Neural Spike Train Synchronisation Indices: Definitions, Interpretations and Applications.

A comparison of previously defined spike train syncrhonization indices is undertaken within a stochastic point process framework. The second order cumulant density (covariance density) is shown to be common to all the indices. Simulation studies were used to investigate the sampling variability of a single index based on the second order cumulant. The simulations used a paired motoneurone model and a paired regular spiking cortical neurone model. The sampling variability of spike trains generated under identical conditions from the paired motoneurone model varied from 50% { 160% of the estimated value. On theoretical grounds, and on the basis of simulated data a rate dependence is present in all synchronization indices. The application of coherence and pooled coherence estimates to the issue of synchronization indices is considered. This alternative frequency domain approach allows an arbitrary number of spike train pairs to be evaluated for statistically significant differences, and combined into a single population measure. The pooled coherence framework allows pooled time domain measures to be derived, application of this to the simulated data is illustrated. Data from the cortical neurone model is generated over a wide range of firing rates (1 - 250 spikes/sec). The pooled coherence framework correctly characterizes the sampling variability as not significant over this wide operating range. The broader applicability of this approach to multi electrode array data is briefly discussed.

Medial prefrontal cortex circuit function during retrieval and extinction of associative learning under anesthesia.

Associative learning is encoded under anesthesia and involves the medial prefrontal cortex (mPFC). Neuronal activity in mPFC increases in response to a conditioned stimulus (CS+) previously paired with an unconditioned stimulus (US) but not during presentation of an unpaired stimulus (CS-) in anesthetized animals. Studies in conscious animals have shown dissociable roles for different mPFC subregions in mediating various memory processes, with the prelimbic (PL) and infralimbic (IL) cortex involved in the retrieval and extinction of conditioned responding, respectively. Therefore PL and IL may also play different roles in mediating the retrieval and extinction of discrimination learning under anesthesia. Here we used in vivo electrophysiology to examine unit and local field potential (LFP) activity in PL and IL before and after auditory discrimination learning and during later retrieval and extinction testing in anesthetized rats. Animals received repeated presentations of two distinct sounds, one of which was paired with footshock (US). In separate control experiments animals received footshocks without sounds. After discrimination learning the paired (CS+) and unpaired (CS-) sounds were repeatedly presented alone. We found increased unit firing and LFP power in PL and, to a lesser extent, IL after discrimination learning but not after footshocks alone. After discrimination learning, unit firing and LFP power increased in PL and IL in response to presentation of the first CS+, compared to the first CS-. However, PL and IL activity increased during the last CS- presentation, such that activity during presentation of the last CS+ and CS- did not differ. These results confirm previous findings and extend them by showing that increased PL and IL activity result from encoding of the CS+/US association rather than US presentation. They also suggest that extinction may occur under anesthesia and might be represented at the neural level in PL and IL.

Basolateral amygdala activity during the retrieval of associative learning under anesthesia.

Associative learning can occur under anesthesia and its neural correlates have begun to be elucidated. During discrimination learning under anesthesia in rats, lateral amygdala excitability increases in response to a conditioned stimulus (CS+) previously paired with electrical stimulation of the paw but not to another stimulus presented alone (CS-). Similarly, medial prefrontal cortex activity increases selectively during CS+ presentation after discrimination learning but this occurs only in neurons receiving input from the basolateral amygdala (BLA), the main source of amygdaloid projections to this region. However, BLA activity during discrimination learning under anesthesia has not been investigated. Here we used in vivo electrophysiology to examine BLA activity before and after associative learning and during later memory retrieval in anesthetized rats. We examined extracellular unit and local field potential (LFP) activity using an auditory discrimination learning paradigm. Rats were repeatedly presented with two distinct sounds, one of which was paired with electrical stimulation of the paw. One hour later, the paired sound (CS+) was presented alone along with the sound not paired with electrical stimulation (CS-). We found increased unit firing late (1 h) but not early (5 min) after learning. LFP power was increased both early and late after learning. In control experiments we also found increased unit and LFP activity late after electrical stimulation alone. After discrimination learning, unit firing increased in response to CS+, but not CS-, presentation. LFP power also showed a modest increase during CS+, compared to CS-, presentation. These findings suggest that discrimination learning under anesthesia can occur at the neural level in BLA. The potential relevance of these results is discussed in relation to previous studies examining neural activity during fear learning and memory processing in conscious animals.

A periodogram-based test for weak stationarity and consistency between sections in time series.

In one approach to spectral estimation, a sample record is broken into a number of disjoint sections, or data is collected over a number of discrete trials. Spectral parameters are formed by averaging periodograms across these discrete sections or trials. A key assumption in this approach is that of weak stationarity. This paper describes a simple test that checks if periodogram ordinates are consistent across sections as a means of assessing weak stationarity. The test is called the Periodogram Coefficient of Variation (PCOV) test, and is a frequency domain test based on a technique of spectral analysis. Application of the test is illustrated to both simulated and experimental data (EMG, physiological tremor, EEG). An additional role for the test as a useful tool in exploratory analysis of time series is highlighted.

Reduction of common motoneuronal drive on the affected side during walking in hemiplegic stroke patients.

OBJECTIVE: The objective of this study was to use motor unit coupling in the time and frequency domains to obtain evidence of changes in motoneuronal drive during walking in subjects with stroke. METHODS: Paired tibialis anterior (TA) EMG activity was sampled during the swing phase of treadmill walking in eight subjects with unilateral stroke. RESULTS: On the unaffected side, short-term synchronization was evident from the presence of a narrow central peak in cumulant densities and from the presence of significant coherence between these signals in the 10-25 Hz band. Such indicators of short-term synchrony were either absent or very small on the affected side. Instead, pronounced 10 Hz coupling was observed. CONCLUSIONS: It is suggested that reduced corticospinal drive to the spinal motoneurones is responsible for the reduced short-term synchrony and coherence in the 10-25 Hz frequency band on the affected side in hemiplegic patients during walking. SIGNIFICANCE: This is of importance for understanding the mechanisms responsible for reduced gait ability and development of new strategies for gait restoration.

Early life programming of hemispheric lateralization and synchronization in the adult medial prefrontal cortex.

Neonatal maternal separation (MS) in the rat increases the vulnerability to stressors later in life. In contrast, brief handling (H) in early life confers resilience to stressors in adulthood. Early life programming of stress reactivity may involve the medial prefrontal cortex (mPFC), a region which modulates various stress responses. Moreover, hemispheric specialization in mPFC may mediate adaptive coping responses to stress. In the present study, neuronal activity was examined simultaneously in left and right mPFC in adult rats previously subjected to MS, H or animal facility rearing (AFR). In vivo electrophysiology, under isoflurane anesthesia, was used to conduct acute recordings of unit and local field potential (LFP) activity in response to systemic administration of N-methyl-beta-carboline-3-carboxamide (FG-7142), a benzodiazepine receptor partial inverse agonist which mimics various stress responses. MS decreased basal unit activity selectively in right mPFC. Basal LFP activity was reduced with MS in left and right mPFC, compared to AFR and H, respectively. Hemispheric synchronization of basal LFP activity was also attenuated by MS at lower frequencies. FG-7142 elicited lateralized effects on mPFC activity with different early rearing conditions. Activity in left mPFC was greater with AFR and MS (AFR>MS), whereas activity was predominantly greater with H in right mPFC. Finally, compared to AFR, MS reduced and H enhanced hemispheric synchronization of LFP activity with FG-7142 treatment in a dose-dependent manner. These results indicate that functionally-relevant alterations in mPFC GABA transmission are programmed by the early rearing environment in a hemisphere-dependent manner. These findings may model the hemispheric specialization of mPFC function thought to mediate adaptive coping responses to stressors. They also suggest the possibility that early environmental programming of hemispheric functional coupling in mPFC is involved in conferring vulnerability or resilience to stressors later in life.

On the use of low-cost computer peripherals for the assessment of motor dysfunction in Parkinson's disease--quantification of bradykinesia using target tracking tasks.

The potential of computer games peripherals to measure the motor dysfunction in Parkinson's diseases is assessed. Of particular interest is the quantification of bradykinesia. Previous studies used modified or custom haptic interfaces, here an unmodified force feedback joystick and steering wheel are used with a laptop. During testing an on screen cursor moves in response to movements of the peripheral, the user has to track a continuously moving target (pursuit tracking), or move to a predetermined target (step tracking). All tasks use movement in the horizontal axis, allowing use of joystick or steering wheel. Two pursuit tracking tasks are evaluated, pseudo random movement, and a swept frequency task. Two step tracking tasks are evaluated, movement between two or between two of five fixed targets. Thirteen patients and five controls took part on a weekly basis. Patients were assessed for bradykinesia at each session using standard clinical measures. A range of quantitative measures was developed to allow comparison between and within patients and controls using analysis of variance (ANOVA). Both peripherals are capable of discriminating between controls and patients, and between patients with different levels of bradykinesia. Recommendations for test procedures and peripherals are given.

A novel computer-based technique for the assessment of tremor in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease and the diagnosis of its idiopathic form remains challenging. The diagnosis of idiopathic form is based on clinical features which can have poor sensitivity with about 25% of patients diagnosed as having the disease actually having other conditions. In this study we assess the suitability and clinical value of a low cost computer-based system as an aid to diagnosis of PD, in particular the presence of tremor. All participants (12 patients and 10 controls) performed a shape-tracing task using a graphic tablet attached to a laptop. To assess the presence of tremors in the collected data, a statistical spectral analysis of the moment-to-moment fluctuations in the position signal of the output from the digitising tablet was performed. This allowed the comparison of power spectrums obtained from the control and patient responses respectively. A peak in log power between the 5 Hz & 6 Hz can clearly be identified in the patient's spectrum and is indicative of Parkinson's related tremor and no similar peak could be seen in the control's spectrum, suggesting this type of sequential task and automated data analysis may be useful in the diagnosis of tremor.

Temporal sub units in dendritic trees.

This simulation study examines the possibility that dendritic sub units can be defined according to temporal aspects in the timing of populations of synaptic inputs. A two cell model with passive dendritic trees is used, which is subject to both common and independent synaptic inputs, the presence of common synaptic input results in a tendency for correlated firing in the two cell model. The strength of this correlation is used to measure the efficacy of the common synaptic inputs in modulating the output discharge of each neurone. Our results suggest that a small fraction of the total synaptic input can effectively modulate the timing of output spikes, this phenomenon is not dependent on the physical location of the inputs on the dendritic tree. This phenomenon depends on the presence of temporal correlation between the pre-synaptic spike trains that provide the common input. We propose to refer to these as temporal sub units.

Organization of common synaptic drive to motoneurones during fictive locomotion in the spinal cat.

The basic locomotor rhythm in the cat is generated by a neuronal network in the spinal cord. The exact organization of this network and its drive to the spinal motoneurones is unknown. The purpose of the present study was to use time (cumulant density) and frequency domain (coherence) analysis to examine the organization of the last order drive to motoneurones during fictive locomotion (evoked by application of nialamide and dihydroxyphenylalanine (DOPA)) in the spinal cat. In all cats, narrow central synchronization peaks (half-width < 3 ms) were observed in cumulants estimated between electroneurograms (ENGs) of close synergists, but not between nerves belonging to muscles acting on different joints or to antagonistic muscles. Coherence was not observed at frequencies above 100 Hz and was mainly observed between synergists. Intracellular recording was obtained from a population of 70 lumbar motoneurones. Significant short-term synchronization was observed between the individual intracellular recordings and the ENGs recorded from nerves of the same pool and of close synergists. Recordings from 34 pairs of motoneurones (10 pairs belonged to the same motor pool, 11 pairs to close synergists and 13 pairs to antagonistic pools) failed to reveal any short-lasting synchronization. These data demonstrate that short-term synchronization during fictive locomotion is relatively weak and is restricted to close synergists. In addition, coherence analysis failed to identify any specific rhythmic component in the locomotor drive that could be associated with this synchronization. These results resemble findings obtained during human treadmill walking and imply that the spinal interneurones participating in the generation of the locomotor rhythm are themselves weakly synchronized. The restricted synchronization within the locomotor drive to motoneuronal pools may be a feature of the locomotor generating networks that is related to the ability of these networks to produce highly adaptive patterns of muscle activity during locomotion.

Reduction of common synaptic drive to ankle dorsiflexor motoneurons during walking in patients with spinal cord lesion.

It is possible to obtain information about the synaptic drive to motoneurons during walking by analyzing motor-unit coupling in the time and frequency domains. The purpose of the present study was to compare motor-unit coupling during walking in healthy subjects and patients with incomplete spinal cord lesion to obtain evidence of differences in the motoneuronal drive that result from the lesion. Such information is of importance for development of new strategies for gait restoration. Twenty patients with incomplete spinal cord lesion (SCL) participated in the study. Control experiments were performed in 11 healthy subjects. In all healthy subjects, short-term synchronization was evident in the discharge of tibialis anterior (TA) motor units during the swing phase of treadmill walking. This was identified from the presence of a narrow central peak in cumulant densities constructed from paired EMG recordings and from the presence of significant coherence between these signals in the 10- to 20-Hz band. Such indicators of short-term synchrony were either absent or very small in the patient group. The relationship between the amount of short-term synchrony and the magnitude of the 10- to 20-Hz coherence in the patients is discussed in relation to gait ability. It is suggested that supraspinal drive to the spinal cord is responsible for short-term synchrony and coherence in the 10- to 20-Hz frequency band during walking in healthy subjects. Absence or reduction of these features may serve as physiological markers of impaired supraspinal control of gait in SCL patients. Such markers could have diagnostic and prognostic value in relation to the recovery of locomotion in patients with central motor lesions.

Functional coupling of motor units is modulated during walking in human subjects.

Time- and frequency-domain analysis of the coupling between pairs of electromyograms (EMG) recorded from leg muscles was investigated during walking in healthy human subjects. For two independent surface EMG signals from the tibialis anterior (TA) muscle, coupling estimated from coherence measurements was observed at frequencies

Magnetoencephalography and stereopsis: rhythmic cortical activity in humans recorded over the parieto-occipital cortex.

We have studied human stereopsis by analysing magnetoencephalographic signals during the presentation of stereograms using frequency analysis. The study of synchronised firing of cortical neurones is a new way of understanding information processing in the brain and it is hypothesised that frequencies greater than 35 Hz are used for higher-order processing. We report the response of cortical neurones involved in stereopsis recorded from over the occipital and parietal cortices using a single channel axial superconducting quantum interference device neuromagnetometer. Our main result was increased cortical activity in the gamma-band at frequencies apparently related to stereopsis and the perception of depth. Our results are consistent with reports in the literature that suggest that frequencies above 40 Hz are involved in attention, pattern recognition and higher order visual activity.

Coherence between low-frequency activation of the motor cortex and tremor in patients with essential tremor.

BACKGROUND: In healthy people, rhythmic activation of the motor cortex in the 15-30 Hz frequency range accompanies and contributes to voluntarily-generated postural contractions of contralateral muscle. In patients with Parkinson's disease, an abnormal low-frequency activation of the motor areas of the cortex occurs and has been directly linked to the characteristic 3-6 Hz rest tremor of this disease. We therefore investigated whether the motor cortex is involved in the transmission of the rhythmic motor drive responsible for generating essential tremor. METHODS: Non-invasive recordings of activity from the hand area of the motor cortex were made from six patients with essential tremor by magnetoencephalography. The recordings were made simultaneously with the electromyogram recorded from contralateral finger muscles during periods of postural tremor. A statistical spectral analysis was done to determine at which frequencies the two signals were correlated. FINDINGS: Spectral analysis of the electromyogram signals showed a significant low-frequency component at the frequency of the tremor bursts. However, there was no coherence between magnetoencephalogram and electromyogram recordings at the tremor frequency, indicating that no correlation existed between the tremor signal and low-frequency activity recorded from the primary motor cortex in individuals with essential tremor. Coherence at frequencies higher than the tremor frequency was similar to that in healthy individuals performing voluntary postural contractions. INTERPRETATION: The absence of significant coherence between the magnetoencephalogram and electromyogram at tremor frequencies suggests that in essential tremor the tremor is imposed on the active muscle through descending pathways other than those originating in the primary motor cortex. These findings challenge the model widely used to explain the efficacy of neurosurgical treatment of essential tremor, are in contrast to those of previous studies of parkinsonian rest tremor, and highlight an important difference in the pathophysiology of essential and parkinsonian tremor.

Weak, stochastic temporal correlation of large scale synaptic input is A major determinant of neuronal bandwidth.

We determine the bandwidth of a model neurone to large-scale synaptic input by assessing the frequency response between the outputs of a two-cell simulation that share a percentage of the total synaptic input. For temporally uncorrelated inputs, a large percentage of common inputs are required before the output discharges of the two cells exhibit significant correlation. In contrast, a small percentage (5%) of the total synaptic input that involves stochastic spike trains that are weakly correlated over a broad range of frequencies exert a clear influence on the output discharge of both cells over this range of frequencies. Inputs that are weakly correlated at a single frequency induce correlation between the output discharges only at the frequency of correlation. The strength of temporal correlation required is sufficiently weak that analysis of a sample pair of input spike trains could fail to reveal the presence of correlated input. Weak temporal correlation between inputs is therefore a major determinant of the transmission to the output discharge of frequencies present in the spike discharges of presynaptic inputs, and therefore of neural bandwidth.

The unilateral and bilateral control of motor unit pairs in the first dorsal interosseous and paraspinal muscles in man.

1. The discharges of two motor units were identified in an intrinsic hand muscle (first dorsal interosseous, FDI) or an axial muscle (lumbar paraspinals, PSP) in ten healthy subjects. Each motor unit was situated in the homologous muscle on either side of the body (bilateral condition) or in the same muscle (ipsilateral condition). The relationship between the times of discharge of the two units was determined using coherence analysis. 2. Motor unit pairs in the ipsilateral FDI showed significant coherence over the frequency bands 1-10 Hz and 12-40 Hz. Motor units in the ipsilateral PSP were significantly coherent below 5 Hz. In contrast there was no significant coherence at any frequency up to 100 Hz in the bilateral FDI condition and only a small but significant band of coherence below 2 Hz in the bilateral PSP condition. 3. Common drive to motor units at frequencies of < 4 Hz was assessed by cross-correlation of the instantaneous frequencies of the motor units. A significantly higher coefficient was found in the ipsilateral FDI, ipsi- and bilateral PSP compared with shifted, unrelated data sets. This was not the case for the bilateral FDI condition. 4. The presence of higher frequency coherence ( > 10 Hz) in the ipsilateral FDI condition and its absence in ipsilateral PSP is consistent with a more direct and influential cortical supply to the intrinsic hand muscles compared with the axial musculature. The presence of low frequency drives (< 4 Hz) in the bilateral PSP condition and its absence in the bilateral FDI condition is consistent with a bilateral drive to axial, but not distal, musculature by the motor pathways responsible for this oscillatory input.

Load-independent contributions from motor-unit synchronization to human physiological tremor.

This study describes two load-independent rhythmic contributions from motor-unit synchronization to normal physiological tremor, which occur in the frequency ranges 1-12 Hz and 15-30 Hz. In common with previous studies, we use increased inertial loading to identify load-independent components of physiological tremor. The data consist of simultaneous recordings of tremor acceleration from the third finger, a surface electromyogram (EMG), and the discharges of pairs of single motor units from the extensor digitorum communis (EDC) muscle, collected from 13 subjects, and divided into 2 data sets: 106 records with the finger unloaded and 84 records with added mass from 5 to 40 g. Frequency domain analysis of motor-unit data from individual subjects reveals the presence of two distinct frequency bands in motor-unit synchronization, 1-12 Hz and 15-30 Hz. A novel Fourier-based population analysis demonstrates that the same two rhythmic components are present in motor-unit synchronization across both data sets. These frequency components are not related to motor-unit firing rates. The same frequency bands are present in the correlation between motor-unit activity and tremor and between surface EMG activity and tremor, despite a significant alteration in the characteristics of the tremor with increased inertial loading. A multivariate analysis demonstrates conclusively that motor-unit synchronization is the source of these contributions to normal physiological tremor. The population analysis suggests that single motor-unit discharges can predict an average of 10% of the total tremor signal in these two frequency bands. Rectified surface EMG can predict an average of 20% of the tremor; therefore within our population of recordings, the two components of motor-unit synchronization account for an average of 20% of the total tremor signal, in the frequency ranges 1-12 Hz and 15-30 Hz. Our results demonstrate that normal physiological tremor is a complex signal containing information relating to motor-unit synchronization in different frequency bands, and lead to a revised definition of normal physiological tremor during low force postural contractions, which is based on using both the tremor spectra and the correlation between motor-unit activity and tremor to characterize the load-dependent and the load-independent components of tremor. In addition, both physiological tremor and rectified EMG emerge as powerful predictors of the frequency components of motor-unit synchronization.

The origin of ocular microtremor in man.

A novel technique for the study of human eye movements was used to investigate the frequency components of ocular drift and microtremor in both eyes simultaneously. The tangential components of horizontal eye accelerations were recorded in seven healthy subjects using light-weight accelerometers mounted on scleral contact lenses during smooth pursuit movements, vestibulo-ocular reflexes and eccentric gaze with and without fixation. Spectral peaks were observed at low (up to 25 Hz) and high (60-90 Hz) frequencies. A multivariate analysis based on partial coherence analysis was used to correct for head movement. After correction, the signals were found to be coherent between the eyes over both low- and high-frequency ranges, irrespective of task, convergence or fixation. It is concluded that the frequency content of ocular drift and microtremor reflects the patterning of low-level drives to the extra-ocular muscle motor units.

Coherent cortical and muscle discharge in cortical myoclonus.

There is increasing evidence in man that the cortical drive to motor neurons is rhythmic. This oscillatory drive may be exaggerated in patients with cortical myoclonus. Spectral analysis of surface bipolar EEG and EMG activity was performed in eight such patients. Only three cases had evidence of giant cortical evoked potentials or a cortical correlate on back-averaging at the time of study. In six subjects, significant coherence between contralateral and vertex EEG and EMG was observed in ranges similar to that previously reported for normal subjects (15-30 and 30-60 Hz). Three out of these six subjects also had significant coherence at higher frequencies (up to 175 Hz). All eight patients had a correlate in the cumulant density estimate between EEG and contralateral EMG. EMG lagged EEG by about 14, 25 and 35 ms for the muscles of the forearm, hand and foot, respectively. These delays were estimated from the slope of the phase curves and the timing of the peaks in the cumulant density estimates, and are appropriate for conduction in fast pyramidal pathways. The results provide clear evidence of a cortical drive synchronizing muscle discharge over a broad range of frequencies in patients with cortical myoclonus. Fourier analysis is a promising technique in the diagnosis and investigation of such patients.