Francesco Sammartino

Tractography‐Based Ventral Intermediate Nucleus Targeting: Novel Methodology and Intraoperative Validation

The ventral intermediate nucleus of the thalamus is not readily visible on structural magnetic resonance imaging. Therefore, a method for its visualization for stereotactic targeting is desirable.

Anterior Nucleus Deep Brain Stimulation for Refractory Epilepsy: Insights Into Patterns of Seizure Control and Efficacious Target.

BACKGROUND Anterior nucleus (AN) deep brain stimulation (DBS) is a palliative treatment for medically refractory epilepsy. The long-term efficacy and the optimal target localization for AN DBS are not well understood. OBJECTIVE To analyze the long-term efficacy of AN DBS and its predictors. METHODS We performed a retrospective review of 16 patients who underwent AN DBS. We selected only patients with reliable seizure frequency data and at least a 1-year follow-up. We studied the duration of the seizure reduction after DBS insertion and before stimulation (the insertional effect) and its association with long-term outcome. We modeled the volume of activation using the active contacts, stimulation parameters, and postoperative imaging. The overlap of this volume was plotted in Montreal Neurological Institute 152 space in 7 patients with significant clinical efficacy. RESULTS Nine patients reported a decrease in seizure frequency immediately after electrode insertion (insertional or microthalamotomy effect). The duration of insertional effect varied from 2 to 4 months. However, 1 patient had a long-term insertional effect of 36 months. Altogether, 11 patients reported >50% decrease in seizure frequency with long-term stimulation. The most common pattern of seizure control was immediate and sustained stimulation benefit (n = 8). In patients with long-term stimulation benefit, the efficacious target was localized in the anteroventral AN in close proximity to the mammillothalamic tract. CONCLUSION AN DBS is efficacious in the control of seizure frequency in selected patients. An insertional effect is commonly observed (56%). The most efficacious site of stimulation appears to be the anteroventral AN. ABBREVIATIONS AN, anterior nucleusDBS, deep brain stimulationMNI, Montreal Neurological InstituteMRE, medical refractory epilepsyMT, mammillothalamic tractSANTE, Stimulation of the Anterior Nucleus of the Thalamus for EpilepsyVNS, vagal nerve stimulation.

Low-frequency Subthalamic Stimulation in Parkinson's Disease: Long- term Outcome and Predictors

BACKGROUND Parkinsons disease patients undergoing subthalamic nucleus deep brain stimulation (STN DBS) at standard frequency (>100 Hz) often develop gait impairment, postural instability and speech difficulties. Low frequency stimulation (<100 Hz, LFS) can improve such axial symptoms, but there are concerns that improvement may be transient. OBJECTIVE To identify long-term outcome and predictors of low-frequency subthalamic stimulation in Parkinsons disease. METHODS Through a chart review we identified 85 out of 324 STN DBS patients who received a trial of LFS and describe their characteristics and outcome predictors. RESULTS Patients were switched to LFS (<100 Hz) 3.8 ± 3.3 years after surgery. Most patients (64%) attained a subjective improvement of gait, speech or balance for 2.0 ± 1.9 years. Motor scores improved within the first year after the stimulation change and showed a slower progression over time when compared to patients switched back to high frequency stimulation. UPDRS III axial score on medication before surgery and the y-axis coordinate of the active contact were independent predictors of LFS retention. CONCLUSIONS This report provides evidence that the use of LFS yields an enduring benefit in a considerable percentage of patients who develop axial motor symptoms during conventional stimulation.

Neuromodulation for Epilepsy

Several palliative neuromodulation treatment modalities are currently available for adjunctive use in the treatment of medically intractable epilepsy. Over the past decades, a variety of different central and peripheral nervous system sites have been identified, clinically and experimentally, as potential targets for chronic, nonresponsive therapeutic neurostimulation. Currently, the main modalities in clinical use, from most invasive to least invasive, are anterior thalamus deep brain stimulation, vagus nerve stimulation, and trigeminal nerve stimulation. Significant reductions in seizure frequency have been demonstrated in clinical trials using each of these neuromodulation therapies.

The effect of dexmedetomidine on the firing properties of STN neurons in Parkinson's disease

Dexmedetomidine (an alpha‐2 adrenergic agonist) sedation is commonly used during subthalamic nucleus (STN) deep‐brain stimulation (DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesised that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analysed microelectrode recording (MER) data from patients with Parkinsons disease who underwent STN DBS. A ‘Dex bolus’ group (dexmedetomidine bolus prior to MER; 27 cells from seven patients) was compared with a ‘no sedation’ group (29 cells from 11 patients). We also performed within‐patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analysed using the Kaneoke–Vitek methodology and local field potential (LFP) oscillatory activity was also investigated. Dexmedetomidine was associated with a slight increase in firing rate (41.1 ± 9.9 vs. 34.5 ± 10.6 Hz, P = 0.02) but a significant decrease in burstiness (number of bursts, P = 0.02; burst index, P < 0.001; percentage of spikes in burst, P = 0.002) of dorsal but not ventral STN neurons. This was not associated with modulation of beta oscillations in the spike‐oscillations analysis(beta peak, P = 0.4; signal‐to‐noise ratio in the beta range for spikes and bursts, P = 0.3 and P = 0.5, respectively) and LFP analysis (Beta power, P = 0.17). As bursting pattern is often used to identify STN and guide electrode placement, we recommend that high‐dose dexmedetomidine should be avoided during DBS surgery.

Diffusion tensor imaging assessment of microstructural brainstem integrity in Chiari malformation Type I

OBJECTIVE The diagnosis of Chiari malformation Type I (CM-I) is primarily based on the degree of cerebellar tonsillar herniation even though it does not always correlate with symptoms. Neurological dysfunction in CM-I presumably results from brainstem compression. With the premise that conventional MRI does not reveal brain microstructural changes, this study examined both structural and microstructural neuroimaging metrics to distinguish patients with CM-I from age- and sex-matched healthy control subjects. METHODS Eight patients with CM-I and 16 controls were analyzed. Image postprocessing involved coregistration of anatomical T1-weighted with diffusion tensor images using 3D Slicer software. The structural parameters included volumes of the posterior fossa, fourth ventricle, and tentorial angle. Fractional anisotropy (FA) was calculated separately in the anterior and posterior compartments of the lower brainstem. RESULTS The mean age of patients in the CM-I cohort was 42.6 ± 10.4 years with mean tonsillar herniation of 12 mm (SD 0.7 mm). There were no significant differences in the posterior fossa volume (p = 0.06) or fourth ventricular volume between the 2 groups (p = 0.11). However, the FA in the anterior brainstem compartment was significantly higher in patients with CM-I preoperatively (p = 0.001). The FA values normalized after Chiari decompression except for persistently elevated FA in the posterior brainstem compartment in patients with CM-I and syrinx. CONCLUSIONS In this case-control study, microstructural alterations appear to be reliably associated with the diagnosis of CM-I, with a significantly elevated FA in the lower brainstem in patients with CM-I compared with controls. More importantly, the FA values normalized after decompressive surgery. These findings should be validated in future studies to determine the significance of diffusion tensor imaging-based assessment of brainstem microstructural integrity as an adjunct to the clinical assessment in patients with CM-I.

Advances in surgery for movement disorders.

Movement disorder surgery has evolved throughout history as our knowledge of motor circuits and ways in which to manipulate them have expanded. Today, the positive impact on patient quality of life for a growing number of movement disorders such as Parkinsons disease is now well accepted and confirmed through several decades of randomized, controlled trials. Nevertheless, residual motor symptoms after movement disorder surgery such as deep brain stimulation and lack of a definitive cure for these conditions demand that advances continue to push the boundaries of the field and maximize its therapeutic potential. Similarly, advances in related fields — wireless technology, artificial intelligence, stem cell and gene therapy, neuroimaging, nanoscience, and minimally invasive surgery — mean that movement disorder surgery stands at a crossroads to benefit from unique combinations of all these developments. In this minireview, we outline some of these developments as well as evidence supporting topics of recent discussion and controversy in our field. Moving forward, expectations remain high that these improvements will come to encompass an even broader range of patients who might benefit from this therapy and decrease the burden of disease associated with these conditions.

Fluorescein-enhanced characterization of additional anatomical landmarks in cerebral ventricular endoscopy.

BACKGROUND Fluorescein enhancement to detect retinal disorder or differentiate cancer tissue in situ is a well-defined diagnostic procedure. It is a visible marker of where the blood-brain barrier is absent or disrupted. Little is reported in the contemporary literature on endoscopic fluorescein-enhanced visualization of the circumventricular organs, and the relevance of these structures as additional markers for safe ventricular endoscopic navigation remains an unexplored field. OBJECTIVE To describe fluorescein sodium-enhanced visualization of circumventricular organs as additional anatomic landmarks during endoscopic ventricular surgery procedures. METHODS We prospectively administered intravenously 500 mg fluorescein sodium in 12 consecutive endoscopic surgery patients. A flexible endoscope equipped with dual observation modes for both white light and fluorescence was used. During navigation from the lateral to the fourth ventricle, the endoscopic anatomic landmarks were first inspected under white light and then under the fluorescent mode. RESULTS After a mean of 20 seconds in the fluorescent mode, the fluorescein enhanced visualization of the choroid plexus of the lateral ventricle, median eminence-tuber cinereum complex, organum vasculosum of the lamina terminalis, choroid plexus of the third and fourth ventricles, and area postrema. CONCLUSION Fluorescein-enhanced visualization is a useful tool for helping neuroendoscopists recognize endoscopic anatomic landmarks. It could be adopted to guide orientation when the surgeon deems an endoscopic procedure unsafe or contraindicated because of unclear or subverted anatomic landmarks. Visualization of the circumventricular organs could add new insight into the functional anatomy of these structures, with possible implications for the site and safety of third ventriculostomy.

Microelectrode recording findings within the tractography-defined ventral intermediate nucleus

OBJECTIVE The ventral intermediate nucleus (VIM) of the thalamus is not visible on structural MRI. Therefore, direct VIM targeting methods for stereotactic tremor surgery are desirable. The authors previously described a direct targeting method for visualizing the VIM and its structural connectivity using deterministic tractography. In this combined electrophysiology and imaging study, the authors investigated the electrophysiology within this tractography-defined VIM (T-VIM). METHODS Thalamic neurons were classified based on their relative location to the T-VIM: dorsal, within, and ventral to the T-VIM. The authors identified the movement-responsive cells (kinesthetic and tremor cells), performed spike analysis (firing rate and burst index), and local field potential analysis (area under the curve for 13-30 Hz). Tremor efficacy in response to microstimulation along the electrode trajectory was also assessed in relation to the T-VIM. RESULTS Seventy-three cells from a total of 9 microelectrode tracks were included for this analysis. Movement-responsive cells (20 kinesthetic cells and 26 tremor cells) were identified throughout the electrode trajectories. The mean firing rate and burst index of cells (n = 27) within the T-VIM are 18.8 ± 9.8 Hz and 4.5 ± 5.4, respectively. Significant local field potential beta power was identified within the T-VIM (area under the curve for 13-30 Hz = 6.6 ± 7.7) with a trend toward higher beta power in the dorsal T-VIM. The most significant reduction in tremor was also observed in the dorsal T-VIM. CONCLUSIONS The electrophysiological findings within the VIM thalamus defined by tractography, or T-VIM, correspond with the known microelectrode recording characteristics of the VIM in patients with tremor.

A Review of the Current Therapies, Challenges, and Future Directions of Transcranial Focused Ultrasound Technology: Advances in Diagnosis and Treatment

Importance Magnetic resonance imaging–guided focused ultrasound ablation has been approved for the treatment of refractory essential tremor and is being studied for other neurological indications, including dyskinesias and tremor in Parkinson disease, dystonia, neuropathic pain, obsessive-compulsive disorder, epilepsy, and brain tumors. Objective To review the scientific foundations of FUS technology, existing neurological applications, and future advances. Evidence Review PubMed was searched for the past 10 years using the terms “transcranial ultrasound,” “focused ultrasound,” and “neurological applications.” Relevant references were selected from the authors reference collection. From the 2855 unique records, 243 publications were screened. After excluding abstracts detailing in vitro studies or non-neurological applications, 86 full texts were retrieved for qualitative review. Findings Advances in the transducer design and electronic phase correction have allowed efficient focusing of ultrasounds for transcranial treatment. The mid-frequency (650 kHz) transducer can make small (4-6 mm in diameter) and precise (accuracy of <2 mm) brain lesions. The treatment monitoring is achieved via “live” anatomical thermography imaging and clinical feedback. The initial results from its clinical application in movement disorders are encouraging. Emerging applications in epilepsy and neurobehavioral and cognitive disorders are being explored. The low-frequency (220 kHz) transducer coupled with microbubbles can potentially enable targeted drug delivery for novel applications, such as Alzheimer disease and brain tumors. Finally, neuromodulation with subthreshold sonications may allow the interrogation of brain areas previously not accessible for electrical stimulation. Conclusions and Relevance Transcranial focused ultrasound for both ablative and nonablative applications is noninvasive, making it suitable for selected patients who are not candidates for conventional surgical options. Future advancements in imaging and sonication algorithms will improve the safety and efficacy of this technology.