Neurophysiological comparisons of subthalamic deep-brain stimulation for Parkinson's disease between patients receiving general and local anesthesia.

OBJECTIVES: Subthalamic nucleus deep-brain stimulation (STN-DBS) is suggested as a standard treatment for patients with Parkinson's disease (PD) and drug-related side effects. Most centers perform the operation under local anesthesia (LA) to ensure better microelectrode recording (MER). Given the advances in imaging and MER, general anesthesia (GA) is perceived as an alternative choice for PD patients undergoing STN-DBS. However, the outcomes in terms of clinical symptoms and MER after GA have rarely been reported. In this report, we compared the outcomes after STN-DBS for PD between patients receiving LA and GA. MATERIALS AND METHODS: We included 16 patients with comparable severity of PD undergoing either GA (n = 8) or LA (n = 8) for STN-DBS. MER was performed in all patients for STN localization, and surgical outcomes were evaluated using the Unified PD Rating Scales, and Mini-mental status examination. All adverse effects were documented. RESULTS: Both groups (GA and LA) acquired similar benefits from STN-DBS, and there were no significant differences in neuropsychiatric outcome analysis between groups. There were no significant differences in stimulation parameters and adverse effects from STN-DBS between groups. The GA group had a trend toward a lower frequency rate of STN firing on MER. CONCLUSION: Although the GA group has a lower neuronal firing frequency in the STN during surgery, STN-DBS under GA showed comparable and non-inferior outcomes as compared with STN-DBS under LA.

Spatiotemporal Changes of Neuronal Responses in the Primary Somatosensory Cortex to Noxious Tail Stimulation in Awake and Pentobarbital-Anesthetized Rats.

Primary somatosensory cortex (SI) is a key area in the processing of nociceptor inputs to our consciousness. To clarify the columnar and laminar organization of SI for pain processing, we compared spatiotemporal changes in neuronal activities of the primary sensorimotor cortex (SmI) of the rat in response to noxious laser heat stimulation applied to the mid-tail. Longitudinal and vertical array microelectrodes were chronically implanted in the cerebral cortex. Evoked neuronal activities, including intracortical local field potentials (LFP) and ensemble single-unit activity (SU) around SmI were simultaneously recorded. The effect of pentobarbital on the neuronal responses was evaluated in comparison with the neuronal responses in conscious animals to explore the potential substrate of nociceptive processing in the conscious state. The results from the experiment with longitudinal microelectrode arrays indicated that noxious stimulation induced a neuronal response which was spread widely around the SmI of the conscious rat, and the range of neuronal responses was limited to the tail region of the SmI under anesthesia. The results from the experiment with vertical microelectrode arrays showed the universal neuronal responses through all cortical layers of the SmI in conscious rats, and sodium pentobarbital suppressed these neuronal responses in the supragranular layers significantly relative to the deeper layers and basal activity. These results imply that a wider range of cortical activation, both in the horizontal or vertical dimension, might be important for nociceptive processing in the conscious state.

Dorsolateral subthalamic neuronal activity enhanced by median nerve stimulation characterizes Parkinson's disease during deep brain stimulation with general anesthesia.

OBJECT: Deep brain stimulation (DBS) surgery under general anesthesia is an alternative option for patients with Parkinson's disease (PD). However, few studies are available that report whether neuronal firing can be accurately recorded during this condition. In this study the authors attempted to characterize the neuronal activity of the subthalamic nucleus (STN) and elucidate the influence of general anesthetics on neurons during DBS surgery in patients with PD. The benefit of median nerve stimulation (MNS) for localization of the dorsolateral subterritory of the STN, which is involved in sensorimotor function, was explored. METHODS: Eight patients with PD were anesthetized with desflurane and underwent contralateral MNS at the wrist during microelectrode recording of the STN. The authors analyzed the spiking patterns and power spectral density (PSD) of the background activity along each penetration track and determined the spatial correlation to the target location, estimated mated using standard neurophysiological procedures. RESULTS: The dorsolateral STN spiking pattern showed a more prominent bursting pattern without MNS and more oscillation with MNS. In terms of the neural oscillation of the background activity, beta-band oscillation dominated within the sensorimotor STN and showed significantly more PSD during MNS (p < 0.05). CONCLUSIONS: Neuronal firing within the STN could be accurately identified and differentiated when patients with PD received general anesthetics. Median nerve stimulation can enhance the neural activity in beta-band oscillations, which can be used as an index to ensure optimal electrode placement via successfully tracked dorsolateral STN topography.

Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats.

Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3-20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light-dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both male and female offsprings in the same manner as morphine. Although prenatal exposure to methadone or buprenorphine increased anxiety-like behaviors in the light-dark transition in both male and female offsprings, the effects were less pronounced as compared to that of morphine. Methadone affected elevated plus-maze in both sex, but buprenorphine only affected the female offsprings. These findings suggest that buprenorphine and methadone maintenance therapy for pregnant women, like morphine, produced detrimental effects on cognitive function and social behaviors, whereas the offsprings of such women might have a lower risk of developing anxiety disorders.

Comparisons of terminal densities of cardiovascular function-related projections from the amygdala subnuclei.

The amygdala is important in higher-level control of cardiovascular functions. In this study, we compared cardiovascular-related projections among the subnuclei of the amygdala. Biotinylated dextran amine was injected into the central, medial, and basolateral nuclei of the amygdala, and the distributions and densities of anterograde-labeled terminal boutons were analyzed. We found that the medial, basolateral, and central nuclei all had projections into the cardiovascular-related areas of the hypothalamus. However, only the central nucleus had a significant direct projection into the medulla. By contrast, the medial nucleus had limited projections, and the basolateral nucleus had no terminals extending into the medulla. We concluded that the medial, central, and basolateral nuclei of the amygdala may influence cardiovascular-related nuclei through monosynaptic connections with cardiovascular-related nuclei in the hypothalamus and medulla.

Effects of spike sorting error on the Granger causality index.

Accurately sorting individual neurons is a technical challenge and plays an important role in identifying information flow among neurons. Spike sorting errors are almost unavoidable and can roughly be divided into two types: false positives (FPs) and false negatives (FNs). This study investigates how FPs and FNs affect results of the Granger causality (GC) analysis, a powerful method for detecting causal interactions between time series signals. We derived an explicit formula based on a first order vector autoregressive model to analytically study the effects of FPs and FNs. The proposed formula was able to reveal the intrinsic properties of the GC, and was verified by simulation studies. The effects of FPs and FNs were further evaluated using real experimental data from the ventroposterior medial nucleus of the thalamus. Some practical suggestions for spike sorting are also provided in this paper.

Involvement of the periaqueductal gray in the effect of motor cortex stimulation.

Several clinical and animal studies of different pain models reported that motor cortex stimulation (MCS) has an antinociceptive effect. In our previous study, the response of the primary somatosensory cortex (SI) to peripheral stimuli decreased after MCS. The aim of the present study was to investigate involvement of the periaqueductal gray (PAG) in this inhibitory effect of MCS. Responses of the SI to electrical stimuli applied to both forepaws of anesthetized rats were monitored to evaluate the effect of MCS. After sensory-evoked potentials (SEPs) were stable, either saline, opioid, or dopamine receptor antagonists were locally microinjected into the PAG. After drug or saline administration, MCS was applied to the forepaw area of the right motor cortex. SEPs after MCS were compared to those before MCS. In the saline group, SEPs ipsilateral to MCS decreased, but SEPs contralateral to MCS did not. The decrease in SEPs was prevented by pretreatment of the PAG with naloxone. Application of a nonspecific dopamine receptor antagonist (α-flupenthixol) to the PAG also blocked the inhibition of SEPs after MCS. Inhibition of SEPs after MCS was blocked by local application of a D1 antagonist (SCH-23390) in the PAG, but not by a D2 antagonist (eticlopride). These results suggest that the PAG participates in the inhibitory effect of MCS, and this effect of MCS may be mediated by opioid and dopamine D1 receptors within thePAG.

Epidural motor cortex stimulation suppresses somatosensory evoked potentials in the primary somatosensory cortex of the rat.

Motor cortex stimulation (MCS) is a promising clinical procedure to help alleviate chronic pain. Animal models demonstrated that MCS is effective in lessening nocifensive behaviors. The present study explored the effects of MCS on cortical somatosensory evoked potentials (SEPs) recorded at the primary somatosensory cortex (SI) of the rat. SEPs were evoked by electrical stimulation applied to the contralateral forepaws. Effects of different intensities, frequencies, and durations of MCS were tested. MCS at ≥2V suppressed SEPs of the ipsilateral SI. Suppression lasted 120 min at an intensity of 5 V. The optimal frequency was 50 Hz, and the duration was 30s. In contrast, MCS did not affect SEPs recorded on the contralateral SI. Cortical stimulation out of the motor cortex did not induce a decrease in the ipsilateral SEPs. We also investigated involvement of the endogenous opioid system in this inhibition of SEPs induced by MCS. The opioid antagonist, naloxone (0.5 mg/kg), was administered 30 min before MCS. Application of naloxone completely prevented the inhibitory effect of MCS on ipsilateral SEPs. These results demonstrate that MCS blocked the transmission of somatosensory information to the primary somatosensory cortex, and this interference was mediated by the endogenous opioid system. This inhibitory effect on sensory transmission induced by MCS may reflect its antinociceptive effect.

Differential involvement of the anterior cingulate and primary sensorimotor cortices in sensory and affective functions of pain.

The present study examined the role of neurons in different pain-related functions of the anterior cingulate cortex (ACC) and primary sensorimotor cortex (SmI) by assessing their abilities to code different levels of noxious heat and activity changes evoked by classical fear conditioning involving electric shocks. Multiple single-unit activity was recorded with microwires implanted in the SmI and ACC of each rat. In the first set of experiments, the middle segment of the tail in each rat was irradiated with laser-heat pulses of various intensities. Neuronal responses in both the SmI and ACC increased with the intensity of the laser heat, although there was a significantly higher percentage of intensity-related units in the SmI. Furthermore, the stimulus-response curve of SmI ensemble activity had a steeper slope than that of the ACC. In the second set of experiments, rats were trained and tested on a conditioned fear-potentiated startle task in which a light was paired with an electric shock and, later, the startle response was elicited by a burst of noise in the presence or absence of light. A higher percentage of ACC units changed their neuronal responses to the conditioned stimulus after the light-shock pairing and the average activity change was also significantly stronger. Our results suggest that SmI neurons are better at coding laser-heat intensity than ACC neurons, whereas more ACC neurons are involved in conditioned fear associated with an electric shock than SmI neurons. These data provide evidence for differential contributions of the SmI and ACC to sensory and affective dimensions of pain.

State-dependent amygdala stimulation-induced cardiovascular effects in rats.

Stimulation of the amygdala is known to produce pressor, depressor, or has no effects. The present study was performed to test whether amygdala cardiovascular effects are influenced by consciousness states and by different types of anesthetics. Adult rats were set up for stimulation amygdala and measurement of blood pressure in a chronic preparation. After recovery, same sites of the amygdala were stimulated electrically for several trials with the rat under conscious or anesthetic states induced by pentobarbital, urethane, ketamine, alpha-chloralose and urethane plus alpha-chloralose, respectively. The interval between any two stimulation trials was at least 2 days. The stimulation was an 80-Hz, 0.5-ms, 100-micro A square wave pulse train lasting for 15 s. Cardiovascular responsive sites were found in the central, medial, and basolateral nuclei of the amygdala. In stimulating these responsive sites, significantly different cardiovascular effects were induced under a conscious state and an anesthetized state of the animal, yet no significant differences were found among the various anesthetic agents. We conclude, that the cardiovascular influence of the amygdala is state-dependent in the rat.

Comparison of anterior cingulate and primary somatosensory neuronal responses to noxious laser-heat stimuli in conscious, behaving rats.

In this study, we investigated single-unit responses of the primary sensorimotor cortex (SmI) and anterior cingulate cortex (ACC) to noxious stimulation of the tail of the rat. The influences of morphine on these nociceptive responses were also compared. Multiple single-unit activities were recorded from two eight-channel microwire arrays chronically implanted in the tail region of the SmI and ACC, respectively. CO2 laser-heat irradiation of the middle part of the tail at an intensity slightly higher than that causing a maximal tail flick response was used as a specific noxious stimulus. Examined individually, ACC neurons were less responsive than SmI neurons to laser-heat stimulus, in that only 51% of the ACC units (n = 125) responded compared with 88% of the SmI units (n = 74). Among these responsive ACC units, many had a very long latency and long-lasting excitatory type of response that was seldom found in the SmI. When ensemble activities were examined, laser heat evoked both short- (60 approximately 150 ms) and long-latency (151 approximately 600 ms) responses in the SmI and ACC. Latencies of both responses were longer in the ACC. Furthermore, a single dose of 2.5-10 mg/kg morphine intraperitoneally suppressed only the long latency response in the SmI, but significantly attenuated both responses in the ACC. These effects of morphine were completely blocked by prior treatment with the opiate receptor blocker, naloxone. These results provide further evidence suggesting that the SmI and ACC may play different roles in processing noxious information.

BOLD signals correlate with ensemble unit activities in rat's somatosensory cortex.

Evoked neural activity (ensemble single-unit activity and evoked field potential) and functional magnetic resonance imaging (fMRI) changes of the primary somatosensory cortex in response to electrical stimulation of the hind paw were studied in rats under anesthesia. The effects of stimulation frequency (ranging from 0.3 to 10 Hz) and types of anesthetics (alpha-chloralose and sodium pentobarbital) on blood oxygen level dependent (BOLD) activation and neural activation were compared. Both ensemble single-unit activity and BOLD signal changes achieved maximal activation at 3 Hz of stimulation and responses were significantly stronger under alpha-chloralose anesthesia. The maximal activation of the integral evoked potential (sigmaEP), in contrast, was the highest at 10 Hz; and the values were similar for alpha-chloralose and pentobarbital. These analyses revealed that fMRI image changes were better correlated with ensemble single-unit activity than with sigmaEP during somatosensory stimulations.

Differential morphine effects on short- and long-latency laser-evoked cortical responses in the rat.

Evoked potential and ensemble neuronal activities were used to study the responses of the primary sensorimotor cortex (SmI) to noxious CO(2) laser irradiation of the middle part of the tail in conscious behaving rats. The hypothesis that systemic morphine treatment preferentially attenuates the longer-latency laser-evoked cortical responses was also tested. Laser-evoked potentials (LEPs) and multiple single-unit (SU) activities were, respectively, recorded from chronically implanted stainless-steel screws and microwire electrodes. When examined individually, many SmI neurons showed either short-latency (<100 ms) or long-latency (300-500 ms) responses to laser irradiation. These neurons are widely dispersed in the tail region and hind limb region of the SmI, and also in the forelimb and head regions of the primary motor cortex (MI). Quantitatively, a higher percentage of neurons in the SmI tail region responded with shorter latencies compared to those in the SmI hind limb region or in the MI. When responses of many simultaneously recorded SU were examined together, short-latency and long-latency SmI ensemble activities matched the LEP1 and LEP2, respectively. Systemic morphine significantly attenuated the long-latency but not the short-latency component in both LEPs as well as ensemble neuronal activity in the tail region of the SmI. These effects were blocked by naloxone pretreatment.

Mindfulness meditation in the control of severe headache.

In the West, the use of the methods of alternative medicine, including meditation, has been on the rise. In the US, Kabat-Zinn and associates have pioneered the extensive use of mindfulness meditation (MM) for the treatment of people facing pain and illness. Among the essentials of MM is the observation of bodily sensations, including pain. In Taiwan, despite the deep cultural roots of meditation, its therapeutic use has received little attention from institutionalized medicine. We report on the case of a man who was prone to developing severe headaches due to activities requiring extreme concentration. He learned to control his pain and discomfort through mindfulness meditation, although this practice in fact induced headaches initially. It is suggested that training in MM may be a medically superior and cost-effective alternative to pain medication for the control of headaches with no underlying organic causes in highly motivated patients.