Imaging findings in MR imaging-guided focused ultrasound treatment for patients with essential tremor.

BACKGROUND AND PURPOSE: MR imaging-guided focused sonography surgery is a new stereotactic technique that uses high-intensity focused sonography to heat and ablate tissue. The goal of this study was to describe MR imaging findings pre- and post-ventralis intermedius nucleus lesioning by MR imaging-guided focused sonography as a treatment for essential tremor and to determine whether there was an association between these imaging features and the clinical response to MR imaging-guided focused sonography. MATERIALS AND METHODS: Fifteen patients with medication-refractory essential tremor prospectively gave consent; were enrolled in a single-site, FDA-approved pilot clinical trial; and were treated with transcranial MR imaging-guided focused sonography. MR imaging studies were obtained on a 3T scanner before the procedure and 24 hours, 1 week, 1 month, and 3 months following the procedure. RESULTS: On T2-weighted imaging, 3 time-dependent concentric zones were seen at the site of the focal spot. The inner 2 zones showed reduced ADC values at 24 hours in all patients except one. Diffusion had pseudonormalized by 1 month in all patients, when the cavity collapsed. Very mild postcontrast enhancement was seen at 24 hours and again at 1 month after MR imaging-guided focused sonography. The total lesion size and clinical response evolved inversely compared with each other (coefficient of correlation = 0.29, P value = .02). CONCLUSIONS: MR imaging-guided focused sonography can accurately ablate a precisely delineated target, with typical imaging findings seen in the days, weeks, and months following the treatment. Tremor control was optimal early when the lesion size and perilesional edema were maximal and was less later when the perilesional edema had resolved.

Deep brain stimulation of the subthalamic nucleus improves reward-based decision-learning in Parkinson's disease.

Recently, the subthalamic nucleus (STN) has been shown to be critically involved in decision-making, action selection, and motor control. Here we investigate the effect of deep brain stimulation (DBS) of the STN on reward-based decision-learning in patients diagnosed with Parkinson's disease (PD). We determined computational measures of outcome evaluation and reward prediction from PD patients who performed a probabilistic reward-based decision-learning task. In previous work, these measures covaried with activation in the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that stimulation of the STN motor regions in PD patients served to improve reward-based decision-learning, probably through its effect on activity in frontostriatal motor loops (prominently involving the putamen and, hence, reward prediction). In a subset of relatively younger patients with relatively shorter disease duration, the effects of DBS appeared to spread to more cognitive regions of the STN, benefiting loops that connect the caudate to various prefrontal areas importantfor outcome evaluation. These results highlight positive effects of STN stimulation on cognitive functions that may benefit PD patients in daily-life association-learning situations.

Functional neurosurgery in the MRI environment.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of microelectrode recording, electrical stimulation, and electrode position checking during functional neurosurgical procedures (DBS, lesion) in the interventional magnetic resonance imaging (iMRI) environment. METHODS: Seventy-six surgical procedures for DBS implant or radiofrequency lesion were performed in an open 0.2 T MRI operating room. DBS implants were performed in 54 patients (72 surgical procedures) and unilateral radiofrequency lesions in three for a total of 76 surgeries in 57 patients. Electrophysiological studies including macrostimulation and microelectrode recordings for localization were obtained in the 0.5 to 10 mT fringes of the magnetic field in 51 surgeries. MRI confirmation of the electrode position during the procedure was performed after electrophysiological localization. RESULTS: The magnetic field associated with the MRI scanner did not contribute significant noise to microelectrode recordings. Anatomical confirmation of electrode position was possible within the MRI artifact from the DBS hardware. Symptomatic hemorrhage was detected in two (2.6 %) patients during the operation. Image quality of the 0.2 T MRI scan was sub-optimal for anatomical localization. However, image fusion with pre-operative scans permitted excellent visualization of the DBS electrode tip in relation to the higher quality 1.5 T MRI anatomical scans. CONCLUSION: This study shows that conventional stereotactic localization, microelectrode recordings, electrical stimulation, implant of DBS hardware, and radiofrequency lesion placement are possible in the open 0.2 T iMRI environment. The convenience of having an imaging modality that can visualize the brain during the operation is ideal for stereotactic procedures.

Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by diminished upper airway muscle phasic and tonic activation during sleep, but enhanced activity during waking. We evaluated neural mechanisms underlying these patterns with functional magnetic resonance imaging procedures during baseline and expiratory loading conditions in nine medication-free OSA and 16 control subjects. Both groups developed similar expiratory loading pressures, but appropriate autonomic responses did not emerge in OSA cases. Reduced neural signals emerged in OSA cases within the frontal cortex, anterior cingulate, cerebellar dentate nucleus, dorsal pons, anterior insula and lentiform nuclei. Signal increases in OSA over control subjects developed in the dorsal midbrain, hippocampus, quadrangular cerebellar lobule, ventral midbrain and ventral pons. Fastigial nuclei and the amygdala showed substantially increased variability in OSA subjects. No group differences were found in the thalamus. OSA patients show aberrant responses in multiple brain areas and inappropriate cardiovascular responses to expiratory loading, perhaps as a consequence of previously-demonstrated limbic, cerebellar and motor area gray matter loss.

A device for feline head positioning and stabilization during magnetic resonance imaging.

Minimization of head movement and reproduction of standard head positions are essential for reliable brain functional magnetic resonance imaging. Devices for stabilization and alignment of feline preparations are not available currently. We describe a system that involves minimal surgery, allows for both acute and chronic atraumatic positioning, and has the potential to be used for unanesthetized animals. The device uses non-metallic materials and stabilizes the head by means of an apparatus that fixes the head with nylon screws and dental cement in the frontal sinuses. Application of the head-stabilizing device decreases head movements by more than a factor of ten. Anatomical images show that this device provides 3 dimensional head placement at a precision comparable to that of a stereotactic frame, i.e. within 1 mm.

Staged bilateral pallidotomy for treatment of Parkinson disease.

OBJECT: Several investigators have described the motor benefits derived from performing unilateral stereotactic pallidotomy for the treatment of Parkinson disease (PD), but little is known about the efficacy and complication rates of bilateral procedures. The goal of this study was to assess both these factors in 12 patients. METHODS: Eleven patients with medically intractable PD underwent staged bilateral pallidotomy and one patient underwent a simultaneous bilateral procedure. Unilateral pallidotomy resulted in an improvement in the patients' Unified Parkinson Disease Rating Scale (UPDRS) total scores and motor subscores, Hoehn and Yahr stages, and Schwab and England Activities of Daily Living scores. There were no complications. The second procedures were performed 5 to 25 months after the first, and nearly complete 3-month follow-up data are available for eight of these patients. Staged bilateral pallidotomy did result in further improvements in some symptoms, but the patients proved to be less responsive to levodopa. In contrast to outcomes of the initial unilateral pallidotomy, there were significant complications. One patient suffered an acute stroke, two patients suffered delayed infarctions of the internal capsule, four patients had mild-to-moderate worsening of speech and increased drooling, and one patient complained of worsening memory. CONCLUSIONS: Bilateral pallidotomy results in modest benefits but is associated with an increased risk of complications.

Correlation between MRI-based stereotactic thalamic deep brain stimulation electrode placement, macroelectrode stimulation and clinical response to tremor control.

In this study we compared the position of the electronically active contact of the thalamic (Vim) deep brain stimulation (DBS) electrode to the stereotactic location of its tip. Fifteen patients with either Parkinson's disease (PD) or essential tremor (ET) underwent stereotactic, MRI-based placement of the Medtronic quadripolar DBS electrode. An overall improvement of 69% was achieved in the tremor scores during a period of 1-13 months after implantation of the DBS electrode. Eleven patients with ET showed 70% clinical improvement of tremor, compared to a 58% response observed in the 4 patients with PD. The electrode tip center was 11.2 +/- 1.54 mm lateral to the third ventricular wall, 5.38 +/- 1.02 mm anterior to the posterior commissure and 2.9 +/- 3.57 mm inferior to the level of AC-PC line. The most significant deviation from the planned stereotactic target was observed in the Z-coordinate. In our group of patients, stimulation settings favored the contacts closer to the AC-PC line, correcting the electrode tip position to 0.80 +/- 2.84 mm (p < 0.001) inferior to the level of the AC-PC line. In our experience, thalamic DBS offers a reversible and adjustable 'lesion' to compensate for the anatomic variabilities encountered in the positioning of the DBS electrode tip.

Motor, cognitive, and behavioral performance following unilateral ventroposterior pallidotomy for Parkinson disease.

OBJECTIVE: To evaluate the effects of ventroposterior pallidotomy on motor disability and on behavior and cognition in patients with medically intractable idiopathic Parkinson disease. DESIGN: Detailed motor testing both while receiving and discontinuing levodopa medication, posturography, and neurocognitive and behavioral assessments were performed before and 3 to 6 months after unilateral ventroposterior pallidotomy. SETTING: University-based movement disorder program. PATIENTS: Thirty-two patients without dementia with medically refractory idiopathic Parkinson disease were studied. MAIN OUTCOME MEASURES: Motor function and disability were measured using the Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, and the Schwab and England Activities of Daily Living Scale. Dynamic balance was measured by sway (amplitude and velocity) using the Chattecx Balance System. Detailed cognitive and behavioral assessments were also performed both before and after surgery. RESULTS: Eighty-three percent of patients experienced improvement of their total Unified Parkinson's Disease Rating Scale score at 3 to 6 months after surgery. Significant improvements were also seen in the contralateral Unified Parkinson's Disease Rating Scale motor subscore (78%) as well as in the contralateral Unified Parkinson's Disease Rating Scale total score both during the on and off period (78% and 79%, respectively). The Hoehn and Yahr stage, Schwab and England Activities of Daily Living Scale score, and dynamic balance when standing on foam also improved following unilateral pallidotomy in many patients. Cognitive performance remained relatively unchanged following surgery with the exception of category fluency, which exhibited a modest decline (P < .04). A significant improvement in depression was found on the Beck Depression Inventory. CONCLUSIONS: Ventroposterior pallidotomy significantly improves motor performance and daily level of function in Parkinson disease. Cognition and behavior are not adversely affected in patients without dementia, and a cognitive screening battery is proposed.

Neuronal synchrony in relation to burst discharge in epileptic human temporal lobes.

1. Synchronous interactions between neurons in mesial temporal structures of patients with complex partial seizures were studied using cross-correlation analyses. We recorded spontaneous activity from 293 neurons in 24 patients during the interictal state. Patients had depth microelectrodes chronically implanted in amygdala, hippocampal formation, and parahippocampal gyrus to record epileptic activity. One hundred twenty-five cells were recorded from the temporal lobe commonly initiating seizures (ipsilateral temporal lobe), and 168 cells from the contralateral temporal lobe. Eight hundred forty-three cross-correlograms were constructed between all pairs of simultaneously recorded neurons. Cross-correlogram peaks or troughs that exceeded confidence limits within 200 ms of the origin were considered evidence of synchronous neuronal interaction. 2. Synchronous neuronal interactions were observed in 223 of 843 cross-correlograms. Eighty-six percent of these 223 cross-correlograms showed significant central peaks (peak interactions), suggesting excitatory interactions, whereas the remainder displayed significant central troughs (trough interactions), suggesting inhibitory interactions. 3. Cross-correlograms constructed using cells from the ipsilateral temporal lobe (ipsilateral cross-correlograms) were more likely to display significant central troughs (14/262) than cross-correlograms constructed using cells from the contralateral temporal lobe (6/376; contralateral cross-correlograms). Similarly, cross-correlograms constructed using one cell from each hemisphere (11/205; bilateral cross-correlograms) were also more likely to display significant central troughs (trough interactions) than contralateral cross-correlograms. Both ipsilateral (77/262) and contralateral cross-correlograms (102/376) were more likely to display significant central peaks (peak interactions) than bilateral cross-correlograms (13/205). 4. Cells from different structures in the ipsilateral temporal lobe were more likely to display significant trough interactions (10/ 114) than neurons in different contralateral structures. We also compared the proportion of significant peak interactions between cells within the ipsilateral and contralateral sides of each structure. Neurons in the contralateral entorhinal cortex were more likely to show peak interactions (21/55) than cells from the ipsilateral entorhinal cortex (3/31). Also, cells in the ipsilateral presubiculum showed a higher proportion of peak interactions (9/16) than their contralateral homologues (5/30). 5. Neuronal burst discharges were defined as three or more action potentials (or spikes) separated by interspike intervals of < or = 30 ms, or two spikes separated by an interval of < or = 15 ms. The contribution of burst discharge to synchronous peak interaction was compared between temporal lobes. Cells used to construct ipsilateral cross-correlograms displaying significant central peaks (n = 154) were found to have significantly reduced burst discharge contributions to the observed synchronous peaks in comparison with their contralateral homologues (n = 204). When cross-correlograms were separated by regions, burst discharge contributions to synchronous peak interactions between cells in the ipsilateral hippocampus (n = 72) were significantly smaller than the contributions from cells in the contralateral hippocampus (n = 44). 6. The results suggest that in the interictal state, synchronous neuronal burst discharge is not a distinguishing feature of epileptogenic regions of patients with complex partial seizures, but inhibitory neuronal interactions are increased in regions of seizure initiation. Increases in the strength and spread of local inhibition in seizure initiating regions in these patients may result in a greater proportion of inhibitory interactions and could also cause increased synchrony between isolated action potentials.(ABSTRACT TRUNCATED)

Interspike intervals during interictal periods in human temporal lobe epilepsy.

We recorded 259 single neurons from mesial temporal lobe structures of 21 patients with complex partial seizures. Interspike intervals within clusters of action potentials (clustered interspike intervals) recorded from cells in mesial temporal structures ipsilateral to seizure initiation were compared to clustered interspike intervals in the contralateral temporal lobe. 'Clusters' were defined as any group of three or more spikes separated by intervals of less than a defined maximum, or two spikes separated by less than half that maximum. The maximum interspike interval which defined a cluster was varied from 5 to 40 ms in 5-ms steps. Significantly smaller proportions of clustered spikes were discharged by neurons in the amygdala, hippocampus and entorhinal cortex from the temporal lobe commonly initiating seizures, compared to neurons in contralateral homotopic regions. When data from the same three structures were combined, significantly fewer cluster interspike intervals between 10 and 25 ms were recorded from cells on the side of seizure onset. Because clustered action potential discharge is a normal pattern of firing for cells that discharge endogenous bursts, the relative decrease in proportions of 10-25 ms clustered interspike intervals occurring in the temporal lobe initiating seizures might reflect a reduction in endogenous burst discharges from that side. Reduced endogenous bursting could be due to the loss of burst discharging neurons as a product of seizure-related excitotoxicity. The identification of decreased interictal single neuronal burst discharge in epileptogenic structures stresses the difference between the interictal and ictal states in patients with complex partial seizures, and the importance of the transition between those states.

Decreased neuronal burst discharge near site of seizure onset in epileptic human temporal lobes.

We examined auto-correlation and interval distribution characteristics of neuronal discharge from patients with complex partial seizures. The objective was to compare the interictal firing patterns of neurons in mesial temporal structures ipsilateral to the site of seizure onset with firing patterns of neurons in homologous contralateral structures. Spontaneous interictal recordings of 258 single neurons were acquired from 23 patients. A "burst area" measure was derived from the neuronal auto-correlation to assess the likelihood of grouped action potential discharge (burst discharge). Large burst area measures indicate a tendency for single neuronal burst discharge, but do not disclose information about interspike intervals within bursts. Although several measures based on single neuronal interspike interval distributions showed no overall difference between hemispheres, burst area was significantly reduced in mesial temporal structures ipsilateral to the site of seizure onset. Possible mechanisms of decreased burst discharge in epileptogenic regions include selective loss of burst-discharging neurons and increased recurrent inhibition.

Interictal heart rate patterns in partial seizure disorders.

Epileptogenic mesial temporal damage may alter interictal autonomic patterning. Analysis of heart rate variability in 19 patients with complex partial seizures revealed cases of persistent, high-amplitude, 4 to 9 per minute fluctuations in heart rate during alert waking. This pattern was most pronounced in poor candidates for anterior temporal lobe resection (2/19). The 4 to 9 per minute heart-rate variability pattern may emerge following diffuse, extratemporal, or bilateral mesial temporal damage, which interferes with descending forebrain influences on cardiovascular regulation.

Correlation of unit recordings with regional cell counts in epileptogenic human temporal lobe.

The previously reported diminished incidence of neuronal activity recorded from areas ipsilateral to a seizure focus may result from either cell loss or pathophysiologic changes in hippocampus and related structures. We examined records of single-cell discharge from 471 electrode bundles in 62 patients who later had cell counts taken from samples of resected tissue. Analysis of variance showed that amygdala and parahippocampal gyrus had more activity than hippocampus and the subicular complex and that the resected side had less activity overall. Only the posterior subicular complex showed more high-amplitude (> 50 microV) activity on the epileptogenic side; all other areas showed more activity contralaterally. Activity between 25 and 50 microV did not differ across sides or structures. Percentage of maximal cell count was correlated with the number of electrodes with high-amplitude activity only in the subicular complex. Low-amplitude activity in nonresected hippocampus, however, was strongly negatively correlated with cell counts on the resected side, perhaps owing to compensatory mechanisms. Cell counts in hippocampus correlated negatively with high-amplitude unit activity in resected amygdala, suggesting reciprocity between these areas. These results suggest that the amount of cell activity recorded from mesiotemporal structures involves bilateral factors more complex than simple cell loss.

Cardiac and respiratory correlations with unit discharge in epileptic human temporal lobe.

We recorded respiratory activity and electrocardiogram (ECG) together with single cell activity from the amygdala and hippocampus of epileptic patients who later received anterotemporal lobectomy. Cross-correlation histograms were used to test for neuronal discharge timing relationships with inspiration or ECG. Linear regression was used to test for correlations of inspiratory time, respiratory period, and heart rate (HR) with tonic unit rate for each breath. Of 129 cells from 16 patients who later had resection, 89 were contralateral and 40 were ipsilateral to the resected lobe. Of the contralateral cells, 19% had a timing relationship with the cardiac cycle and only 1% had such a relationship with the respiratory cycle. Tonic correlations with HR were noted in 22% and with respiratory period and inspiratory time in 11 and 6%. Neither these percentages nor mean discharge rate differed between structures, although variance in rate was much higher on the resected side. Amygdala cells on the resected side showed more correlations with the cardiac cycle (55 vs. 20%), respiratory period (46 vs. 3%), and inspiratory time (27 vs. 7%) and were more likely to show several types of correlation. The results suggest a selective loss of ipsilateral amygdala cells and/or afferents, favoring relationships with cardiac- and respiratory-related systems and a possible synaptic reorganization of remaining cardiorespiratory afferents.

Recurring discharge patterns in multiple spike trains. II. Application in forebrain areas related to cardiac and respiratory control during different sleep-waking states.

Simultaneously recorded spike trains were obtained using microwire bundles from unrestrained, drug-free cats during different sleep-waking states in forebrain areas associated with cardiac and respiratory activity. Cardiac and respiratory activity was simultaneously recorded with the spike trains. We applied the recurring discharge patterns detection procedure described in a companion paper (Frostig et al. 1990) to the spike and cardiorespiratory trains. The pattern detection procedure was applied to detect only precise (in time and structure) recurring patterns. Recurring discharge patterns were detected in all simultaneously recorded groups. Recurring discharge patterns were composed of up to ten spikes per pattern and involved up to four simultaneously recorded spike trains. Fourty-two percent of the recurring patterns contained cardiac and/or respiratory events in addition to neuronal spikes. When patterns were compared over different sleep-waking states it was found the the same units produced different patterns in different states, that patterns were significantly more compact in time during quiet sleep, and that changes in the discharge rates accompanying changes in sleep-waking states were not correlated with changes in pattern rate.

Cardiac and respiratory correlations with unit discharge in human amygdala and hippocampus.

Animal studies have shown that epileptiform seizures can cause cardiac arrhythmias and death. The amygdala and hippocampus are implicated in epileptogenesis and autonomic and respiratory control. We examined cardiac and respiratory correlations with single cell discharge in hippocampus and amygdala of patients with epilepsy. We recorded respiration, ECG, and neuronal discharge of amygdala and hippocampus from patients undergoing chronic depth electrode monitoring. Cross-correlation histograms were used to test for neuronal discharge timing relationships with inspiration or the ECG. Inspiratory time, respiratory period and heart rate were calculated for each breath, and linear regression was used to test for correlations with tonic unit rate. Of 183 cells from 24 patients, 20% had cardiac timing relationships and 23% showed tonic correlations with changes in heart rate. Only 2% had timing relationships with the respiratory cycle, while 15% showed tonic rate relationships with respiratory period. Recording sites did not differ in mean discharge rate or proportion of cells showing these correlations. These results indicate that a significant number of human forebrain cells show discharge modulation by the cardiac cycle and discharge rate correlation with changes in respiration and heart rate. This is supportive of animal models designed to explore the role of mesial temporal lobe structures in regulation of cardiovascular and respiratory systems, although a lower proportion of cells in human temporal lobe showed timing relationships with respiration and there was no clear evidence of anatomic specificity between amygdala and hippocampus.

Cardiovascular and respiratory relationships with neuronal discharge in the central nucleus of the amygdala during sleep-waking states.

We examined state-related relationships of neuronal discharge in the central nucleus of the amygdala (ACE) with cardiac and respiratory patterning. ACE cell discharges correlated with cardiac and respiratory timing, arterial pressure, and several respiratory parameters in undrugged, freely moving cats during waking, quiet sleep, and rapid eye movement sleep. Phasic discharge with the cardiac or respiratory cycle was examined using cross-correlation histograms. Of 80 cells in 8 cats, 24% showed a timing relationship with the cardiac or respiratory cycle, i.e., a tendency to discharge with each cardiac R-wave or with each breath, 12% with the cardiac cycle, and 14% with the respiratory cycle (2 cells showed both). All timing relationships were state dependent, usually observed in only one sleep-waking state per cell. Over half the cells showed a significant Pearson's r rate correlation with respiratory period or arterial pressure. Two-thirds of the cells showing arterial pressure correlations also correlated with respiratory period. A substantial proportion of ACE cells thus shows a state-dependent modulation of discharge rate and pattern by cardiovascular and respiratory variables. Rate and timing relationships were mutually exclusive within states, suggesting a state-dependent functional differentiation within the ACE.