Ignition's glow: Ultra-fast spread of global cortical activity accompanying local "ignitions" in visual cortex during conscious visual perception.

Despite extensive research, the spatiotemporal span of neuronal activations associated with the emergence of a conscious percept is still debated. The debate can be formulated in the context of local vs. global models, emphasizing local activity in visual cortex vs. a global fronto-parietal "workspace" as the key mechanisms of conscious visual perception. These alternative models lead to differential predictions with regard to the precise magnitude, timing and anatomical spread of neuronal activity during conscious perception. Here we aimed to test a specific aspect of these predictions in which local and global models appear to differ - namely the extent to which fronto-parietal regions modulate their activity during task performance under similar perceptual states. So far the main experimental results relevant to this debate have been obtained from non-invasive methods and led to conflicting interpretations. Here we examined these alternative predictions through large-scale intracranial measurements (Electrocorticogram - ECoG) in 43 patients and 4445 recording sites. Both ERP and broadband high frequency (50-150 Hz - BHF) responses were examined through the entire cortex during a simple 1-back visual recognition memory task. Our results reveal short latency intense visual responses, localized first in early visual cortex followed (at ∼200 ms) by higher order visual areas, but failed to show significant delayed (300 ms) visual activations. By contrast, oddball image repeat events, linked to overt motor responses, were associated with a significant increase in a delayed (300 ms) peak of BHF power in fronto-parietal cortex. Comparing BHF responses with ERP revealed an additional peak in the ERP response - having a similar latency to the well-studied P3 scalp EEG response. Posterior and temporal regions demonstrated robust visual category selectivity. An unexpected observation was that high-order visual cortex responses were essentially concurrent (at ∼200 ms) with an ultra-fast spread of signals of lower magnitude that invaded selected sites throughout fronto-parietal cortical areas. Our results are compatible with local models in demonstrating a clear task-dependence of the 300 ms fronto-parietal activation. However, they also reveal a more global component of low-magnitude and poor content selectivity that rapidly spreads into fronto-parietal sites. The precise functional role of this global "glow" remains to be elucidated.

Spatial characterization of interictal high frequency oscillations in epileptic neocortex.

Interictal high frequency oscillations (HFOs), in particular those with frequency components in excess of 200 Hz, have been proposed as important biomarkers of epileptic cortex as well as the genesis of seizures. We investigated the spatial extent, classification and distribution of HFOs using a dense 4 x 4 mm(2) two dimensional microelectrode array implanted in the neocortex of four patients undergoing epilepsy surgery. The majority (97%) of oscillations detected included fast ripples and were concentrated in relatively few recording sites. While most HFOs were limited to single channels, approximately 10% occurred on a larger spatial scale with simultaneous but morphologically distinct detections in multiple channels. Eighty per cent of these large-scale events were associated with interictal epileptiform discharges. We propose that large-scale HFOs, rather than the more frequent highly focal events, are the substrates of the HFOs detected by clinical depth electrodes. This feature was prominent in three patients but rarely seen in only one patient recorded outside epileptogenic cortex. Additionally, we found that HFOs were commonly associated with widespread interictal epileptiform discharges but not with locally generated 'microdischarges'. Our observations raise the possibility that, rather than being initiators of epileptiform activity, fast ripples may be markers of a secondary local response.

Solubilized adenosine receptors in the brain: regulation of guanine nucleotides.

Adenosine receptors associated with a reduction of adenylate cyclase and labeled by tritium-labeled cyclohexyladenosine can be solubilized from brain membranes with sodium cholate. Regulation of receptor binding by guanine nucleotides is retained in the soluble state. Influences of cations observed in membrane preparations of adenosine receptors are no longer detected with the solubilized receptors. The apparent retention of a complex of receptors and guanosine triphosphate binding but not cation binding protein in the soluble state may permit a molecular analysis of receptor regulation.

Adenosine receptors: autoradiographic evidence for their location on axon terminals of excitatory neurons.

Adenosine receptors were made visible on light microscopy by autoradiography with tritiated cyclohexyladenosine. In the cerebellum, adenosine receptors were absent in Weaver mice, which lack granule cells, and were displaced in Reeler mice, which have displacements of granule cells. Thus, adenosine receptors appear to be located on the axon terminals of excitatory granule cells in the cerebellum. Removal of one eye of a rat depleted adenosine receptors in the contralateral superior colliculus, suggesting that the receptors occur on axon terminals of excitatory projections from retinal ganglion cells. The presence of adenosine receptors on excitatory axon terminals may explain synaptic inhibition by adenosine and the behavioral effects of xanthines.

Relationship of clinical efficacy to postmortem-determined anatomic subthalamic stimulation in Parkinson syndrome.

OBJECTIVE/BACKGROUND: Patients with medically refractory Parkinson's disease (PD) obtain significant clinical benefit from subthalamic nucleus (STN) stimulation. The degree to which a successful outcome relates to the anatomic location of the stimulating electrode has not yet been clearly established. Many studies have attempted to correlate the clinical result with the electrode location using postoperative magnetic resonance imaging (MRI) and there have been a few that used autopsy-determined locations. In this report, we describe long-term clinical follow-up in a patient with autopsy-determined electrode tip anatomic location. METHODS: A 67-year-old patient with a 27-year history of idiopathic PD complicated by disabling motor fluctuations and dopaminergic dyskinesias underwent bilateral STN deep brain stimulation (DBS). He was prospectively followed in a long-term clinical protocol until his death 40 months after electrode placement. Postoperative magnetic resonance (MR) imaging and postmortem studies of this patient's brain were performed to localize DBS tip locations. RESULTS: STN stimulation produced improvement of the patient's motor fluctuations, dyskinesias and clinical motor performance, especially appendicular tremors, rigidity and bradykinesia. MRI showed the electrode tips to be within 2 mm of the intended target. Postmortem brain analysis identified the right DBS tip location at the dorsomedial edge of the STN, with the left electrode in the vicinity (but not within) the STN. Chronic DBS elicited minor reactive changes were confined to the immediate vicinity of the electrode tracks. The pathological analysis demonstrated numerous cortical Lewy bodies and degenerative encephalopathy, establishing the diagnosis of transitional type diffuse Lewy body disease (DLBD) rather than simple PD. CONCLUSION: This patient obtained clinical benefit from STN stimulation typical of that seen for most PD patients. Both the MR analysis and the autopsy demonstrated electrode placement at or outside the boundaries of the STN, suggesting that that clinical efficacy may not depend on electrode location within the central region of the STN.

Adenosine receptor localization in rat testes: biochemical and autoradiographic evidence for association with spermatocytes.

[3H]Cyclohexyladenosine ( [3H]CHA) labels adenosine receptors in rat testes. Testicular adenosine receptors are regulated by guanine nucleotides and divalent cations in a similar fashion to brain adenosine receptors. Endocrine manipulations which selectively decrease sperm cells reduce biochemically determined numbers of [3H]CHA labeled adenosine receptors, whereas adenosine receptor number is not affected by manipulations that primarily influence Leydig cells. Autoradiographic analysis of [3H]CHA binding in the rat testes reveals a localization within seminiferous tubules. Receptor related silver grains occur within tubular epithelium as well as in the lumen of tubules but are absent in interstitial tissue and blood vessels. These data suggest an association of adenosine receptors with spermatocytes within the seminiferous tubule epithelium.

Stereotaxic implantation of autologous adrenal medulla into caudate nucleus in four patients with parkinsonism. One-year follow-up.

Four patients with levodopa-responsive parkinsonism (aged 26, 35, 45, and 49 years) received autologous adrenal medullary implants into or near the left caudate nucleus by stereotaxic implantation after flank adrenalectomy. All patients had an immediate response to implantation lasting several days, during which parkinsonian signs and symptoms decreased. This period was followed by a gradual reappearance of symptoms in all but one patient. This patient had had a dramatic increase in "on" time without dyskinesias and a decrease in the severity and duration of "off" time. He died of multifocal glioblastoma 1 year after transplantation. Autopsy revealed no surviving adrenal cells. In one case, the stereotaxic implantation missed the basal ganglia, resulting in the placement of the adrenal medullary tissue into the medial thalamus and near the third ventricle; the patient did not improve. In the other two cases, a modest but definite increase in "on" time without dyskinesia and a reduction in the severity and duration of "off" time has been observed. The role of autologous adrenal medullary transplantation in patients with parkinsonism remains to be determined. Patients with a family history of cerebral malignancy may be at increased risk for the development of transplant-induced malignancy.

Anatomic dissociation of auditory and visual naming in the lateral temporal cortex.

BACKGROUND AND OBJECTIVE: Visual object naming traditionally has been used to identify cortical areas essential for naming (i.e., word retrieval), and investigators have found critical naming sites in the middle and posterior temporal region in most patients. Based on clinical observation, empirical findings, and the pathophysiology of temporal lobe epilepsy, the authors hypothesized that naming sites identified from auditory cues might also be relevant, and that within the temporal region, these sites would be anatomically distinct and located anterior to naming sites based on visual cues. METHODS: Twenty patients requiring resective surgery involving the left (language dominant) temporal lobe underwent pre-resection language mapping using direct cortical stimulation. Visual and auditory naming were tested at lateral temporal sites extending from 1 cm from the anterior tip to the parietal operculum. RESULTS: Auditory naming was consistently disrupted by stimulation in the anterior temporal lobe, whereas both auditory and visual naming were impaired by stimulation in the posterior temporal region. CONCLUSIONS: This pattern may explain why word finding difficulties sometimes arise or worsen following surgical procedures in which the anterior temporal region is resected without language mapping, or when resection is based on mapping that identifies language cortex exclusively using visual tasks. These results suggest that utilization of auditory based naming tasks might improve pre-resection identification of essential language cortex during direct stimulation cortical mapping, as well as noninvasive localization of dysfunction during presurgical cognitive testing.

MRI of Creutzfeldt-Jakob disease: asymmetric high signal intensity of the basal ganglia.

We report a pathologically proven case of Creutzfeldt-Jakob disease (CJD) with striking asymmetry in abnormal high signal intensity of the basal ganglia on long-repetition-time MRI. Symmetric or asymmetric high signal intensity of the basal ganglia, in the appropriate clinical setting, may be a specific finding of CJD.

Treatment of amyotrophic lateral sclerosis with the TRH analog DN-1417.

Thyrotropin-releasing hormone has been reported to increase strength in patients with amyotrophic lateral sclerosis (ALS). DN-1417 is an analog of thyrotropin-releasing hormone, which has less endocrinologic activity, but more anterior horn cell stimulating effect (with no "autorefractory state"). However, 2 mg DN-1417, IM twice a day for 1 month in an open-label trial, produced no objective improvement of strength in nine patients with ALS. No patient entered the double-blind, placebo-controlled phase of the trial.

Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome.

This open pilot study of vagus nerve stimulation (VNS) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD(28) measure, 34.0% for the Montgomery-Asberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p =.0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.

Autoradiographic analysis of mu1, mu2, and delta opioid binding in the central nervous system of C57BL/6BY and CXBK (opioid receptor-deficient) mice.

The recent development of in vitro autoradiography techniques has enabled investigators to determine the distribution and relative levels of multiple ligand binding sites in discrete anatomical areas. In this study we used semi-quantitative in vitro autoradiography to compare the levels of binding to central mu1, mu2, and delta opioid sites in two strains of mice, C57BL/6BY and CXBK. The CXBK strain is known to be deficient in whole brain opioid binding sites and to be less sensitive than the C57 strain to the analgesic and locomotor stimulatory effects of opiates and opioids. Delta sites were visualized using [3H](D-Ala2-D-Leu5]-enkephalin (DADL) plus a low concentration of morphine, total mu sites (mu1 and mu2) were visualized using [3H] dihydromorphine (DHM), and mu2 sites were visualized using [3H]DHM plus a low concentration of DADL. Binding to mu1 sites was determined by subtracting mu2 binding from total mu binding. We found that the two strains did not consistently differ in the levels of delta site; in some areas the CXBKs had lower levels but in many areas they had levels equal to or greater than those for the C57s. The CXBK strain, however, either had less or the same amount of mu binding as the C57 strain in all areas studied. The CXBK strain was especially deficient in mu1 binding, particularly in areas involved in pain processing.

Autoradiographic distribution of mu1 and mu2 opioid binding in the mouse central nervous system.

Several types of opioid binding sites have been differentiated using biochemical and pharmacological criteria. We have used quantitative in vitro autoradiography to compare the levels of mu1 and mu2 opioid binding in the mouse central nervous system. Mu1 sites have a high affinity for all labeled opioids studied to date and have been associated with their analgesic effects, whereas mu2 sites have a high affinity only for opiate alkaloids and have been associated with their respiratory depressant effects. We used [3H]dihydromorphine (DHM) to visualize total mu sites (mu1 and mu2) and [3H]DHM plus a low concentration of [D-Ala2-D-Leu5]enkephalin (DADL) to visualize mu2 sites. Levels of mu1 binding were determined by subtracting mu2 binding from total mu binding. This mu1 distribution was confirmed in selected regions by an alternate method using [3H]DADL. High ratios of mu1 to mu2 binding were noted in frontal cortex, nucleus accumbens, rostral striatum, ventral pallidum, ventral periaqueductal gray matter, and laminae I and II of the spinal cord. The observation of high densities of mu1 binding in certain pain processing areas correlates with behavioral and pharmacological studies suggesting that analgesia from opiates and opioids is mediated primarily by mu1 sites. In other areas, such as the limbic system, dorsal nucleus of the vagus nerve, and nucleus of the solitary tract, either a low ratio of mu1 to mu2 binding or no mu1 binding was observed. This differential regional localization of mu1 and mu2 binding provides further evidence for the distinctness of these sites.

Neurotensin-containing cell bodies, fibers and nerve terminals in the brain stem of the rat: immunohistochemical mapping.

Neurotensin immunoreactive perikarya, fibers and nerve terminals, visualized by the indirect immunohistofluorescent method in colchicine-pretreated animals, are localized in many discrete regions of the rat brain stem. Cell body groups are found in the inner aspect of the substantia gelatinosa of the caudal trigeminal nuclear complex, the nucleus of the solitary tract, the parabrachial nuclei, the locus coeruleus, the dorsal raphé nucleus, the periaqueductal gray matter, and the ventral tegmental area of Tsai. These areas of cell body density are accompanied by concentrations of fibers and terminals, while the occasional positive perikaryon noted in the dorsal cochlear nucleus is accompanied by only sparse fluorescent fiber/terminal patterns. Other brain stem regions, such as the floor of the fourth ventricle and aspects of the caudal ventrolateral reticular formation, possess substantial numbers of fibers and terminals that are not accompanied by cell bodies. Many aspects of this distribution coincide with the brain stem distribution of the enkephalin pentapeptides, though significant differences in localization are also evident. Interactions of neurotensin with other neurotransmitter candidates are also suggested by its presence in areas enriched in norepinephrine, dopamine, serotonin, and substance P. Certain neurotensin localizations suggest an association of the peptide with functional brain systems preferentially involving these regions. In particular periaqueductal gray and substantia gelatinosa neurotensin synapses are plausible sites for the analgesia elicited after intercisternal injection of low doses of neurotensin.

Autoradiography of [3H]beta-endorphin binding in brain.

The autoradiographic regional localization of [3H]beta-endorphin binding in rat brain differed from that of either [3H]dihydromorphine or [3H]D-Ala2-D-Leu5-enkephalin. Comparisons were made from sequential sections through 3 regions of rat brain: striatum, hypothalamus/thalamus, and brainstem. [3H]beta-endorphin labeled some clusters as well as the subcallosal streak in the striatum, the nucleus accumbens, lamina IV of the cortex, medial regions of the thalamus, hippocampus, inferior colliculus, dorsal raphe, median raphe and pontine nuclei. White matter regions had little binding. Although many of these structures were also labeled with either [3H]dihydromorphine or [3H]D-Ala2-D-Leu5-enkephalin, the overall pattern of [3H]beta-endorphin labeling appeared unique, consistent with the proposal of central epsilon receptors.

Immunohistochemical mapping of enkephalin containing cell bodies, fibers and nerve terminals in the brain stem of the rat.

Enkephalin immunoreactive perikarya, fibers and nerve terminals, visualized by the indirect immunohistofluorescent method in colchicine-pretreated animals, are localized in many discrete regions of the rat brain stem. These specific immunohistofluorescent patterns are similar after staining with selective primary antisera directed against either methionine-enkephalin or leucine-enkephalin. Cell bodies are found in the substantia gelatinosa and interpolaris zones of the trigeminal nuclear complex, the nucleus of the solitary tract, in the vicinity of the nucleus raphé magnus, in the dorsal cochlear, medial vestibular, and paraolivary nuclei and, dorsal to this last region, in the parabrachial nuclei and the dorsal tegmental nucleus of Gudden, in the periaqueductal gray matter and interpeduncular nucleus and along the borders of the lateral lemniscus and medial geniculate. In some areas, such as the parabrachial region, nucleus of the solitary tract and substantia gelatinosa of the trigeminal nucleus, these perikarya are associated with densities of fibers and terminals. Other regions, such as the dorsal cochlear nucleus and the vicinity of the nucleus raphé magnus, contain cell bodies associated with low densities of processes and terminals. In still other nuclei, such as the nucleus of the facial nerve and the locus coeruleus, fiber and terminal densities without associated cell bodies are evident. Many of these enkephalin localizations can be rationalized on the basis of known actions of opiate drugs and the brain stem distribution of opiate receptors.

Regional differences in mu 1-binding of [3H][D-Ala2,D-Leu5]-enkephalin: comparisons of thalamus and cortex in the rat.

Typically, mu 1-sites represent approximately 25-35% of binding in rat brain homogenates. Competition studies indicated that approximately 60% of [3H][D-Ala2,D-Leu5]-enkephalin ([3H]DADLE) binding in the thalamus was inhibited by low concentrations of morphine (2-5 nM). This high proportion of mu 1-binding was anticipated based upon the low levels of delta-sites and the high levels of mu 1-sites in this region observed in autoradiography studies. In contrast, morphine lowered [3H]DADLE binding by only approximately 5-15% in the cortex, a region known to possess large amounts of delta- and few mu 1-receptors. These results support previous autoradiography studies and illustrate the advantages of using tissue regions in the characterization of opiate receptor subtypes.

Reversible signal abnormalities in the hippocampus and neocortex after prolonged seizures.

PURPOSE: To investigate the phenomenon of reversible increased signal intensity of medial temporal lobe structures and cerebral neocortex seen on MR images of six patients with recent prolonged seizure activity. METHODS: After excluding patients with known causes of reversible signal abnormalities (such as hypertensive encephalopathy), we retrospectively reviewed the clinical findings and MR studies of six patients whose MR studies showed reversible signal abnormalities. MR pulse sequences included T2-weighted spin-echo coronal views or conventional short-tau inversion-recovery coronal images of the temporal lobes. RESULTS: All six MR studies showed increased signal intensity within the medial temporal lobe, including the hippocampus in five studies. All follow-up MR examinations showed partial or complete resolution of the hyperintensity within the medial temporal lobe and the neocortex. In one patient, results of a brain biopsy revealed severe cerebral cortical gliosis. Temporal lobectomy performed 4 years later showed moderate cortical gliosis and nonspecific hippocampal cell loss and gliosis. CONCLUSION: Significant hyperintensity within the temporal lobe is demonstrable on MR images after prolonged seizure activity, suggestive of seizure-induced edema or gliosis. Damage to medial temporal lobe structures by prolonged seizure activity indicates a possible mechanism of epileptogenic disorders.

Magnetic resonance imaging-directed stereotactic endoscopic third ventriculostomy.

Third Ventriculostomy has been proposed as the procedure of choice for many patients with acquired obstructive hydrocephalus. Various techniques have been used to perform this procedure. This report describes the use of magnetic resonance images to guide the performance of a stereotactic third ventriculostomy with a rigid endoscope, allowing continuous direct visualization. This procedure has been performed on three patients, yielding clinical improvement without the need for extracranial shunting. Magnetic resonance imaging allows accurate identification of the important anatomical landmarks (i.e., foramen of Monro and interpeduncular cistern), with axial, coronal, and sagittal images, and is readily used in conjunction with the Cosman-Roberts-Wells stereotactic apparatus.

Acoustic schwannoma and epidermoid cyst occurring as a single cerebellopontine angle mass.

The case of a 66-year-old man with a 3-year progressive hearing loss and a homogeneous left cerebellopontine angle mass on magnetic resonance imaging scan is described. At surgery, the major portion of the mass was a typical encapsulated, solid, acoustic schwannoma, but the most rostral portion was a distinct, flaky, cystic mass without a well-defined capsule, typical of an epidermoid cyst. The radiographic and operative findings of this unique coexistence of two different benign cerebellopontine angle masses are presented.