Threshold for Tonic Motor Effects from Random Waveform in a Rat Experimental Model of Frontal Cortex Stimulation.

BACKGROUND: Brain stimulation is utilized to treat a variety of neurological disorders. Clinical brain stimulation technologies currently utilize charge-balanced pulse stimulation. The brain may better respond to other stimulation waveforms. This study was designed to evaluate the motor threshold of the brain to stimulation with various waveforms. METHODS: Three stimulation waveforms were utilized on rats with surgically implanted brain electrodes: pulses, square waves, and random waveform. The peak-to-peak stimulation voltage was increased in a step-wise manner until motor signs were elicited. RESULTS: The random waveform had the highest motor threshold with brain stimulation compared to the other waveforms. Random waveform stimulation reached maximum voltage without motor side effects while stimulating through both 1 and 8 electrodes. In contrast, the stimulation thresholds for motor side effects of the other two waveforms were on average less than half of the maximum voltage and lower for stimulation through 8 electrodes than stimulation through 1 electrode (p < 0.0005). CONCLUSION: The random waveform was better tolerated than the other waveforms and may allow for the use of higher stimulation voltage without side effects.

Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation.

OBJECTIVE: To study the incidence and clinical features of sudden unexpected death in epilepsy (SUDEP) in patients treated with direct brain-responsive stimulation with the RNS System. METHODS: All deaths in patients treated in clinical trials (N = 256) or following U.S. Food and Drug Administration (FDA) approval (N = 451) through May 5, 2016, were adjudicated for SUDEP. RESULTS: There were 14 deaths among 707 patients (2208 postimplantation years), including 2 possible, 1 probable, and 4 definite SUDEP events. The rate of probable or definite SUDEP was 2.0/1000 (95% confidence interval [CI] 0.7-5.2) over 2036 patient stimulation years and 2.3/1000 (95% CI 0.9-5.4) over 2208 patient implant years. Stored electrocorticograms around the time of death were available for 4 patients with probable/definite SUDEP and revealed the following: frequent epileptiform activity ending abruptly (n = 2), no epileptiform activity or seizures (n = 1), and an electrographic and witnessed seizure with cessation of postictal electrocorticography (ECoG) activity associated with apnea and pulselessness (n = 1). SIGNIFICANCE: The SUDEP rate of 2.0/1000 patient stimulation years among patients treated with the RNS System is favorable relative to treatment-resistant epilepsy patients randomized to the placebo arm of add-on drug studies or with seizures after resective surgery. Our findings support that treatments that reduce seizures reduce SUDEP risk and that not all SUDEPs follow seizures.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

A historical perspective: stereotactic lesions for the treatment of epilepsy.

PURPOSE: Most deep brain stimulation targets for movement disorders were derived from effective ablative surgery targets. Similarly effective lesion targets for epilepsy control may help refine brain stimulation targeting for epilepsy. A literature review of past stereotactic lesions for epilepsy treatment was performed to provide historical context and possible anatomical guidance for current and future attempts at controlling epilepsy with electrical stimulation. This work was undertaken to provide insights for electrical stimulation targets in epilepsy treatment based on outcomes from previous ablative therapies. METHODS: A MEDLINE search was conducted for studies with the words "stereotactic surgery" and "epilepsy." Post-operative results for 619 patients with stereotactic brain lesions targeting various anatomical foci were standardized using a modified Engel scale (1 'free of seizures' to 3 'no significant improvement'). Each individual patient was entered into a database as a unique data point. RESULTS: There was a statistically significant difference in reported seizure control among the different procedures and seizure types. The procedures that produced the best seizure control outcomes were the hippocampectomy, pallido - amygdalotomy, and amygdalohippocampectomy. Simple partial motor and combined generalized tonic clonic with complex partial seizure types demonstrated the best outcomes following surgery; complex partial and generalized tonic had the worst outcomes. CONCLUSIONS: The results of this study demonstrate the location of brain lesions has a significant effect on seizure control. Thus, future research designed to optimize brain stimulation targets for epilepsy control may be informed by previous ablative outcomes.

Stereotactic lesions for the treatment of psychiatric disorders.

OBJECT: The use of deep brain stimulation (DBS) has recently been expanded to the investigational treatment of specific psychiatric disorders. Much like movement disorders, the targets selected for DBS are based on past experience with stereotactic lesions. A literature review of past studies incorporating stereotactic lesions for psychiatric disorders was performed to provide historical context and possible guidance for current and future attempts at treating psychiatric disorders with DBS. METHODS: Original copies of the proceedings of the second, third, fourth, and fifth World Congresses of Psychiatric Surgery meetings were reviewed, and a Medline search was conducted for studies with the word "psychosurgery" and each of 14 highly prevalent psychiatric conditions identified by the National Institute of Mental Health. Postoperative results for 1145 patients with stereotactic brain lesions targeting various anatomical foci were standardized using a 5-point scale (3 [free of symptoms] to -1 [worse]). Each patient was entered into a database as a unique data point and used for this literature review. RESULTS: General anxiety disorder and obsessive-compulsive disorder had the greatest reported improvements from anterior capsulotomy, and bipolar disorder, depression, and schizoaffective disorder had the greatest reported improvements from anterior cingulotomy, supporting these areas for DBS investigation. Addiction and schizophrenia showed the least improvement from surgery. Therefore, pursuing the treatment of these disorders with DBS using the targets in these studies may be ineffective. CONCLUSIONS: This study provides retrospective data that suggest which anatomical focus may be effective to lesion or stimulate for the treatment of each of several psychiatric disorders.

The effect of acute postoperative pain and chronic neuropathic pain on subsequent weight gain in the rat.

OBJECT: Acute postoperative pain has demonstrated effects on appetite and weight gain in human studies. This study was designed to test the hypothesis that chronic neuropathic pain has a more significant effect on weight than acute postsurgical pain. METHODS: One hundred eighteen rats were separated into 3 groups: common sciatic nerve ligation, surgery without ligation, and no surgery. Each group was further divided to undergo testing at 3, 7, and 14 days. On the day of testing, the rats were tested for signs of pressure and heat hyperalgesia and were weighed. RESULTS: The effect on the percentage of change in body weight from the day of surgery to the day of testing was statistically significant for both the condition (F = 15.0, p < 0.0001) and the day of testing (F = 43.3, p < 0.0001). The rats that received no surgery had a change in weight of 2.3% on Day 3, 4.0% on Day 7, and 10.7% on Day 14. In the nonligation surgery group, the change was -3.8% on Day 3, 2.0% on Day 7, and 9.7% on Day 14. In the ligation surgery group, the change was -6.3% on Day 3, -0.7% on Day 7, and 4.9% on Day 14. This group began gaining weight by Day 14 but continued to have less weight gain than the other groups by Day 14. CONCLUSIONS: Neuropathic pain inhibits weight gain more than normal, postsurgical pain. Recognizing the difference and initiating effective treatment for neuropathic pain may have an impact on the patient's nutrition.

Cortical synchrony changes detected by scalp electrode electroencephalograph as traumatic brain injury patients emerge from coma.

BACKGROUND: Recent studies show conscious perception is correlated with firing rate synchronization across multiple neuronal assemblies. This study explores the synchrony between multiple cortical surface sites as brain injury patients emerge from coma. METHODS: Scalp electrode EEG recordings were collected and analyzed from 13 traumatic brain injury patients during their stay in a neurosurgical intensive care unit. Neuronal synchrony was calculated between various electrode pairs during comatose and conscious periods defined by the GCS. Frequency bands from 1 to 30 Hz were evaluated in each patient. RESULTS: As patients emerged from coma at GCS 3 to GCS scores > or =8, synchrony values from all electrode pairs revealed a global decrease in synchrony at higher GCS scores. No significant effects were detected relative to the amount of sedation given, but at higher GCS scores significantly increased neuronal synchrony was observed between occipital lobes and right parietal and temporal lobe sites. Synchrony was decreased between frontal-occipital, frontal-parietal, and parietal-occipital electrodes. CONCLUSIONS: In frequencies from 1 to 30 Hz, synchrony between right parietal and temporal lobes, as well as bilateral occipital lobes, tends to be increased as patients emerge from comatose states. However, synchrony between most intrahemispheric cortical sites is decreased at higher GCS scores in most of the above frequency bands. Thus, brain injury patients demonstrate both increased and decreased cortical surface synchrony between different lobes during emergence from coma.

Alpha2-adrenergic receptor subtype specificity of intrathecally administered tizanidine used for analgesia for neuropathic pain.

OBJECT: Intrathecally administered alpha2-adrenergic receptor subtype-specific antagonists were used to determine which alpha2-adrenergic receptor subtype mediates the analgesic effect of intrathecally administered tizanidine in a chronic constriction injury (CCI) rat model of neuropathic pain. METHODS: Seven days after CCI and intrathecal catheter surgeries had been performed in Sprague-Dawley rats, baseline neuropathic pain tests including cold-floor ambulation and paw pinch were performed. Either the dimethyl sulfoxide vehicle (seven rats) or one of the antagonists--5, 23, or 46 microg yohimbine (22 rats); 5, 25, 50, or 100 microg prazosin (25 rats); or 5, 45, or 90 microg WB4101 (11 rats)--were intrathecally administered to the animals, followed in 30 minutes by 50 microg intrathecally administered tizanidine. The neuropathic pain tests were repeated 30 minutes later. The resulting profile showed a descending order of antagonist efficacy for yohimbine, prazosin, and WB4101 for the cold-floor ambulation test and for the paw-pinch test of the affected paw. As expected given tizanidine's lack of analgesic effect on the contralateral, normal paw, there were no effects of antagonists on contralateral paw responses. The results of the paw-pinch test on the affected side were compared with binding data cited in the existing literature for the three different alpha2-adrenergic receptor subtypes (alpha2A, alpha2B, and alpha2C) with yohimbine, prazosin, and WB4101. The antagonist response profile for the paw-pinch test of the affected paw most closely approximated the alpha2B receptor binding profile. CONCLUSIONS: The antagonist profile from the current study is most consistent with the theory that the alpha2B-adrenergic receptor subtype mediates the analgesic effect of intrathecally administered tizanidine on CCI-associated neuropathic pain.

Decreased spinal alpha2a- and alpha2c-adrenergic receptor subtype mRNA in a rat model of neuropathic pain.

Northern blot analyses performed on the lumbar spinal cords (L4-L6) of rats with the Bennett and Xie chronic constriction injury (CCI) nerve ligation model of neuropathic pain were compared to non-ligation surgery and unoperated control rats to determine if there is a change in alpha2-adrenergic receptor mRNA expression with neuropathic pain. Compared to unoperated rats, CCI rats had bilaterally lower RG-20 mRNA, corresponding to the alpha2A-adrenergic receptor subtype (affected 62.4 +/- 22.1% and contralateral 69.5 +/- 16.6% of unoperated, P<0.05), and RG-10 mRNA, corresponding to the alpha2C-adrenergic receptor subtype (affected 49.2 +/- 19.1% and contralateral 50.0 +/- 14.4% of unoperated, P<0.05). These results would suggest a corresponding decrease in alpha2A- and alpha2C-adrenergic receptor concentrations in the CCI and non-ligation surgery rats' spinal cords.

The analgesic effects of intrathecally pumped saline and artificial cerebrospinal fluid in a rat model of neuropathic pain.

Objective. This experiment was performed to test the hypothesis that intrathecally pumped saline, but not artificial cerebrospinal fluid (CSF), would be analgesic in a rat model of neuropathic pain. Materials and Methods. Surgery for the chronic constriction injury (CCI) model of neuropathic pain and intrathecal catheter placement were performed on the rats, baseline pain testing and pump implantation were performed 7 days later, and pain tests were repeated on days 1, 4, 7, and 14 after pump implantation. Results. Intrathecally pumped saline and artificial CSF were analgesic for cold allodynia (p < 0.05), and intrathecally pumped saline but not CSF for heat nociception in the affected paw (p < 0.005) compared to rats with unattached subcutaneous pumps. No analgesia was observed on tests of spontaneous pain or pressure hyperalgesia (p > 0.1). Conclusions. Intrathecally pumped saline and artificial CSF have analgesic effects on some neuropathic and normal, nociceptive pain signs in CCI rats.