mean age 36 years, follow-up 61 months, baseline YBOCS score of 30). In patients treated with DBS there was a 40% decrease in YBOCS score, compared with a 51% decrease for those who underwent AC (p = 0.004). Patients who underwent AC were 9% more likely to go into remission than patients treated with DBS (p = 0.02). No difference in complication rates was noted. Anterior capsulotomy is an efficient procedure for refractory OCD. Deep brain stimulation in the VC/VS and NAcc area is an emerging and promising therapy. The current popularity of DBS over ablative surgery for OCD is not due to nonefficacy of AC, but possibly because DBS is perceived as more acceptable by clinicians and patients.

The nature of tremor circuits in parkinsonian and essential tremor.

Tremor is a cardinal feature of Parkinson's disease and essential tremor, the two most common movement disorders. Yet, the mechanisms underlying tremor generation remain largely unknown. We hypothesized that driving deep brain stimulation electrodes at a frequency closely matching the patient's own tremor frequency should interact with neural activity responsible for tremor, and that the effect of stimulation on tremor should reveal the role of different deep brain stimulation targets in tremor generation. Moreover, tremor responses to stimulation might reveal pathophysiological differences between parkinsonian and essential tremor circuits. Accordingly, we stimulated 15 patients with Parkinson's disease with either thalamic or subthalamic electrodes (13 male and two female patients, age: 50-77 years) and 10 patients with essential tremor with thalamic electrodes (nine male and one female patients, age: 34-74 years). Stimulation at near-to tremor frequency entrained tremor in all three patient groups (ventrolateral thalamic stimulation in Parkinson's disease, P=0.0078, subthalamic stimulation in Parkinson's disease, P=0.0312; ventrolateral thalamic stimulation in essential tremor, P=0.0137; two-tailed paired Wilcoxon signed-rank tests). However, only ventrolateral thalamic stimulation in essential tremor modulated postural tremor amplitude according to the timing of stimulation pulses with respect to the tremor cycle (e.g. P=0.0002 for tremor amplification, two-tailed Wilcoxon rank sum test). Parkinsonian rest and essential postural tremor severity (i.e. tremor amplitude) differed in their relative tolerance to spontaneous changes in tremor frequency when stimulation was not applied. Specifically, the amplitude of parkinsonian rest tremor remained unchanged despite spontaneous changes in tremor frequency, whereas that of essential postural tremor reduced when tremor frequency departed from median values. Based on these results we conclude that parkinsonian rest tremor is driven by a neural network, which includes the subthalamic nucleus and ventrolateral thalamus and has broad frequency-amplitude tolerance. We propose that it is this tolerance to changes in tremor frequency that dictates that parkinsonian rest tremor may be significantly entrained by low frequency stimulation without stimulation timing-dependent amplitude modulation. In contrast, the circuit influenced by low frequency thalamic stimulation in essential tremor has a narrower frequency-amplitude tolerance so that tremor entrainment through extrinsic driving is necessarily accompanied by amplitude modulation. Such differences in parkinsonian rest and essential tremor will be important in selecting future strategies for closed loop deep brain stimulation for tremor control.

Long-term outcome of subthalamic nucleus deep brain stimulation for Parkinson's disease using an MRI-guided and MRI-verified approach.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) represents a well-established treatment for patients with advanced Parkinson's disease (PD) insufficiently controlled with medical therapies. This study presents the long-term outcomes of patients with PD treated with STN-DBS using an MRI-guided/MRI-verified approach without microelectrode recording. METHODS: A cohort of 41 patients who underwent STN-DBS were followed for a minimum period of 5 years, with a subgroup of 12 patients being followed for 8-11 years. Motor status was evaluated using part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III), in on- and off-medication/on-stimulation conditions. Preoperative and postoperative assessments further included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), neuropsychological and speech assessments, as well as evaluation of quality of life. Active contacts localisation was calculated and compared with clinical outcomes. RESULTS: STN-DBS significantly improved the off-medication UPDRS-III scores, compared with baseline. However, UPDRS scores increased over time after DBS. Dyskinesias, motor fluctuations and demands in dopaminergic medication remained significantly reduced in the long term. Conversely, UPDRS-III on-medication scores deteriorated at 5 and 8 years, mostly driven by axial and bradykinesia subscores. Quality of life, as well as depression and anxiety scores, did not significantly change at long-term follow-up compared with baseline. In our series, severe cognitive decline was observed in 17.1% and 16.7% of the patients at 5 and 8 years respectively. CONCLUSIONS: Our data confirm that STN-DBS, using an MRI-guided/MRI-verified technique, remains an effective treatment for motor 'off' symptoms of PD in the long term with low morbidity.

The effect of posterior hypothalamus region deep brain stimulation on sleep.

BACKGROUND: Early observations by von Economo showed that the posterior part of the hypothalamus (PH) plays a prominent role in sleep-wake regulation. The PH is a candidate area involved in cluster headaches and other trigeminal autonomic cephalalgias (TACs) and is targeted for deep brain stimulation (DBS). CASE REPORTS: Sleep studies in two men, 69- and 39-years-old, with pre-existing sleep disorders, before and after PH-DBS for pharamacoresistant cluster headache and SUNCT syndrome showed that PH-DBS led to a dramatic alteration of the patients' sleep patterns. This coincided with an improvement of the predominantly diurnal TACs, suggesting a PH-DBS-induced change in sleep patterns. Hypnograms after DBS demonstrated disrupted sleep and a prolonged period of wakefulness after midnight in both patients, which was reproduced the second night. CONCLUSIONS: PH-DBS, a promising treatment for severe refractory TACs, affects sleep quality and pre-existing sleep disorders. This needs to be considered when treating patients with PH-DBS.

Phase dependent modulation of tremor amplitude in essential tremor through thalamic stimulation.

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.

Subthalamic nucleus activity optimizes maximal effort motor responses in Parkinson's disease.

The neural substrates that enable individuals to achieve their fastest and strongest motor responses have long been enigmatic. Importantly, characterization of such activities may inform novel therapeutic strategies for patients with hypokinetic disorders, such as Parkinson's disease. Here, we ask whether the basal ganglia may play an important role, not only in the attainment of maximal motor responses under standard conditions but also in the setting of the performance enhancements known to be engendered by delivery of intense stimuli. To this end, we recorded local field potentials from deep brain stimulation electrodes implanted bilaterally in the subthalamic nuclei of 10 patients with Parkinson's disease, as they executed their fastest and strongest handgrips in response to a visual cue, which was accompanied by a brief 96-dB auditory tone on random trials. We identified a striking correlation between both theta/alpha (5-12 Hz) and high-gamma/high-frequency (55-375 Hz) subthalamic nucleus activity and force measures, which explained close to 70% of interindividual variance in maximal motor responses to the visual cue alone, when patients were ON their usual dopaminergic medication. Loud auditory stimuli were found to enhance reaction time and peak rate of development of force still further, independent of whether patients were ON or OFF l-DOPA, and were associated with increases in subthalamic nucleus power over a broad gamma range. However, the contribution of this broad gamma activity to the performance enhancements observed was only modest (≤13%). The results implicate frequency-specific subthalamic nucleus activities as substantial factors in optimizing an individual's peak motor responses at maximal effort of will, but much less so in the performance increments engendered by intense auditory stimuli.

Therapeutic subthalamic nucleus deep brain stimulation reverses cortico-thalamic coupling during voluntary movements in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted treatment for patients experiencing the motor complications of Parkinson's disease (PD). While its successes are becoming increasingly apparent, the mechanisms underlying its action remain unclear. Multiple studies using radiotracer-based imaging have investigated DBS-induced regional changes in neural activity. However, little is known about the effect of DBS on connectivity within neural networks; in other words, whether DBS impacts upon functional integration of specialized regions of cortex. In this work, we report the first findings of fMRI in 10 subjects with PD and fully implanted DBS hardware receiving efficacious stimulation. Despite the technical demands associated with the safe acquisition of fMRI data from patients with implanted hardware, robust activation changes were identified in the insula cortex and thalamus in response to therapeutic STN DBS. We then quantified the neuromodulatory effects of DBS and compared sixteen dynamic causal models of effective connectivity between the two identified nodes. Using Bayesian model comparison, we found unequivocal evidence for the modulation of extrinsic (between region), i.e. cortico-thalamic and thalamo-cortical connections. Using Bayesian model parameter averaging we found that during voluntary movements, DBS reversed the effective connectivity between regions of the cortex and thalamus. This casts the therapeutic effects of DBS in a fundamentally new light, emphasising a role in changing distributed cortico-subcortical interactions. We conclude that STN DBS does impact upon the effective connectivity between the cortex and thalamus by changing their sensitivities to extrinsic afferents. Furthermore, we confirm that fMRI is both feasible and is tolerated well by these patients provided strict safety measures are adhered to.