Mojgan Hodaie

Chronic anterior thalamus stimulation for intractable epilepsy.

Summary:  Purpose: A significant number of patients with epilepsy remain poorly controlled despite antiepileptic medication (AED) treatment and are not eligible for resective surgery. Novel therapeutic methods are required to decrease seizure burden in this population. Several observations have indicated that the anterior thalamic region plays an important role in the maintenance and propagation of seizures. We investigated neuromodulation of the anterior thalamus by using deep‐brain stimulation (DBS) in patients with intractable seizures.

Effects of subthalamic nucleus stimulation on motor cortex plasticity in Parkinson disease.

Objective: We hypothesized that subthalamic nucleus (STN) deep brain stimulation (DBS) will improve long-term potentiation (LTP)-like plasticity in motor cortex in Parkinson disease (PD). Methods: We studied 8 patients with PD treated with STN-DBS and 9 age-matched healthy controls. Patients with PD were studied in 4 sessions in medication (Med) OFF/stimulator (Stim) OFF, Med-OFF/Stim-ON, Med-ON/Stim-OFF, and Med-ON/Stim-ON states in random order. Motor evoked potential amplitude and cortical silent period duration were measured at baseline before paired associated stimulation (PAS) and at 3 different time intervals (T0, T30, T60) up to 60 minutes after PAS in the abductor pollicis brevis and abductor digiti minimi muscles. Results: Motor evoked potential size significantly increased after PAS in controls (+67.7% of baseline at T30) and in patients in the Med-ON/Stim-ON condition (+55.8% of baseline at T30), but not in patients in the Med-OFF/Stim-OFF (−0.4% of baseline at T30), Med-OFF/Stim-ON (+10.3% of baseline at T30), and Med-ON/Stim-OFF conditions (+17.3% of baseline at T30). Cortical silent period duration increased after PAS in controls but not in patients in all test conditions. Conclusions: Our findings suggest that STN-DBS together with dopaminergic medications restore LTP-like plasticity in motor cortex in PD. Restoration of cortical plasticity may be one of the mechanisms of how STN-DBS produces clinical benefit.

Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: Case report and review of the literature

Indications for the use of radiotherapy in the management of a variety of benign intracranial neoplastic and nonneoplastic pathologies are increasing. Although the short-term risks are minimal, the long-term risks of radiation-induced de novo secondary neoplasms or malignant progression of the primary benign tumor need to be considered. There are currently 19 reported cases of tumors linked with stereotactic radiotherapy/radiosurgery, to which we add our second institutional experience of a patient who succumbed to a glioblastoma multiforme (GBM) after stereotactic radiotherapy for an acoustic neuroma (AN). Review of these 20 cases revealed 10 de novo secondary tumors, of which eight were malignant, with six being malignant gliomas. The majority of the cases (14 of 20) involved AN, with most being in patients with neurofibromatosis-2 (NF2; 8 of 14), reflecting the large numbers and long-term use of radiotherapy for AN. Accelerated growth of the primary benign AN, some 2 to 6 years after focused radiotherapy, was found in six of eight NF2 patients, with pathological verification of a malignant nerve sheath tumor documented in most. The exact carcinogenic risk after radiotherapy is unknown but likely extremely low. However, the risk is not zero and requires discussion with the patient, with specific consideration in young patients and those with a cancer predisposition.

Increased Gamma Oscillatory Activity in the Subthalamic Nucleus During Tremor in Parkinson's Disease Patients

Rest tremor is one of the main symptoms in Parkinsons disease (PD), although in contrast to rigidity and akinesia, the severity of the tremor does not correlate well with the degree of dopamine deficiency or the progression of the disease. Studies suggest that akinesia in PD patients is related to abnormal increased beta (15-30 Hz) and decreased gamma (35-80 Hz) synchronous oscillatory activity in the basal ganglia. Here we investigated the dynamics of oscillatory activity in the subthalamic nucleus (STN) during tremor. We used two adjacent microelectrodes to simultaneously record neuronal firing and local field potential (LFP) activity in nine PD patients who exhibited resting tremor during functional neurosurgery. We found that neurons exhibiting oscillatory activity at tremor frequency are located in the dorsal region of STN, where neurons with beta oscillatory activity are observed, and that their activity is coherent with LFP oscillations in the beta frequency range. Interestingly, in 85% of the 58 sites examined, the LFP exhibited increased oscillatory activity in the low gamma frequency range (35-55 Hz) during periods with stronger tremor. Furthermore, in 17 of 26 cases where two LFPs were recorded simultaneously, their coherence in the gamma range increased with increased tremor. When averaged across subjects, the ratio of the beta to gamma coherence was significantly lower in periods with stronger tremor compared with periods of no or weak tremor. These results suggest that resting tremor in PD is associated with an altered balance between beta and gamma oscillations in the motor circuits of STN.

Deep brain stimulation of the anterior nucleus of the thalamus: Effects of electrical stimulation on pilocarpine-induced seizures and status epilepticus

PURPOSE Electrical stimulation of the anterior nucleus of the thalamus appears to be effective against seizures in animals and humans. As the optimal stimulation settings remain elusive, we studied the effects of different stimulation parameters against pilocarpine induced seizures and status epilepticus (SE). METHODS Adult rats had electrodes implanted bilaterally into the AN. Five days later, different groups of animals were stimulated with 1000 microA, 500 microA, or 200 microA and frequencies of either 20 Hz or 130 Hz. Pilocarpine (350 mg/kg i.p.) was injected 5 min after stimulation onset and seizures were monitored. Sham-treated controls had electrodes implanted but did not receive stimulation until they developed SE. After SE, these animals had the electrodes turned on to assess whether AN stimulation could arrest ongoing ictal activity. RESULTS Compared to sham-treated controls (n=8), stimulation at 500 microA (n=13) significantly increased the latency for seizures and SE by 1.9-2.2-fold. In contrast, stimulation at 1000 microA (n=8) produced a non-significant decrease in the latencies to these events. No major effect was observed with stimulation at 200 microA (n=11). Similar results were obtained for each current intensity, regardless of the stimulation frequency used (20 Hz and 130 Hz). In sham-treated controls that had the electrodes turned on after SE, stimulation was not able to arrest ongoing ictal activity. CONCLUSIONS The anticonvulsant effects of AN stimulation against pilocarpine-induced seizures were mainly determined by the current and not the frequency of stimulation. AN stimulation initiated after SE onset was ineffective.

The Nature and Time Course of Cortical Activation Following Subthalamic Stimulation in Parkinson's Disease

We studied the time course and nature of interactions between the subthalamic nucleus (STN) and the motor cortex in 8 Parkinson disease (PD) patients with chronically implanted STN deep-brain stimulation (DBS) electrodes. We first identified the cortical evoked potentials following STN stimulation. The most consistent potential was positive wave with peak latency of 22.2 +/- 1.2 ms from stimulation of clinically effective contacts. We then stimulated the motor cortex with transcranial magnetic stimulation (TMS) at 2-15 ms and at the latency of the evoked potential ( approximately 23 ms) following STN DBS. TMS induced currents in 3 directions: lateral-medial (LM) direction activated corticospinal axons directly, posterior-anterior (PA), and anterior-posterior (AP) directions activated corticospinal neurons transynaptically. Motor-evoked potentials (MEP) elicited by AP and PA TMS were facilitated at short (2-4 ms) and medium latencies (21-24 ms). However, MEPs elicited by LM TMS were not modified by STN DBS. Short-latency antidromic stimulation of the corticosubthalamic projections and medium latency transmission likely through the basal ganglia-thalamocortical circuit led to cortical evoked potentials and increased motor cortex excitability at specific intervals following STN stimulation at clinically effective contacts. Cortical activation may be related to the clinical effects of STN DBS in PD.

Bilateral pallidal stimulation in cervical dystonia: blinded evidence of benefit beyond 5 years

The local injection of botulinum toxin is accepted as the first-line treatment of primary cervical dystonia. This approach provides adequate symptomatic relief for most patients, but up to one-third will have an unsatisfactory response. Deep brain stimulation of the globus pallidus internus has been increasingly used in dystonic syndromes that are refractory to best pharmacological approaches. Although cervical dystonia is the most common idiopathic focal dystonia, evidence for long-term responsiveness to pallidal stimulation is limited. The primary objective of this study was to prospectively collect outcome data from baseline to last clinical follow-up on patients with idiopathic cervical dystonia treated with bilateral pallidal stimulation. Blinded video assessment of examinations performed preoperatively and at last video assessment were performed. Ten patients had complete prospective clinical follow-up. Baseline total Toronto Western Spasmodic Torticollis Rating Scale score (±standard deviation) was 54.5 ± 12.4 (range, 35.0-70.3). Comparison of the blinded severity sub-score on baseline video and at last video assessment at a mean of 7.7 years postoperatively demonstrated a mean improvement of 47.6% (P = 0.002) and strong inter-observer correlation between blinded raters (Spearman r = 0.78, 95% confidence interval 0.49-0.92, P = 0.0001). All 10 patients had 5 years of open prospective follow-up, documenting a 47.4 ± 26.4% (P < 0.01) mean improvement with respect to baseline. This was maintained at a mean of 7.8 years at last follow-up after surgery (range, 4.9-10.7 years) with a 54.4 ± 27.4% mean improvement (P < 0.01). Deep brain stimulation of the globus pallidus is an effective and long-lasting second-line treatment of cervical dystonia, with benefit in some of our patients extending to >10 years. More data are needed to explain variations in individual responses and to guide individual programming parameters.

Oscillatory activity in the globus pallidus internus: Comparison between Parkinson’s disease and dystonia

OBJECTIVE Deep brain stimulation in the globus pallidus internus (GPi) is used to alleviate the motor symptoms of both Parkinsons disease (PD) and dystonia. We tested the hypothesis that PD and dystonia are characterized by different temporal patterns of synchronized oscillations in the GPi, and that the dopaminergic loss in PD makes the basal ganglia more susceptible to oscillatory activity. METHODS Neuronal firing and local field potentials (LFPs) were simultaneously recorded from the GPi in four PD patients and seven dystonia patients using two independently driven microelectrodes. RESULTS In the PD patients, beta (11-30 Hz) oscillations were observed in the LFPs and the firing activity of ∼30% of the neurons was significantly coherent with the LFP. However, in the dystonia group, the peak frequency of LFP oscillations was lower (8-20 Hz) and there was a significantly smaller proportion of neurons (∼10%) firing in coherence with the LFP (P<0.001). CONCLUSIONS These findings suggest that synchronization of neuronal firing with LFP oscillations is a more prominent feature in PD than in dystonia. SIGNIFICANCE This study adds to the growing evidence that dopaminergic loss in PD may increase the sensitivity of the basal ganglia network to rhythmic oscillatory inputs.

Anterior thalamus deep brain stimulation at high current impairs memory in rats

Deep brain stimulation (DBS) of the anterior thalamic nucleus (AN), an important relay in the circuitry of memory, is currently being proposed as a treatment for epilepsy. Despite the encouraging results with the use of this therapy, potential benefits and adverse effects are yet to be determined. We show that AN stimulation at relatively high current disrupted the acquisition of contextual fear conditioning and impaired performance on a spatial alternating task in rats. This has not been observed at parameters generating a charge density that approximated the one used in clinical practice. At settings that impaired behavior, AN stimulation induced a functional depolarization block nearby the electrode, increased c-Fos expression in cerebral regions projecting to and receiving projections from the AN, and influenced hippocampal activity. This suggests that complex mechanisms might be involved in the effects of AN DBS, including a local target inactivation and the modulation of structures at a distance. Though translating data from animals to humans has to be considered with caution, our study underscores the need for carefully monitoring memory function while selecting stimulation parameters during the clinical evaluation of AN DBS.

Anesthesia for Functional Neurosurgery: Review of Complications

The use of functional stereotactic neurosurgery is increasing for treatment of patients with movement disorders and other chronic illnesses. The anesthetic considerations include the influence of the anesthetic agents on the microelectrode recordings and stimulation testing of an awake patient. The purpose of this study was to review the anesthetic management and incidences of intraoperative complications during functional neurosurgery in our institution. One hundred seventy-eight patients underwent an ablative procedure (n = 6) or the insertion of deep brain stimulator (n = 172) under monitored anesthesia care for movement disorders (n = 124), chronic pain (n = 20), and other procedures (n = 34). Local anesthetic was used for head frame pin sites and burr holes. No sedation/analgesia was administered to 57 (32%) patients. One patient required conscious sedation and another general anesthesia for the entire procedure. The remainder received small increments (mean ± SD) of propofol (113 ± 73 mg), midazolam (1.6 ± 0.8 mg), and/or fentanyl (93 ± 55 μg). Intraoperative complications that occurred in 16% of the patients included seizures (n = 8), change in neurologic status (n = 5), airway obstruction (n = 2), and hypertension (n = 7). Functional neurosurgery can be performed with minimal anesthesia in many patients. Awareness and vigilance can improve the identification and early treatment of intraoperative complications such as seizures, loss of airway, and changes in the neurologic status.