Acceptance of evidence-supported hypotheses generates a stronger signal from an underlying functionally-connected network.

Choosing one's preferred hypothesis requires multiple brain regions to work in concert as a functionally connected network. We predicted that a stronger network signal would underlie cognitive coherence between a hypothesis and the available evidence. In order to identify such functionally connected networks in magnetoencephalography (MEG) data, we first localized the generators of changes in oscillatory power within three frequency bands, namely alpha (7-13 Hz), beta (18-24 Hz), and theta (3-7 Hz), with a spatial resolution of 5mm and temporal resolution of 50 ms. We then used principal component analysis (PCA) to identify functionally connected networks reflecting co-varying post-stimulus changes in power. As predicted, PCA revealed a functionally connected network with a stronger signal when the evidence supported accepting the hypothesis being judged. This difference was driven by beta-band power decreases in the left dorsolateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (VMPFC), posterior cingulate cortex (PCC), and midline occipital cortex.

Neuropsychiatric thalamocortical dysrhythmia: surgical implications.

Clearly, more clinical experience must be amassed to define in detail the possibilities of this surgical approach in disabling neuropsychiatric disorders. We propose, however, that the evidence for benign and efficient surgical intervention against the neuropsychiatric TCD syndrome is already compelling. The potential appearance of strong postoperative reactive manifestations requires a close association between surgery and psychotherapy, with the latter providing support for the integration of the new situation as well as the resolution of old unresolved issues.

Consciousness and the brain. The thalamocortical dialogue in health and disease.

The goal of this paper is to explore the basic assumption that largescale, temporal coincidence of specific and nonspecific thalamic activity generates the functional states that characterize human cognition.

Words without mind.

A woman (LR), unconscious for 20 years, spontaneously produces infrequent, isolated words unrelated to any environmental context. Fluorodeoxy-glucose-positron emission tomography (FDG-PET) imaging coregistered with magnetic resonance imaging (MRI) revealed a mean brain metabolism equivalent to deep anesthesia. Nevertheless, PET imaging demonstrated islands of modestly higher metabolism that included Broca's and Wernicke's areas. Functional brain imaging with magnetoencephalographic (MEG) imaging, a technique providing a temporal resolution of better than 1 msec, identified preserved dynamic patterns of spontaneous and evoked brain activity in response to sensory stimulation. Specifically, we examined spontaneous gamma-band activity (near 40 Hz) and its reset or modification during early auditory processing, a measure that correlated with human perception of sensory stimuli (Joliot, Ribary, & Llinás, 1994). Evidence of abnormal and incomplete gamma-band responses appeared in the left hemisphere only in response to auditory or somatosensory stimulation. MEG single-dipole reconstructions localized to the auditory cortex in the left hemisphere and overlapped with metabolically active regions identified by FDG-PET. The observation demonstrates that isolated neuronal groups may express well-defined fragments of activity in a severely damaged, unconscious brain. The motor fixed-action pattern character of her expressed words supports the notion of brain modularity in word generation.

Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography.

Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency theta rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent theta activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic gamma-band activation, which we refer to as the "edge effect." This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level.

The neuronal basis for consciousness.

Attempting to understand how the brain, as a whole, might be organized seems, for the first time, to be a serious topic of inquiry. One aspect of its neuronal organization that seems particularly central to global function is the rich thalamocortical interconnectivity, and most particularly the reciprocal nature of the thalamocortical neuronal loop function. Moreover, the interaction between the specific and non-specific thalamic loops suggests that rather than a gate into the brain, the thalamus represents a hub from which any site in the cortex can communicate with any other such site or sites. The goal of this paper is to explore the basic assumption that large-scale, temporal coincidence of specific and non-specific thalamic activity generates the functional states that characterize human cognition.

Coordinated expression in chronically unconscious persons.

The clinically described 'persistent vegetative state' (PVS), consists of wakefulness unaccompanied by any evidence of the subject's awareness of self or environment. Past studies from our own and other laboratories have used positron emission tomography (PET) to study brain metabolism in approximately 20 such patients during wakeful periods. All those efforts identified global cerebral glucose metabolism at or below levels encountered during deep barbiturate anaesthesia. Nevertheless, the clinical literature includes rare reports of relatively isolated cognitive functions expressed by PVS patients late in their course. The observation raises the question of whether such activity reflects awareness or unconscious automatic behaviour. We employed magnetometry (MEG), PET scanning, MR imaging and 24-hour EEG recordings to evaluate three patients clinically vegetative between six months and 20 years after onset. Neither meticulous clinical examinations nor 24-hour EEG and video monitoring provided any hint of cognitive interaction in any subject. Nevertheless, patient 1 uttered single words once every 48 hours or more; patient 2 frequently expressed coordinated, non-purposeful, non-dystonic movements in arms and/or legs; and, patient 3 expressed strong emotional negativity without motor responses to noxious stimuli with occasional quieting in response to prosodic stimuli. All patients had whole-brain averaged global metabolism levels below 50% of normal. Patient 1, however, demonstrated preserved islands of increased metabolism in the posterior frontal and posterior temporal lobes, as well as MEG activations of Heschl's gyrus all located in the left hemisphere. In patient 2, selected increased metabolism was confined to the frontal poles and related subcortical structures. MRI in patient 3 demonstrated severe, bilateral post-traumatic cerebral atrophy. PET metabolism was diffusely reduced to 40% of normal but MEG evoked potentials indicated early and late sensory processing with abnormal later evoked components. The correlation of fragmentary behaviour with preserved metabolic and physiologic activity in cortical and subcortical regions known to support specific modular functions is novel. The finding demonstrates the capacity of severely damaged brains to partially express surviving modular functions without evidence of integrative processes that would be necessary to produce consciousness. We conclude that the mere expression of isolated neuropsychologic activity by isolated modules is insufficient to generate consciousness in overwhelmingly damaged brains.

Magnetoencephalographic mapping: basic of a new functional risk profile in the selection of patients with cortical brain lesions.

OBJECTIVE: Surgical management of cortical lesions adjacent to or within the eloquent cerebral cortex requires a critical risk: benefit analysis of the procedure before intervention. This study introduced a measure of surgical risk, based on preoperative magnetoencephalographic (MEG) sensory and motor mapping, and tested its value in predicting surgical morbidity. METHODS: Forty patients (21 men and 19 women; mean age, 36.5 yr) with cortical lesions (12 arteriovenous malformations and 28 tumors) in the vicinity of the sensorimotor cortex were classified into high-, medium-, or low-risk categories by using the MEG-defined functional risk profile (FRP). This was based on the minimal distance between the lesion margin and the sensory and motor MEG sources, superimposed on a magnetic resonance imaging scan. Case management decisions were based on the MEG mapping-derived FRP in combination with biopsy pathological findings, radiographic findings, and anatomic characteristics of the lesion. A recently developed protocol was used to transform MEG source locations into the stereotactic coordinate system. This procedure provided intraoperative access to MEG data in combination with stereotactic anatomic data displays routinely available on-line during surgery. RESULTS: It was determined that 11 patients diagnosed as having gliomas had high FRPs. The margin of the lesion was less than 4 mm from the nearest MEG dipole or involved the central sulcus directly. A nonoperative approach was used for six patients of this group, based on the MEG mapping-derived FRP. In the group with arteriovenous malformations, 6 of 12 patients with high or medium FRPs underwent nonoperative therapy. The remaining 28 patients, whose lesions showed satisfactory FRPs, underwent uneventful lesion resection, without postoperative neurological deficits. CONCLUSION: Our results suggest that MEG mapping-derived FRPs can serve as powerful tools for use in presurgical planning and during surgery.

The interactive use of magnetoencephalography in stereotactic image-guided neurosurgery.

OBJECTIVE: To expand the use of magnetoencephalography (MEG) functional mapping in the operating room as well as preoperatively, a method of integrating the MEG sensorimotor mapping information into a stereotactic database, using computed tomographic scans, magnetic resonance imaging scans, and digital angiography, was developed. The combination of functional mapping and the stereotactic technique allows simultaneous viewing of the spatial relationship between the MEG-derived functional mapping, the radiological/structural anatomic characteristics, and the pathological abnormality. METHODS: MEG data were collected using a MAGNES II Biomagnetometer and were incorporated into the COMPASS frame-based and REGULUS frameless stereotactic systems. The transformation process, by calculating a translational vector and a rotation matrix, integrates functional and anatomic information that is then directly available intraoperatively in the stereotactic database. This procedure was employed in 10 patients undergoing computer-assisted stereotactic volumetric resections for lesions involving the sensorimotor cortex. The principles of coregistration and coordinate transformation are reviewed in the context of preoperative functional mapping. We introduce innovations to apply these techniques to intraoperative stereotactic systems. RESULTS: Tests of the accuracy of the intraoperative integration of functional information in patients and calibration phantoms indicated close agreement with earlier preoperative methods. The intraoperative availability of functional information was a significant aid to the surgeon because it provided more accurate information on the location of functional tissue than could be derived solely by radiological criteria. CONCLUSION: The real-time availability of functional mapping information in an interactive fashion can reduce surgical risk and minimize functional morbidity. Within the ever-expanding realm of functional mapping and image-guided neurosurgery, further progress and integration of these methods is critical for resection of lesions involving eloquent cortex.

Central motor loop oscillations in parkinsonian resting tremor revealed by magnetoencephalography.

A variety of clinical and experimental findings suggest that parkinsonian resting tremor results from the involuntary activation of a central mechanism normally used for the production of rapid voluntary alternating movements. However, such central motor loop oscillations have never been directly demonstrated in parkinsonian patients. Using magnetoencephalography, we recorded synchronized and tremor-related neuromagnetic activity over wide areas of the frontal and parietal cortex. The spatial and temporal organization of this activity was studied in seven patients suffering from early-stage idiopathic Parkinson's disease (PD). Single equivalent current dipole (ECD) analysis and fully three-dimensional distributed source solutions (magnetic field tomography, MFT) were used in this analysis. ECD and MFT solutions were superimposed on high-resolution MRI. The findings indicate that 3 to 6 Hz tremor in PD is accompanied by rhythmic subsequent electrical activation at the diencephalic level and in lateral premotor, somatomotor, and somatosensory cortex. Tremor-evoked magnetic activity can be attributed to source generators that were previously described for voluntary movements. The interference of such slow central motor loop oscillations with voluntary motor activity may therefore constitute a pathophysiologic link between tremor and bradykinesia in PD.

Introduction of magnetoencephalography to stereotactic techniques.

Magnetoencephalography (MEG), a noninvasive functional brain mapping technique, was used for preoperative localization of the sensorimotor cortex in patients harboring lesions involving these eloquent regions. Prior to surgery, MEG source locations were transferred onto high-resolution MRI pictures which were then used for preoperative evaluation, risk analysis, and planning. We have developed a process to transform the MEG-derived sensorimotor localization coordinates into the COMPASS stereotactic coordinate system. Thus the MEG-derived functional information is incorporated into the stereotactic database, enabling the simultaneous visualization of functional and anatomical data. This information can be used for the selection of cases and in planning safe approaches for computer-assisted volumetric resections. The integration of MEG and stereotactic neurosurgery also allows a more precise comparison between MEG and intraoperative direct electrocorticographic mapping (ECoG). Seven patients were studied with good correlation between MEG and intraoperative mapping. In 4, the correlation was only based on gross visual comparison between intraoperative identification of the gyrus pattern and MEG photographs. The availability of the MEG coordinates in the stereotactic system, however, allows a more precise correlation between MEG and ECoG. In all 3 patients studied in this manner, the MEG coordinates (pinpointed to a precise cortical representation of a few millimeters) overlapped with ECoG results. In summary, we compared functional MEG data to intraoperative ECoG and conclude that the introduction of MEG into stereotactic neurosurgery can provide precise functional and anatomic information for image-guided surgical planning and resection.

Human oscillatory brain activity near 40 Hz coexists with cognitive temporal binding.

Spontaneous oscillatory electrical activity at a frequency near 40 Hz in the human brain and its reset by sensory stimulation have been proposed to be related to cognitive processing and to the temporal binding of sensory stimuli. These experiments were designed to test this hypothesis and to determine specifically whether the minimal interval required to identify separate auditory stimuli correlates with the reset of the 40-Hz magnetic signal. Auditory clicks were presented at varying times, while magnetic activity was recorded from awake human subjects. Experimental and modeling results indicate a stimulus-interval-dependent response with a critical interval of 12-15 ms. At shorter intervals only one 40-Hz response, to the first stimulus, was observed. With longer intervals, a second 40-Hz wave abruptly appeared, which coincided with the subject's perception of a second distinct auditory stimulus. These results indicate that oscillatory activity near 40 Hz represents a neurophysiological correlate to the temporal processing of auditory stimuli. It also supports the view that 40-Hz activity not only relates to primary sensory processing, but also could reflect the temporal binding underlying cognition.

Neuromagnetic studies of the lip area of primary somatosensory cortex in humans: evidence for an oscillotopic organization.

Magnetic trigeminal somatosensory responses from human subjects were recorded using a 14-channel magnetoencephalographic system. Sensory stimuli comprising a 15-ms vibration at frequencies of 50 Hz, 150 Hz and 250 Hz were given at randomized interstimulus intervals. Using a single dipole model, the neuronal sources of the evoked responses were determined, and mapped onto magnetic resonance images of each subject. Source localization analysis was based on the main peak of the averaged signal (M55). All of the sources were located deep in the anterior bank of the postcentral gyrus, corresponding to area 3b of somatosensory cortex SI. In all cases, the source for the upper lip was significantly higher in the vertical axis (0.6-1.1 cm) than for the lower lip, while the lower lip stimulation produced a larger response than the upper lip. Furthermore, statistically significant differences were found between the locations of the dipoles evoked by different frequency stimulation. The location of the response shifted with change in stimulation frequency, showing a trend among all subjects with medial shift between 150 and 250 Hz for both upper and lower lip. The accuracy of source localization calculated from magnetic fields ranged between +/- 0.9 and +/- 3.0 mm (SEM). These results demonstrate (1) that a large area of the somatosensory cortex is utilized for lip representation and (2) that the spatial displacement of the trigeminal somatosensory response may be related to the discrimination of frequency.

Somatosensory cortical plasticity in adult humans revealed by magnetoencephalography.

Microelectrode recordings in adult mammals have clearly demonstrated that somatosensory cortical maps reorganize following peripheral nerve injuries and functional modifications; however, such reorganization has never been directly demonstrated in humans. Using magnetoencephalography, we have been able to demonstrate the somatotopic organization of the hand area in normal humans with high spatial precision. Somatosensory cortical plasticity was detected in two adults who were studied before and after surgical separation of webbed fingers (syndactyly). The presurgical maps displayed shrunken and nonsomatotopic hand representations. Within weeks following surgery, cortical reorganization occurring over distances of 3-9 mm was evident, correlating with the new functional status of their separated digits. In contrast, no modification of the somatosensory map was observed months following transfer of a neurovascular skin island flap for sensory reconstruction of the thumb in two subjects in whom sensory transfer failed to occur.

Coherent 40-Hz oscillation characterizes dream state in humans.

Magnetic recording from five normal human adults demonstrates large 40-Hz coherent magnetic activity in the awake and in rapid-eye-movement (REM) sleep states that is very reduced during delta sleep (deep sleep characterized by delta waves in the electroencephalogram). This 40-Hz magnetic oscillation has been shown to be reset by sensory stimuli in the awake state. Such resetting is not observed during REM or delta sleep. The 40 Hz in REM sleep is characterized, as is that in the awake state, by a fronto-occipital phase shift over the head. This phase shift has a maximum duration of approximately 12-13 msec. Because 40-Hz oscillation is seen in wakefulness and in dreaming, we propose it to be a correlate of cognition, probably resultant from coherent 40-Hz resonance between thalamocortical-specific and nonspecific loops. Moreover, we proposed that the specific loops give the content of cognition, and a nonspecific loop gives the temporal binding required for the unity of cognitive experience.

Magnetic field tomography of coherent thalamocortical 40-Hz oscillations in humans.

This paper introduces the use of magnetic field tomography (MFT), a noninvasive technique based on distributed source analysis of magnetoencephalography data, which makes possible the three-dimensional reconstruction of dynamic brain activity in humans. MFT has a temporal resolution better than 1 msec and a spatial accuracy of 2-5 mm at the cortical level, which deteriorates to 1-3 cm at depths of 6 cm or more. MFT is used here to visualize the origin of a spatiotemporally organized pattern of coherent 40-Hz electrical activity. This coherence, initially observed during auditory input, was proposed to be generated by recurrent corticothalamic oscillation. In support of this hypothesis, we illustrate well-defined 40-Hz coherence between cortical-subcortical sites with a time shift that is consistent with thalamocortical conduction times. Studies on Alzheimer patients indicate that, while a similar activity pattern is present, the cortical component is reduced in these subjects.

Anatomical localization revealed by MEG recordings of the human somatosensory system.

A 14-channel cryogenic magnetometer system (BTi) was used to record the magnetic fields over the left hemisphere of 3 human subjects in order to locate the sources of responses to tactile stimulation of the index, the thumb and the little finger of the right hand. The locations of the active dipole sources determined using the spherical model were then projected onto the magnetic resonance image (MRI) of the individual subjects providing an anatomical localization. The MRI slices were also used to construct a 3-dimensional image to enhance visualization of the area of the calculated sources. The locations of the dipole sources from the 3 fingers were distinct from one another in all subjects. An analysis of variance ('ANOVA') showed the most significant (P less than 0.05) difference in source location between the little finger and the thumb with the former being superior to the sources of the other 2 fingers in all of the subjects. In all cases, the sources were found to be located on the postcentral gyrus. The strength of the equivalent dipole sources and the amplitudes of the responses to stimulation for all 3 fingers showed a consistent trend among all of the 3 subjects, with the thumb having the largest response. In general, no signs of habituation were found.

Effects of acute and chronic prenatal nicotine treatment on central catecholamine systems of male and female rat fetuses and offspring.

The effect of acute and chronic prenatal administration of nicotine on central catecholamine systems was studied in Long Evans rats. A single injection of nicotine (1 mg/kg s.c.) to urethane-anesthetized time-pregnant dams at gestational day (GD) 21 increased dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid (determined by radioenzymatic assay and high-performance liquid chromatography with electrochemical detection, respectively) in male and female fetal forebrain within 30 min. No significant change was seen in norepinephrine (NE) and MOPEG, but the MOPEG/NE ratio increased in male fetuses. After the administration of nicotine by an osmotic minipump (0.25 mg/kg x hour or vehicle for controls) between GD 12 and 18/19, MOPEG was elevated at GD 18 and reduced at postnatal day (PN) 15 in both sexes; the reduction persisted in males until adulthood (2.5 months). 3,4-dihydroxyphenylacetic acid was affected by chronic drug treatment only in males with an increase at GD 18 and PN 15 and a decrease in adulthood. In contrast, homovanillic acid was reduced in adult offspring of both sexes. Male NE and dopamine of both sexes was above control level at PN 15. Cross-fostering data demonstrate that the changes were due to prenatal influences. The observations indicate that central fetal catecholamine systems are responsive to acute administration of nicotine and that chronic prenatal exposure to the drug results in persistent alterations in the functional state of these neurons. The drug-induced pattern of neurochemical alterations changes during ontogeny until adulthood; it depends upon the sex of the offspring.