Limb Preference Changes after Focused-Ultrasound Thalamotomy for Tremor.

BACKGROUND: Magnetic resonance-guided focused-ultrasound (MRgFUS) thalamotomy is an effective treatment for essential and other tremors. It targets the ventrointermedius (Vim) nucleus, which is the thalamic relay in a proprioceptive pathway, and contains kinesthetic cells. Although MRgFUS thalamotomy reduces some risks associated with more invasive surgeries, it still has side effects, such as balance and gait disturbances; these may be caused by the lesion impacting proprioception. OBJECTIVES: Our aim was to quantitatively measure the effects of MRgFUS on proprioception and limb use in essential tremor patients. We hypothesized that this thalamotomy alters proprioception, because the sensorimotor Vim thalamus is lesioned. METHODS: Proprioception was measured using the Kinarm exoskeleton robot in 18 patients. Data were collected pre-operatively, and then 1 day, 3 months, and 1 year after surgery. Patients completed four tasks, assessing motor coordination and postural control, goal-directed movement and bimanual planning, position sense, and kinesthesia. RESULTS: Immediately after surgery there were changes in posture speed (indicating tremor improvement), and in bimanual hand use, with the untreated limb being preferred. However, these measures returned to pre-operative baseline over time. There were no changes in parameters related to proprioception. None of these measures correlated with lesion size or lesion-overlap with the dentato-rubro-thalamic tract. CONCLUSIONS: This is the first quantitative assessment of proprioception and limb preference following MRgFUS thalamotomy. Our results suggest that focused-ultrasound lesioning of the Vim thalamus does not degrade proprioception but alters limb preference. This change may indicate a required "relearning" in the treated limb, because the effect is transient. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Predicting high-intensity focused ultrasound thalamotomy lesions using 2D magnetic resonance thermometry and 3D Gaussian modeling.

PURPOSE: To develop a method of using two-dimensional (2D) magnetic resonance thermometry, and three-dimensional (3D) Gaussian modeling to predict the volume, shape, and location of 1 day postoperative T1w high-intensity focused ultrasound lesions in medication refractory tremor patients; thereby facilitating a better comprehension of thermal damage thresholds, which can be utilized to reduce adverse events, and improve patient outcome. METHODS: Fifteen patients underwent magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy, which was performed at our center using an InSightec ExAblate 4000 system (Haifa, Israel), and guided by magnetic resonance imaging using a 3 T Discovery 750 (General Electric Healthcare, Waukesha, WI, USA). For treatment monitoring, 2D MR thermometry (temperature sensitivity: -0.00909 ppm/°C, bandwidth: 279 Hz/pixel) was performed in multiple orthogonal planes (sagittal, coronal, and axial) intraoperatively. These images were temporally filtered using a general linear model approach to reduce noise. Temporal volumes of filtered temperature maps with a peak temperature ≥ 47°C were aligned and fitted with a 3D Gaussian to create a canonical heating model. We then fitted the filtered 2D temperature maps with a 3D Gaussian, and used the relationships derived from the 3D heating model to estimate the 3D temperature distribution. These temperature distributions were converted into thermal dose distributions and accumulated across time to create an accumulated thermal dose (ATD) profile. Thresholded ATD profiles were then correlated with manually traced T1-weighted 1 day postoperative lesion volumes across patients, and linear regression slopes were plotted against varying ATD thresholds. Additionally, the Dice-Sørensen coefficient (DSC) was calculated to quantify the volumetric overlap between predicted, and actual lesions. RESULTS: On average, 18.1 (standard deviation (SD): ±4.6, range: 10-29) sonications were performed with an average peak temperature achieved of 62.4°C (SD: ±2.4, range: 58.2-67.7). An ATD threshold of 35.8 CEM43 was found to give a unity linear regression slope; this corresponded to an average DSC of 0.689 (SD: ±0.090, range: 0.476-0.815). CONCLUSIONS: Using multiplanar 2D MR thermometry and 3D Gaussian modeling, we were able to achieve very good (DSC = 0.689) predictions of T1w 1 day postoperative lesion volume, shape and location at an ATD threshold of approximately 36 CEM43. Furthermore, this method has the potential to be used in clinical evaluations to further elucidate the relationship between thermal damage and clinical outcome. Accurate 3D lesion prediction will facilitate improved clinical decision making in future MRgFUS thalamotomies.

Medical Methods Patents in Neuromodulation.

There is a rapidly growing number of patents on methods of modulating brain regions. Despite this trend, and the massive potential of neuromodulation for treating patients, researchers and physicians who use neuromodulation techniques and technologies often have little idea of the significant ways these patents could affect their work. This article describes medical method patents, including a brief history of their development, and analyzes their potential direct and indirect effects on neuromodulation treatment and research efforts. As neuromodulation rapidly matures into a commercial and medical reality it is important to consider these effects in a forward thinking and value driven manner. The paper concludes with recommendations concerning how neuromodulation method patents may be used, or not, depending on the values of the inventor.

Both 50 and 30 Hz continuous theta burst transcranial magnetic stimulation depresses the cerebellum.

The cerebellum is implicated in the pathophysiology of numerous movement disorders, which makes it an attractive target for noninvasive neurostimulation. Continuous theta burst stimulation (cTBS) can induce long lasting plastic changes in human brain; however, the efficacy of different simulation protocols has not been investigated at the cerebellum. Here, we compare a traditional 50-Hz and a modified 30-Hz cTBS protocols at modulating cerebellar activity in healthy subjects. Seventeen healthy adults participated in two testing sessions where they received either 50-Hz (cTBS50) or 30-Hz (cTBS30) cerebellar cTBS. Cerebellar brain inhibition (CBI), a measure of cerebello-thalamocortical pathway strength, and motor evoked potentials (MEP) were measured in the dominant first dorsal interosseous muscle before and after (up to ~ 40 min) cerebellar cTBS. Both cTBS protocols induced cerebellar depression, indicated by significant reductions in CBI (P < 0.001). No differences were found between protocols (cTBS50 and cTBS30) at any time point (P = 0.983). MEP amplitudes were not significantly different following either cTBS protocol (P = 0.130). The findings show cerebellar excitability to be equally depressed by 50-Hz and 30-Hz cTBS in heathy adults and support future work to explore the efficacy of different cerebellar cTBS protocols in movement disorder patients where cerebellar depression could provide therapeutic benefits.

Functional electrical stimulation and spinal cord injury.

Spinal cord injuries (SCI) can disrupt communications between the brain and the body, resulting in loss of control over otherwise intact neuromuscular systems. Functional electrical stimulation (FES) of the central and peripheral nervous system can use these intact neuromuscular systems to provide therapeutic exercise options to allow functional restoration and to manage medical complications following SCI. The use of FES for the restoration of muscular and organ functions may significantly decrease the morbidity and mortality following SCI. Many FES devices are commercially available and should be considered as part of the lifelong rehabilitation care plan for all eligible persons with SCI.

Occipital stimulation for chronic migraine: patient selection and complications.

BACKGROUND: Chronic migraine is a significant cause of disability world-wide and occipital region stimulation (OS) has been proposed to treat it. While participating in an industry-sponsored pilot trial of OS, we aimed to collect data regarding our surgical complications and long term usage of OS in our chronic migraine patients. METHODS: Ten patients (8 female, median age 46.5 years) were enrolled based on criteria established by the sponsoring company, screened in the headache clinic, and followed for a median of 33 months. We did not access data collected by industry for this report and instead collected our own data prospectively, including predominant location of headache, location of paresthesia evoked by OS, and complications. RESULTS: Adverse events included three possible early infections requiring antibiotics but not hardware removal, one late implantable pulse generator erosion requiring removal, one generator malfunction requiring revision, and loss of paresthetic coverage requiring four revisions in four patients. Two patients experienced new symptoms requiring psychiatric intervention. Five patients had no benefit and have been explanted. Of those who remain using their device, the proportion of their pre-operative pain located in the occipital region was 0.62 ± 0.14, whereas in those patients who have been explanted, the proportion was 0.31 ± 0.18 (t = 3.15, p=0.01). CONCLUSIONS: Complication rates with OS are higher than those seen with other stimulation techniques, despite identical hardware and similar surgery. The location of migraine pain did predict outcome, and suggests that only those with primarily occipital region headache are candidates for this therapy.

Designing a thalamic somatosensory neural prosthesis: consistency and persistence of percepts evoked by electrical stimulation.

Intuitive somatosensory feedback is required for fine motor control. Here we explored whether thalamic electrical stimulation could provide the necessary durations and consistency of percepts for a human somatosensory neural prosthetic. Continuous and cycling high-frequency (185 Hz, 0.21 ms pulse duration charge balanced square wave) electrical pulses with the cycling patterns varying between 7% and 67% of duty cycle were applied in five patients with chronically implanted deep brain stimulators. Stimulation produced similar percepts to those elicited immediately after surgery. While consecutive continuous stimuli produced decreasing durations of sensation, the amplitude and type of percept did not change. Cycling stimulation with shorter duty cycles produced more persisting percepts. These features suggest that the thalamus could provide a site for stable and enduring sensations necessary for a long term somatosensory neural prosthesis.

Designing a somatosensory neural prosthesis: percepts evoked by different patterns of thalamic stimulation.

Although major advances have been made in the development of motor prostheses, fine motor control requires intuitive somatosensory feedback. Here we explored whether a thalamic site for a somatosensory neural prosthetic could provide natural somatic sensation to humans. Different patterns of electrical stimulation (obtained from thalamic spike trains) were applied in patients undergoing deep brain stimulation surgery. Changes in pattern produced different sensations, while preserving somatotopic representation. While most percepts were reported as 'unnatural', some stimulations produced more 'natural' sensations than others. However, the additional patterns did not elicit more 'natural' percepts than high-frequency (333 Hz) electrical stimulation. These features suggest that despite some limitations, the thalamus may be a feasible site for a somatosensory neural prosthesis and different stimulation patterns may be useful in its development.

Clinical and experimental aspects of deep brain stimulation.

This presentation will review the effects of deep brain stimulation (DBS) for movement disorders in patients, and the cellular mechanisms that may explain these effects.

Cellular mechanisms preventing sustained activation of cortex during subcortical high-frequency stimulation.

Axonal excitation has been proposed as a key mechanism in therapeutic brain stimulation. In this study we examined how high-frequency stimulation (HFS) of subcortical white matter tracts projecting to motor cortex affects downstream postsynaptic responses in cortical neurons. Whole cell recordings were performed in the primary motor cortex (M1) and ventral thalamus of rat brain slices. In M1, neurons showed only an initial depolarization in response to HFS, after which the membrane potential returned to prestimulation levels. The prolonged suppression of excitation during stimulation was neither associated with GABAergic inhibition nor complete action potential failure in stimulated axons. Instead we found that HFS caused a depression of excitatory synaptic currents in postsynaptic neurons that was specific to the stimulated subcortical input. These data are consistent with the hypothesis that axonal HFS produces a functional deafferentation of postsynaptic targets likely from depletion of neurotransmitter.

Selective attenuation of afferent synaptic transmission as a mechanism of thalamic deep brain stimulation-induced tremor arrest.

Deep brain stimulation (DBS) of the ventrolateral thalamus stops several forms of tremor. Microelectrode recordings in the human thalamus have revealed tremor cells that fire synchronous with electromyographic tremor. The efficacy of DBS likely depends on its ability to modify the activity of these tremor cells either synaptically by stopping afferent tremor signals or by directly altering the intrinsic membrane currents of the neurons. To test these possibilities, whole-cell patch-clamp recordings of ventral thalamic neurons were obtained from rat brain slices. DBS was simulated (sDBS) using extracellular constant current pulse trains (125 Hz, 60-80 micros, 0.25-5 mA, 1-30 s) applied through a bipolar electrode. Using a paired-pulse protocol, we first established that thalamocortical relay neurons receive converging input from multiple independent afferent fibers. Second, although sDBS induced homosynaptic depression of EPSPs along its own pathway, it did not alter the response from a second independent pathway. Third, in contrast to the subthalamic nucleus, sDBS in the thalamus failed to inhibit the rebound potential and the persistent Na+ current but did activate the Ih current. Finally, in eight patients undergoing thalamic DBS surgery for essential tremor, microstimulation was most effective in alleviating tremor when applied in close proximity to recorded tremor cells. However, stimulation could still suppress tremor at distances incapable of directly spreading to recorded tremor cells. These complementary data indicate that DBS may induce a "functional deafferentation" of afferent axons to thalamic tremor cells, thereby preventing tremor signal propagation in humans.

Mechanisms of deep brain stimulation: an intracellular study in rat thalamus.

High-frequency deep brain stimulation (DBS) in the thalamus alleviates most kinds of tremor, yet its mechanism of action is unknown. Studies in subthalamic nucleus and other brain sites have emphasized non-synaptic factors. To explore the mechanism underlying thalamic DBS, we simulated DBS in vitro by applying high-frequency (125 Hz) electrical stimulation directly into the sensorimotor thalamus of adult rat brain slices. Intracellular recordings revealed two distinct types of membrane responses, both of which were initiated with a depolarization and rapid spike firing. However, type 1 responses repolarized quickly and returned to quiescent baseline during simulated DBS whereas type 2 responses maintained the level of membrane depolarization, with or without spike firing. Individual thalamic neurones exhibited either type 1 or type 2 response but not both. In all neurones tested, simulated DBS-evoked membrane depolarization was reversibly eliminated by tetrodotoxin, glutamate receptor antagonists, and the Ca(2+) channel antagonist Cd(2+). Simulated DBS also increased the excitability of thalamic cells in the presence of glutamate receptor blockade, although this non-synaptic effect induced no spontaneous firing such as that found in subthalamic nucleus neurones. Our data suggest that high-frequency stimulation when applied in the ventral thalamus can rapidly disrupt local synaptic function and neuronal firing thereby leading to a 'functional deafferentation' and/or 'functional inactivation'. These mechanisms, driven primarily by synaptic activation, help to explain the paradox that lesions, muscimol and DBS in thalamus all effectively stop tremor.

Is the target for thalamic deep brain stimulation the same as for thalamotomy?

Deep brain stimulation (DBS) has virtually replaced thalamotomy for the treatment of essential tremor. It is thought that the site for DBS is the same as the optimal lesion site; however, this match has not been investigated previously. We sought to determine whether the location of thalamic DBS matched the site at which thalamotomy would be performed. Eleven patients who had detailed microelectrode recording and stimulation for placement of DBS electrodes and subsequent successful tremor control were analysed. An experienced surgeon, blinded to outcome and final electrode position, selected the ideal thalamotomy site based on the reconstructed maps obtained intraoperatively. When the site of long-term clinically used DBS and theoretical thalamotomy location was calculated in three-dimensional space and compared for each of the x, y, and z axes in stereotactic space, there was no significant difference in the mediolateral location of DBS and theoretical lesion site. There was also no difference between the theoretical lesion site and the placement of the tip of the electrode; however, the active electrodes used for chronic stimulation were significantly more anterior (P = 0.005) and dorsal (P = 0.034) to the ideal thalamotomy target. This mismatch may reflect the compromise required between adverse and beneficial effects with chronic stimulation, but it also suggests different mechanisms of effect of DBS and thalamotomy.

Neural substrates of microstimulation-evoked tingling: a chronaxie study in human somatosensory thalamus.

Intra-operative micro-electrode stimulation of sensorimotor thalamus produces paraesthesia or tingling in various body regions and is used to map somatotopy prior to implantation of deep brain-stimulating electrodes in awake patients. The neural elements affected by such microstimulation are unknown. Using paraesthesia as the behavioural-physiological response threshold, we measured chronaxie times for microstimuli applied to both somatosensory thalamic nuclei (cellular region) and its axonal afferents, the medial lemniscus. White matter chronaxie times were relatively unimodal, whereas two different clusters of chronaxie times were identified in grey matter: one corresponding to that of the medial lemniscus and the other about five times longer and compatible with that obtained from cell somata. Therefore, excitations of local axons and/or cell bodies can both contribute to the paraesthesia evoked during intra-operative thalamic mapping.