Cortical spreading depression and migraine: new insights from imaging?

The possibility that spreading depression (SD) of cortical activity, a phenomenon observed in all vertebrates, causes the aura of migraine remains an open question in spite of nearly half a century of investigation. SD is also thought to be associated with the progressive neuronal injury observed during cerebral ischaemia. Thus, the ability to detect and investigate SD in humans might prove clinically significant. Animal studies of cortical spreading depression (CSD) have benefited greatly from the advent of relatively non-invasive imaging techniques. The use of these new imaging techniques for clinical studies will accelerate progress in this area of neurobiology.

Linear coupling between functional magnetic resonance imaging and evoked potential amplitude in human somatosensory cortex.

The interpretation of task-induced functional imaging of the brain is critically dependent on understanding the relationship between observed blood flow responses and the underlying neuronal changes. However, the exact nature of this neurovascular coupling relationship remains unknown. In particular, it is unclear whether blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) responses principally reflect neuronal synaptic activity. In order to address this issue directly in humans, we measured the increase in somatosensory evoked potential amplitude and fMRI BOLD changes to increases in intensity of median nerve electrical stimulation in five healthy non-anaesthetized subjects. We found that mean N20-P22 amplitudes increased significantly with stimulus intensity in all subjects, as did fMRI BOLD percentage signal intensity change. Moreover, the intensity of the BOLD signal was found to correlate linearly with evoked potential amplitude in four of the five subjects studied. This suggests that the BOLD response correlates with synchronized synaptic activity, which is the major energy consuming process of the cortex.

What aspect of the fMRI BOLD signal best reflects the underlying electrophysiology in human somatosensory cortex?

The interpretation of task-induced functional imaging of the brain is critically dependent on understanding the relationship between observed haemodynamic responses and the underlying neural changes. However, the precise nature of this neurovascular coupling relationship remains unknown. In particular, it is unclear which measure of functional magnetic resonance imaging blood oxygen level dependent (fMRI BOLD) activity is the best correlate of neural activity. We measured the somatosensory evoked potential (SEP) amplitude at the scalp, and fMRI BOLD signal to increases in intensity of contralateral median nerve electrical stimulation in healthy non-anaesthetised subjects. We compared correlation analyses between SEP amplitude and both peak voxel fMRI BOLD percentage signal change and mean voxel fMRI BOLD percentage signal change across a somatosensory cluster, and we also performed a voxel-by-voxel correlation between fMRI BOLD activity and SEP amplitude. We found that fMRI BOLD changes in primary somatosensory cortex correlate significantly with SEP amplitudes, suggesting a linear neurovascular coupling relationship under the conditions investigated. We also found that mean changes across a cluster correlate less well with SEP amplitude than peak voxel levels. This suggests that the area of haemodynamic activity correlating with SEP amplitude is smaller than the entire cluster observed.

Retinal adaptation of visual processing time delays.

A significant proportion of the processing delays within the visual system are luminance dependent. Thus placing an attenuating filter over one eye causes a temporal delay between the eyes and thus an illusion of motion in depth for objects moving in the fronto-parallel plane, known as the Pulfrich effect. We have used this effect to study adaptation to such an interocular delay in two normal subjects wearing 75% attenuating neutral density filters over one eye. In two separate experimental periods both subjects showed about 60% adaptation over 9 days. Reciprocal effects were seen on removal of the filters. To isolate the site of adaptation we also measured the subjects' flicker fusion frequencies (FFFs) and contrast sensitivity functions (CSFs). Both subjects showed significant adaptation in their FFFs. An attempt to model the Pulfrich and FFF adaptation curves with a change in a single parameter in Kelly's [(1971) Journal of the Optical Society of America, 71, 537-546] retinal model was only partially successful. Although we have demonstrated adaptation in normal subjects to induced time delays in the visual system we postulate that this may at least partly represent retinal adaptation to the change in mean luminance.

Intracortically distributed neurovascular coupling relationships within and between human somatosensory cortices.

The coupling of neuronal cellular activity to its blood supply is of critical importance to the physiology of the human brain and has been under discussion for more than a century. Linearity in this relationship has been demonstrated in some animal studies, but evidence is lacking in humans. In this study, we compared scalp evoked potentials and the functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) signal from healthy human volunteers with changes in the intensity of a somatosensory stimulus. By weighting the fMRI images according to the evoked potential amplitude at corresponding intensities, we tested for positive and negative covariation between these 2 data sets and the extent to which these were linear. Hemodynamic changes in primary somatosensory cortex covaried positively with neuronal activity in a predominantly linear manner, with a small quadratic contribution. Simultaneously, other cortical areas corresponding to the nonstimulated limbs were found to covary negatively and linearly in the hemispheres ipsilateral and contralateral to the stimulus. These concurrent and bilateral cortical dynamics, as well as the intraregional features of this neurovascular coupling, are both more complex than had been considered to date, with considerable implications.

Endovascular electroencephalography: the technique and its application during carotid amytal assessment.

The EEG was recorded using an endovascular guide wire as the electrode. This was Teflon coated except for its terminal portion, which was placed distal to the origin of the middle cerebral artery. Four hemispheres were sampled sequentially in two patients with intractable complex partial seizures who were undergoing routine preoperative carotid amytal assessment. Epileptiform spikes were detected in one patient, concordant with decreased hippocampal volume on MRI and scalp EEG changes. Endovascular EEG during the amytal procedure is less invasive than other intracranial EEG methods and may develop a role in preoperative assessment of selected patients with intractable epilepsy.

Suppression and long latency excitation of single spinal motoneurons by transcranial magnetic stimulation in health, multiple sclerosis, and stroke.

Whether or not suppression at the level of the spinal motoneuron plays a role in motor deficits such as central paresis is unknown. In this study suppression in the firing of tonically active low threshold single motoneurons following low intensity transcranial magnetic stimulation is described in health and disease. Changes in firing probability in the absence of an early excitatory response were studied in a total of 14 motor units from 4 healthy subjects, 5 patients with multiple sclerosis, and 1 patient with stroke. Firing probability began to fall 18-59 ms after the stimulus and remained low for a period of 27-133 ms. There were no obvious differences between the three subject groups. The change in firing probability was not associated with specific physical signs. Late rises in firing probability were seen in 7 of the 14 motor units at latencies that were similar to the secondary peak which is known to occur with higher stimulus intensities. It is argued that the mechanism of partial suppression is not dependent on the full integrity of the pyramidal tract and is likely to involve a transient withdrawal of descending excitatory drive rather than an inhibitory postsynaptic potential at the spinal motoneuron.

Origin of the secondary increase in firing probability of human motor neurons following transcranial magnetic stimulation. Studies in healthy subjects, type I hereditary motor and sensory neuropathy and multiple sclerosis.

In tonically active human motor neurons serving upper limb muscles there is a late rise in firing probability following transcranial magnetic stimulation termed the secondary peak (SP). The aim was to study the mechanism of SP and the pathway that mediates it. For this purpose, the response to transcranial magnetic stimulation of 62 repetitively firing low threshold single motor units from upper limb muscles was studied with peri-stimulus time histograms in 8 healthy subjects and in 13 patients with either Type I hereditary motor and sensory neuropathy (HMSN) or multiple sclerosis (MS). Separate peri-stimulus time histograms, constructed for trials in which the motor unit fired in the primary peak (PP) and those in which it fired in SP, showed that SP was not caused by a resumption of firing after the preceding PP. In the first dorsal interosseous muscle, the observed increase in the interval between PP and SP in patients with either HMSN or MS, when compared with healthy subjects, suggested that the pathway mediating SP had both peripheral and central components. Evidence for a peripheral component was substantiated by the observed slope of the line relating the latency of SP in different upper limb muscles to peripheral conduction distance, which was more than 3 times greater than that for PP, and by comparisons in the same motor unit made between the latency of responses to finger taps and to transcranial magnetic stimulation. Evidence for the origin of SP was consistent with a long loop reflex, or with collateral activation of gamma motor neurons and subsequent motor neuron firing from muscle afferent inputs. SP discharges were found to occur earlier than expected on the basis of the spontaneous motor unit firing rate, suggesting that SP was caused by the rising phase of an excitatory post-synaptic potential, rather than by the decay of an inhibitory postsynaptic potential.

The firing probability of single motor units following transcranial magnetic stimulation in healthy subjects and patients with neurological disease.

Magnetic stimuli applied to the scalp can cause single motor units (MUs) to discharge in intrinsic hand or more proximal arm muscles. MUs are much more likely to be fired by stimuli if they are being activated voluntarily at the same time. The changes in firing probability induced by magnetic stimuli in such tonically active MUs have been studied in healthy subjects and patients using peri-stimulus time histograms (PeSTHs). The mean firing level in the 250 msec before the stimulus, was used to define 2 peaks of increased firing after the stimulus. The first, termed the primary peak (PP), was always present, had an onset latency in first dorsal interosseous (FDI) muscle of 20-31 msec and was short in duration (mean 4.9 msec). A second increase in firing probability, the secondary peak (SP), was present in about half the FDI MUs studied, had a mean peak latency of 81.5 msec and had a duration up to about 40 msec. PP often consisted of a number of sub-peaks with intermodal intervals of around 1.5 msec. It is believed that PP is the result of activation of corticospinal (CS) fibres making monosynaptic connections and that sub-peaks within PP are due to the arrival at the motoneuron of successive CS impulses produced by the stimulus. SP is probably due to operation of other excitatory inputs to the motoneuron. In patients, a number of different abnormalities have been identified. PP has been found to be normal, absent, delayed and dispersed or having abnormally separated sub-peaks. Clearly the technique is a powerful tool for dissecting abnormalities in CS projections at the synaptic level.

Responses of single spinal motoneurons to magnetic brain stimulation in healthy subjects and patients with multiple sclerosis.

Magnetic stimuli delivered over the scalp can cause single motor units to discharge in intrinsic hand muscles. The discharge characteristics of 26 tonically active, low threshold single motor units in the first dorsal interosseous muscle of 13 healthy subjects and of 21 motor units in 9 patients with multiple sclerosis (MS) were studied. Up to 500 transcranial magnetic stimuli were delivered at the vertex and were given randomly with respect to, or at a fixed delay after, the previous voluntary discharge. Peristimulus time histograms (PSTHs) of motor unit discharges were constructed. In healthy subjects, two periods of increased firing probability were seen at onset latencies of 20-31 ms and 56-90 ms after the stimulus. These periods have been termed the primary peak and the secondary peak. The primary peak had a mean duration of 4.6 ms and was found to be multimodal in 17 motor units. Subpeaks had intermodal intervals of between 0.6 and 2.4 ms. Subpeaks probably result from a sequence of excitatory postsynaptic potentials (EPSPs) induced at the motoneuron by corticospinal impulses. In patients with MS, the primary peak could be absent, delayed in onset, of increased duration without discernible subpeaks, or showing increased intermodal intervals between subpeaks. In 3 motor units from patients with MS, PSTHs with normal features were found. It is postulated from this study of the corticospinal inputs to single motoneurons that motor impairment in MS can be due to a number of mechanisms including slowed conduction in corticospinal fibres, dispersion of arrival times of corticospinal impulses at spinal motoneurons and conduction block in corticospinal fibres, which may be frequency dependent.

How does neurophysiological assessment influence the management and outcome of patients with carpal tunnel syndrome?

The objective of this study was to determine how neurophysiological assessment influenced the management and outcome of 100 consecutive patients referred to a department of clinical neurophysiology in a district general hospital with a provisional clinical diagnosis of carpal tunnel syndrome. Nerve conduction studies excluded the diagnosis in 36 patients who may have otherwise received inappropriate treatment. The decision whether to perform a carpal tunnel decompression was greatly influenced by a positive study. Symptoms subsequently resolved in 72-86% of patients treated on this basis, depending on the mode of treatment and the nerve conduction study findings, with similar outcomes for surgical and conservative measures. The clinical and estimated resource implications of this diagnostic service were found to be substantial.

Magnetic brain stimulation with a double coil: the importance of coil orientation.

The human motor cortex can be excited by currents induced by a transient magnetic field generated in a coil over the scalp. A 9 cm mean diameter circular coil centered at the vertex is optimally placed for exciting the hand area. Anticlockwise current flow in the coil preferentially excites the left hemisphere and vice versa. A double coil has been used to investigate the orientation of inducing currents at which activation of cortical neural elements is maximal. The inducing current flowed in the same direction in the central segment of the coil and followed a monophasic wave form. The coil was rotated through 360 degrees over the motor area in increments of 45 degrees and compound muscle action potentials from the first dorsal interosseous muscle were recorded. The largest responses were obtained with the coil at about 50 degrees to the parasagittal plane with a backward flowing inducing current. The optimal angle did not depend on stimulus intensity or background voluntary contraction. This orientation corresponds to an maximal induced current flowing forwards approximately at right angles to the central sulcus. It is postulated that horizontal neural elements are aligned in this direction and are preferentially excited by these monophasic magnetic stimuli. The results have important implications for mapping the motor areas with magnetic stimulators.

Transient epileptic amnesia: a description of the clinical and neuropsychological features in 10 cases and a review of the literature.

OBJECTIVES: To clarify the clinical and neuropsychological aspects of transient epileptic amnesia (TEA) based on 10 personally studied cases as well as review of 21 previously published cases; and to propose tentative diagnostic criteria for the diagnosis of TEA. METHODS: All 10 patients and informants underwent a standardised clinical interview. The radiological and neurophysiological (EEG) data were also reviewed in all cases. The diagnosis of transient epileptic amnesia was made on the basis of the following criteria: (1) there was a history of recurrent witnessed episodes of transient amnesia; (2) cognitive functions other than memory were judged to be intact during typical episodes by a reliable witness; (3) there was evidence for a diagnosis of epilepsy. This evidence was provided by either (a) wake or sleep EEG, or (b) the co-occurrence of other seizure types (if their roughly concurrent onset or close association with episodes of transient amnesia suggested a connection), or (c) a clear cut response to anticonvulsant therapy, or by a combination of these three factors. In addition all patients were administered a comprehensive neuropsychological test battery designed to assess verbal and non-verbal anterograde memory and retrograde memory for famous personalities and personal events. Their results were compared with those of 25 age and IQ matched normal controls. RESULTS: TEA usually begins in later life, with a mean age of 65 years in this series. Episodes are typically brief, lasting less than one hour, and recurrent, with a mean frequency of three a year. Attacks on waking are characteristic. Repetitive questioning occurs commonly during attacks. The anterograde amnesia during episodes is, however, often incomplete so that patients may later be able to "remember not being able to remember". The extent of the retrograde amnesia during attacks varies from days to years. Most patients experience other seizure types compatible with an origin in the temporal lobes, but transient amnesia is the only manifestation of epilepsy in about one third of patients. Epileptiform abnormalities arising from the temporal lobes are most often detected on interictal sleep EEG. Despite normal performance on tests of anterograde memory, many patients complain of persistent interictal disturbance of autobiographical memory, involving a significant but variable loss of recall for salient personal episodes. The epochs affected may predate the onset of epilepsy by many years. CONCLUSIONS: TEA is an identifiable syndrome and comprises episodic transient amnesia with an epileptic basis, without impairment of other aspects of cognitive function. Future studies should consider the question of whether TEA reflects ictal activity or a postictal state, and the mechanism of the persistent autobiographical amnesia. It is hypothesised that the latter may result in part from impairment of very long term memory consolidation as a result of epileptic activity in mesial temporal structures.

Changes in focal interictal epileptiform activity during and after the performance of verbal and visuospatial tasks in a patient with intractable partial seizures.

An 18-year-old male with intractable complex partial seizures is described in whom localised epileptiform discharges in the EEG were influenced in a specific manner by different cognitive tasks. The patient had impaired verbal skills but above average visuospatial ability, and seizures probably arising in the left temporal lobe. Comparison of verbal and visuospatial tasks showed that focal epileptiform activity was suppressed or enhanced depending on the nature of the immediate and preceding cognitive tasks. The finding of particular interest was the activity of a posterior temporal spike focus only during rest periods after verbal tasks, by contrast with an independent mid-to-anterior temporal focus that was suppressed during verbal tasks.

[Changes in the responses of motor units to transcranial magnetic stimulation in patients with multiple sclerosis and stroke]. / Veränderungen der Reizantworten motorischer Einheiten auf transkranielle Magnetstimulation bei Patienten mit multipler Sklerose und zerebralem Insult.

In multiple sclerosis and stroke the muscle responses to transcranial magnetic stimulation are frequently delayed, reduced in amplitude or absent. To investigate the underlying pathophysiological mechanisms, responses of single motor units to transcranial magnetic stimulation were analysed using peri-stimulus time histograms. The following response patterns were detected: 1. prolongation of latency and duration of the primary peak which occurs in healthy controls 17 to 30 ms after the stimulus and has a duration of 2 to 8 ms, 2. lack of an excitatory response, 3. prolongation of the interval between sub-peaks within the primary peak and 4. multimodal responses. Possible mechanisms for these changes are: reduction and dispersion of conduction velocities in corticospinal axons associated with impaired summation of excitatory post-synaptic potentials at the spinal motoneurone, frequency-dependent or complete conduction block in corticospinal neurones and compensatory activation of other descending motor pathways.

Attention differentially modulates the coupling of fMRI BOLD and evoked potential signal amplitudes in the human somatosensory cortex.

Blood oxygenation dependent contrast (BOLD) fMRI is used increasingly to probe "connectivity" based on temporal correlations between signals from different brain regions. This approach assumes that there is constant local coupling of neuronal activity to the associated BOLD response. Here we test the alternative hypothesis that there is not a fixed relationship between these by determining whether attention modulates apparent neurovascular coupling. Electrical stimulation of the median nerve was applied with and without a concurrent distractor task (serial subtraction). Increasing stimulation intensity increased discomfort ratings ( p<0.001) and was associated with a significant increase in both somatosensory evoked potential (SEP) N20-P25 amplitude and BOLD fMRI response in the contralateral primary (SI) and bilaterally in the secondary somatosensory cortices. Attention to stimulation was reduced during distractor task performance and resulted in an overall trend for reduction in discomfort ( p=0.056), which was significant at the highest stimulation level ( p<0.05). A volume of interest analysis confined to SI confirmed a reduction in BOLD response with distraction ( p<0.001). However, distraction did not measurably affect SEP magnitude. The quantitative relationship between the BOLD fMRI response and the local field potential measured by the early SEP response therefore varies with attentional context. This may be a consequence of differences in either local spatial or temporal signal summation for the two methods. Either interpretation suggests caution in assuming a simple, fixed relationship between local BOLD changes and related electrophysiological activity.

Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin.

Within one month of starting oral prednisolone treatment weakness unexpectedly increased in four patients aged 34 to 75 years with purely motor forms of acquired chronic demyelinating neuropathy. By contrast, steroids produced the expected improvement in 11 other patients with symmetric sensorimotor chronic inflammatory demyelinating polyneuropathy. Two of the patients with purely motor demyelinating neuropathy were subsequently treated with high dose IVIg (0.4 g/kg/day for five days) with prompt improvements in strength measurements and motor nerve conduction. Thus IVIg seems to be the treatment of choice and steroids should be used with extreme caution, if at all, in patients with purely motor forms of acquired demyelinating polyneuropathy.

Dopaminergic effects on electrophysiological and functional MRI measures of human cortical stimulus-response power laws.

Power laws have been widely used to formulate relationships between objective intensity of stimulation and subjective intensity of sensation. We investigated the effects of dopaminergic drug treatment (sulpiride) on the relationship between somatosensory stimulus intensity and cortical response measured electrophysiologically by somatosensory-evoked potentials (SEP) and functional magnetic resonance imaging (fMRI). The intensity of stimulation was related by a simple power law to both electrophysiological and fMRI measures of cortical response, with overlapping confidence intervals for both power law exponents. Sulpiride did not modulate the power law exponent, but significantly attenuated the "gain" of both stimulus-response functions. Using path analysis we decomposed dopaminergic effects on fMRI data into an indirect component (16%), predictable by drug effects on SEP, and a direct component (84%), not explained electrophysiologically. Results indicate that sulpiride has comparable effects on power law parameters estimated from SEP and fMRI, but fMRI has superior sensitivity to detect drug effects on somatosensory cortical recruitment by graded stimulation.

Investigation of the effect of chlormethiazole on cerebral chemistry in neurosurgical patients: a combined study of microdialysis and a neuroprotective agent.

AIMS: Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatment of patients with stroke and head injury have not been translated into benefit during clinical trials. The objective of the study was to assess the feasibility of administrating a potential neuro-protective drug (chlormethiazole) in conjunction with multimodality monitoring (including microdialysis) to patients with severe head injury in order to determine the effect of the agent on surrogate endpoints and penetration into the brain. METHODS: Multimodality monitoring including cerebral and peripheral microdialysis was applied to five head-injured patients on the neuro-intensive care unit. Chlormethiazole (0.8%) was administered as a rapid (10 ml min(-1)) intravenous loading infusion for 5 min followed by a slow (1 ml min(-1)) continuous infusion for 60 min. The following parameters were monitored: heart rate, mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, peripheral oxygen saturation, continuous arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial temperature, cerebral tissue oxygen pressure, cerebral tissue carbon dioxide pressure, cerebral pH, cerebral temperature, electroencephalograph (EEG), bi-spectral index, plasma glucose, plasma chlormethiazole, and cerebral and peripheral microdialysis assay for chlormethiazole, glucose, lactate, pyruvate and amino acids. RESULTS: Despite achieving adequate plasma concentrations, chlormethiazole was not detected in the peripheral or cerebral microdialysis samples. The drug was well tolerated and did not induce hypotension, hyperglycaemia or withdrawal seizures. The drug did not change the values of the physiological or chemical parameters including levels of GABA, lactate/pyruvate ratio and glutamate. The drug did, however, induce EEG changes, including burst suppression in two patients. CONCLUSIONS: Chlormethiazole can be safely given to ventilated patients with severe head injury. There was no evidence of hypotension or withdrawal seizures. Combining a pilot clinical study of a neuro-protective agent with multimodality monitoring is feasible and, despite the lack of effect on physiological and chemical parameters in this study, may be a useful adjunct to the development of neuro-protective drugs in the future. Further investigation of the capability of microdialysis in this setting is required. By investigating the effect of a drug on surrogate end-points, it may be possible to identify promising agents from small pilot clinical studies before embarking on large phase III clinical trials.