Sensing with deep brain stimulation device in epilepsy: Aperiodic changes in thalamic local field potential during seizures.

OBJECTIVE: Thalamic deep brain stimulation (DBS) is an effective therapeutic option in patients with drug-resistant epilepsy. Recent DBS devices with sensing capabilities enable chronic, outpatient local field potential (LFP) recordings. Whereas beta oscillations have been demonstrated to be a useful biomarker in movement disorders, the clinical utility of DBS sensing in epilepsy remains unclear. Our aim was to determine LFP features that distinguish ictal from inter-ictal states, which may aid in tracking seizure outcomes with DBS. METHODS: Electrophysiology data were obtained from DBS devices implanted in the anterior nucleus (N = 12) or centromedian nucleus (N = 2) of the thalamus. Power spectra recorded during patient/caregiver-marked seizure events were analyzed with a method that quantitatively separates the oscillatory and non-oscillatory/aperiodic components of the LFP using non-parametric statistics, without the need for pre-specification of the frequency bands of interest. Features of the LFP parameterized using this algorithm were compared with those from inter-ictal power spectra recorded in clinic. RESULTS: Oscillatory activity in multiple canonical frequency bands was identified from the power spectra in 86.48% of patient-marked seizure events. Delta oscillations were present in all patients, followed by theta (N = 10) and beta (N = 9). Although there were no differences in oscillatory LFP features between the ictal and inter-ictal states, there was a steeper decline in the 1/f slope of the aperiodic component of the LFP during seizures. SIGNIFICANCE: Our work highlights the potential and shortcomings of chronic LFP recordings in thalamic DBS for epilepsy. Findings suggest that no single frequency band in isolation clearly differentiates seizures, and that features of aperiodic LFP activity may be clinically-relevant biomarkers of seizures.

Pallido-putaminal connectivity predicts outcomes of deep brain stimulation for cervical dystonia.

Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables. We conclude that modulation of the primary motor putamen-posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting.

Transcranial MR-Guided Focused Ultrasound and Hyperostosis Calvariae Diffusa: Case Report and Systematic Review of the Literature.

We describe a 74-year-old male with intractable essential tremor (ET) and hyperostosis calvariae diffusa who was unsuccessfully treated with magnetic resonance-guided focused ultrasound (MRgFUS). A computed tomography performed prior to the procedure demonstrated a skull density ratio (SDR) of 0.37 and tricortical hyperostosis calvariae diffusa. No lesion was evident on post-MRgFUS MRI, and no improvement in the patient's hand tremor was noted clinically. We systematically reviewed the literature to understand outcomes for those patients with hyperostosis who have undergone MRgFUS. A comprehensive literature search using the PubMed, Cochrane, and Google Scholar databases identified 3 ET patients with hyperostosis who failed treatment with MRgFUS. Clinical findings, skull characteristics, treatment parameters, and outcomes were summarized, demonstrating different patterns/degrees of bicortical hyperostosis and variable SDRs (i.e., from 0.38 to ≥0.45). Although we have successfully treated patients with bicortical hyperostosis frontalis interna (n = 50), tricortical hyperostosis calvariae diffusa appears to be a contraindication for MRgFUS despite acceptable SDRs.

Tractography patterns of pedunculopontine nucleus deep brain stimulation.

Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson's disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = -0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.

Supraspinal Effects of Dorsal Root Ganglion Stimulation in Chronic Pain Patients.

OBJECTIVES: Dorsal root ganglion stimulation (DRGS) has become a popular neuromodulatory treatment for neuropathic pain. We used magnetoencephalography (MEG) to investigate potential biomarkers of pain and pain relief, based on the differences in power spectral density (PSD) during varying degrees of pain and how these oscillations change during DRGS-mediated pain relief. MATERIALS AND METHODS: Thirteen chronic pain patients with implanted dorsal root ganglion stimulators were included in the MEG analysis. MEG Recordings were performed at rest while the stimulator was turned ON or OFF. Numerical rating scale (NRS) scores were also recorded before and after DRGS was turned OFF and ON. Power spectral and source localization analyses were then performed on preprocessed MEG recordings. RESULTS: With DRGS-OFF, patients in severe pain had significantly increased cortical theta (4-7 Hz) power and decreased cortical alpha (7-13 Hz) power compared to patients reporting less pain. This shift in power toward lower frequencies was contrasted by a shift toward the higher frequency power spectrum (low beta 13-20 Hz activity) during DRGS-mediated pain relief. A significant correlation was found between the increase in low beta activity and the degree of reported pain relief. CONCLUSION: Our results demonstrate increased low-frequency power spectral activity in chronic pain patients in the absence of stimulation which shifts toward higher frequency power spectrum activity in response to therapeutic DRGS. These cortical changes in response to DRGS provide support for the use of neuroimaging in the search for potential biomarkers of pain.

Invasive Electrical Neuromodulation for the Treatment of Painful Diabetic Neuropathy: Systematic Review and Meta-Analysis.

OBJECTIVES: Neuromodulation is a treatment option for people suffering from painful diabetic neuropathy (PDN) unresponsive to conventional pharmacotherapy. We systematically examined the pain outcomes of patients with PDN receiving any type of invasive neuromodulation for treatment of neuropathic pain. MATERIALS AND METHODS: MEDLINE and Embase were searched through 10 January 2020, without language restriction. All study types were included. Two reviewers independently screened publications and extracted data. Quantitative meta-analysis was performed with pain scores converted to a standard 100-point scale. Randomized controlled trial (RCT) scores were pooled using the inverse variance method and expressed as mean differences. RESULTS: RCTs of tonic spinal cord stimulation (t-SCS) showed greater pain improvement than best medical therapy at six months (intention-to-treat: 38/100, 95% CI: 29-47). By per-protocol analysis, case series of t-SCS and dorsal root ganglion stimulation (DRGS) showed improvement by 56 (95% CI: 39-73) and 55 (22-87), respectively, at 12 months. For t-SCS, the rate of failing a therapeutic stimulation trial was 16%, the risk of infection was 4%, and the rate of lead problems requiring surgery to resolve was 4% per year of follow-up. High-frequency SCS and burst SCS both showed efficacy, with few patients studied. CONCLUSION: Efficacious, lasting and safe surgical pain management options are available to diabetic patients suffering from PDN. Tonic-SCS is the established standard of treatment; however, other SCS paradigms and DRGS are emerging as promising treatments offering comparable pain benefits, but with few cases published to date. Randomized controlled trials are ongoing to assess their relative merits.

Delayed diffuse cerebellar swelling after resection of medulloblastoma: case report and review of literature.

INTRODUCTION: Delayed diffuse cerebellar swelling is a rare life-threatening complication following medulloblastoma resection. PRESENTATION: We present our experience of managing a 4-year-old who developed diffuse cerebellar swelling with upward herniation 41 days after resection of a large cell anaplastic medulloblastoma. CONCLUSION: Emergency chemotherapy alone was sufficient in promoting regression of swelling and recovery from coma. Reports of similar cases are scant. Chemotherapy may be a critical component of treatment.

Delayed Craniospinal Metastasis of Aggressive Nonfunctioning Pituitary Adenomas as Pituitary Carcinomas.

Background Clinical behavior of pituitary neoplasms is peculiar and notoriously difficult to predict. While aggressive tumors are common, metastasis is very rare, can be highly delayed, and there are no histological or clinical features to meaningfully predict this happening. Endocrinologically silent tumors are particularly difficult, as there is less opportunity to detect early metastasis. Together, this amounts to a situation of uncertainty over the appropriate management of such tumors before and after metastasis. Case Description The authors report two cases of nonfunctioning aggressive pituitary adenoma (APA) each requiring two transsphenoidal surgeries, a transcranial resection and radiotherapy. Both these tumors subsequently metastasized caudally along the neuraxis, years later, as a null cell carcinoma associated with a germline CHEK2 mutation and a silent Crooke's cell carcinoma. The former represents a novel oncogenetic association. Conclusion Delayed drop dural metastasis of pituitary carcinoma is becoming increasingly recognized. Surgical resection of the distant disease to confirm the diagnosis and relieve the mass effect, followed by temozolomide chemotherapy, is the current treatment of choice. The need for both long-term follow-up in patients with APA, and a high degree of suspicion toward dural-based radiographic findings is emphasized.

Cerebellar High-Grade Glioma: A Translationally Oriented Review of the Literature.

World Health Organization (WHO) grade 4 gliomas of the cerebellum are rare entities whose understanding trails that of their supratentorial counterparts. Like supratentorial high-grade gliomas (sHGG), cerebellar high-grade gliomas (cHGG) preferentially affect males and prognosis is bleak; however, they are more common in a younger population. While current therapy for cerebellar and supratentorial HGG is the same, recent molecular analyses have identified features and subclasses of cerebellar tumors that may merit individualized targeting. One recent series of cHGG included the subclasses of (1) high-grade astrocytoma with piloid features (HGAP, ~31% of tumors); (2) H3K27M diffuse midline glioma (~8%); and (3) isocitrate dehydrogenase (IDH) wildtype glioblastoma (~43%). The latter had an unusually low-frequency of epidermal growth factor receptor (EGFR) and high-frequency of platelet-derived growth factor receptor alpha (PDGFRA) amplification, reflecting a different composition of methylation classes compared to supratentorial IDH-wildtype tumors. These new classifications have begun to reveal insights into the pathogenesis of HGG in the cerebellum and lead toward individualized treatment targeted toward the appropriate subclass of cHGG. Emerging therapeutic strategies include targeting the mitogen-activated protein kinases (MAPK) pathway and PDGFRA, oncolytic virotherapy, and immunotherapy. HGGs of the cerebellum exhibit biological differences compared to sHGG, and improved understanding of their molecular subclasses has the potential to advance treatment.

Connectivity-based thalamus parcellation and surgical targeting of somatosensory subnuclei.

OBJECTIVE: The anatomy of the posterolateral thalamus varies substantially between individuals, presenting a challenge for surgical targeting. Patient-specific, connectivity-based parcellation of the thalamus may effectively approximate the ventrocaudal nucleus (Vc). This remains to be robustly validated or assessed as a method to guide surgical targeting. The authors assessed the validity of connectivity-based parcellation for targeting the Vc and its potential for improving clinical outcomes of pain surgery. METHODS: A cohort of 19 patients with regional, chronic neuropathic pain underwent preoperative structural and diffusion MRI, then progressed to deep brain stimulation targeting the Vc based on traditional atlas coordinates. Surgical thalami were retrospectively segmented and then parcellated based on tractography estimates of thalamocortical connectivity. The location of each patient's electrode array was analyzed with respect to their primary somatosensory cortex (S1) parcel and compared across patients with reference to the thalamic homunculus. RESULTS: Ten patients achieved long-term pain relief. Sixty-one percent of an average array (interquartile range 42%-74%) was located in the S1 parcel. In patients who achieved long-term benefit from surgery, array location in the individually generated S1 parcels was medial for face pain, centromedial for arm pain, and centrolateral for leg pain. Patients who did not benefit from surgery did not follow this pattern. Standard stereotactic coordinates of electrode locations diverged from this pattern. CONCLUSIONS: Connectivity-based parcellation of the thalamus appears to be a reliable method for segmenting the Vc. Identifying the Vc in this way, and targeting mediolaterally as appropriate for the region of pain, merits exploration in an effort to increase the yield of successful surgical procedures.

Sellar Remodeling after Surgery for Nonfunctioning Pituitary Adenoma: Intercarotid Distance as a Predictor of Recurrence.

Introduction As they grow, pituitary adenoma can remodel the sella turcica and alter anatomical relationships with adjacent structures. The intercarotid distance (ICD) at the level of the sella is a measure of sella width. The purpose of this study was to (1) assess how ICD changes after transsphenoidal surgery and (2) explore whether the extent of ICD change is associated with tumor recurrence. Methods A retrospective analysis of preoperative and postoperative coronal magnetic resonance imaging (MRI) scans was carried out by two independent assessors on patients who underwent transsphenoidal surgery for nonfunctioning pituitary macroadenomas. Preoperative tumor volume and any change in ICD following surgery were recorded and compared between groups. Logistic regression models of recurrence were generated. Results In 36 of 42 patients, ICD fell after surgery (mean = 1.8 mm) and six cases were static. At time of follow-up (mean = 77 months), 25 had not required further intervention and 17 had undergone second surgery or radiosurgery. In patients in whom no further intervention has yet been necessary, the postoperative reduction in ICD was significantly smaller than in those who required repeat intervention (1.1 vs. 2.7 mm respectively, p < 0.01). ICD decrease was weakly correlated with tumor volume ( r = 0.35). ICD decrease was a significant predictor of recurrence (odds ratio [OR] = 3.15; 95% confidence interval [CI]: 1.44-6.87), largely independent of tumor volume. Conclusion For most patients, ICD falls following surgical excision of a nonfunctioning pituitary macroadenoma. A greater reduction in ICD postsurgery appears to predict recurrence. Change in ICD shows promise as a radiographic tool for prognosticating clinical course after surgery.

Dorsal Root Ganglion Stimulation Modulates Cortical Gamma Activity in the Cognitive Dimension of Chronic Pain.

A cognitive task, the n-back task, was used to interrogate the cognitive dimension of pain in patients with implanted dorsal root ganglion stimulators (DRGS). Magnetoencephalography (MEG) signals from thirteen patients with implanted DRGS were recorded at rest and while performing the n-back task at three increasing working memory loads with DRGS-OFF and the task repeated with DRGS-ON. MEG recordings were pre-processed, then power spectral analysis and source localization were conducted. DRGS resulted in a significant reduction in reported pain scores (mean 23%, p = 0.001) and gamma oscillatory activity (p = 0.036) during task performance. DRGS-induced pain relief also resulted in a significantly reduced reaction time during high working memory load (p = 0.011). A significant increase in average gamma power was observed during task performance compared to the resting state. However, patients who reported exacerbations of pain demonstrated a significantly elevated gamma power (F(3,80) = 65.011612, p < 0.001, adjusted p-value = 0.01), compared to those who reported pain relief during the task. Our findings demonstrate that gamma oscillatory activity is differentially modulated by cognitive load in the presence of pain, and this activity is predominantly localized to the prefrontal and anterior cingulate cortices in a chronic pain cohort.

Multitarget deep brain stimulation for clinically complex movement disorders.

Deep brain stimulation (DBS) of single-target nuclei has produced remarkable functional outcomes in a number of movement disorders such as Parkinson's disease, essential tremor, and dystonia. While these benefits are well established, DBS efficacy and strategy for unusual, unclassified movement disorder syndromes is less clear. A strategy of dual pallidal and thalamic electrode placement is a rational approach in such cases where there is profound, medically refractory functional impairment. The authors report a series of such cases: midbrain cavernoma hemorrhage with olivary hypertrophy, spinocerebellar ataxia-like disorder of probable genetic origin, Holmes tremor secondary to brainstem stroke, and hemiballismus due to traumatic thalamic hemorrhage, all treated by dual pallidal and thalamic DBS. All patients demonstrated robust benefit from DBS, maintained in long-term follow-up. This series demonstrates the flexibility and efficacy, but also the limitations, of dual thalamo-pallidal stimulation for managing axial and limb symptoms of tremors, dystonia, chorea, and hemiballismus in patients with complex movement disorders.