Decoupling neuronal oscillations during subthalamic nucleus stimulation in the parkinsonian primate.

Subthalamic nucleus (STN) stimulation is a popular treatment for Parkinson's disease; however, its effect on neuronal activity is unclear. We performed simultaneous multi-electrode recordings in the STN and its targets, the globus pallidus internus (GPi) and externus (GPe) in the parkinsonian non-human primate during high frequency STN macro-stimulation. Our results indicate that in the parkinsonian state the abnormal neuronal oscillatory activity in the 10-15 Hz range is coherent within and between nuclei. We further show that STN macro-stimulation results in a reduction of oscillatory activity in the globus pallidus. In addition, a functional decoupling of the STN from its pallidal targets is evidenced by the reduced STN-GPi coherence, that effectively removes the STN synchronous oscillatory drive of basal ganglia output. This decoupling results in reduced coherence between neurons within the GPi which resume an independent neuronal activity pattern. This decorrelation of the basal ganglia output may result in a reduction of the fluctuations of the basal ganglia inhibitory control over thalamic neurons which may potentially contribute to the beneficial effects of deep brain high-frequency stimulation.

Subthalamic nucleus functional organization revealed by parkinsonian neuronal oscillations and synchrony.

The emergence of oscillations and synchrony among neurons of the basal ganglia is a well-known characteristic of Parkinson's disease. In this study we used intra-operative microelectrode recording to investigate this interrelationship between these two phenomena in the subthalamic nucleus (STN) neurons of 39 human Parkinson's disease patients undergoing deep brain stimulation surgery. From the recorded neuronal traces both neuronal spike trains and their background activity were extracted, and their spectral characteristics were evaluated. We have used the background oscillations as a marker for synchronized activity in the local population in the neuron vicinity and studied its relation to single neuron oscillations. Spike train background oscillations were evaluated using a procedure of background reconstruction that consisted of spikes removal from the original traces and full wave rectification followed by standard spectral analysis. Coherence and phase analysis between oscillatory spike trains and their oscillatory background were also conducted to study the phase relationship between the two. Of the 231 neuronal spike-trains which were sorted offline, 82 (35%) showed significant oscillatory activity. These neurons were found to oscillate mostly in two bands; 3-7 Hz, termed the Tremor Frequency Band (TFB), and 8-20 Hz, termed the High-Frequency Band (HFB). While HFB neurons oscillated for longer periods and always coherently with their background activity, TFB neurons oscillated more episodically and only a half were coherent with their background. These findings indicate that the two neuronal populations are the outcome of very different oscillatory drives deriving from different local functional neuronal organizations.

Stepping out of the box: information processing in the neural networks of the basal ganglia.

The Albin-DeLong 'box and arrow' model has long been the accepted standard model for the basal ganglia network. However, advances in physiological and anatomical research have enabled a more detailed neural network approach. Recent computational models hold that the basal ganglia use reinforcement signals and local competitive learning rules to reduce the dimensionality of sparse cortical information. These models predict a steady-state situation with diminished efficacy of lateral inhibition and low synchronization. In this framework, Parkinson's disease can be characterized as a persistent state of negative reinforcement, inefficient dimensionality reduction, and abnormally synchronized basal ganglia activity.

Behavior of hindbrain neurons during the transition from rest to evoked locomotion in a newt.

Trains of electrical stimuli were delivered to the mesencephalic 'locomotor region' in the rough skin newt. The current (3-12 mcA) and the interstimulus interval (100 to 200 ms) were adjusted so that locomotion arose in approximately 10 s, or so that the train remained subthreshold for initiation of locomotion. Impulses of single neurons in the hindbrain were recorded during the transition period from rest to locomotion. Time-locked synaptic responses were bi- or unimodal with typical latencies close to 18, 23 or 28 ms, and weak irregular mode near 13 ms. Impulses that were not locked to the stimuli arose in some silent neurons, and the rate of firing of neurons with background discharge was sometimes enhanced. Composite responses consisted of both time-locked component and impulses distributed throughout the interstimulus interval. The data suggest that short-lived, wave-like propagation of the input volley ceases or is transformed into asynchronous activity after three or four translations. The latter variant could occur if the train reached the threshold for initiation of locomotion. The asynchronous activity persisted throughout interstimulus interval and could coexist with time-locked impulses. Some neurons generated only a few impulses, while others remained active from beginning to end of the train. These active neurons could either spike at a steady rate, or decrement or augment their rate of firing during the train. The time course of their activity was related to the initial rate of firing. The augmenting type of firing in a subset of neurons may arise due to the interaction of neurons with unstable, steady state and decrementing activity.

The neuronal refractory period causes a short-term peak in the autocorrelation function.

Autocorrelation functions are a major tool for the understanding of single-cell firing patterns. Short-term peaks in autocorrelation functions have previously been interpreted as a tendency towards bursting activity or elevated probability to emit spikes in a short time-scale. These peaks can actually be a result of the firing of a neuron with a refractory period followed by a period of constant firing probability. Analytic studies and simulations of such neurons replicate the autocorrelation functions of real-world neurons. The relative size of the peak increases with the refractory period and with the firing rate of the cell. This phenomenon is therefore more notable in areas such as the globus pallidus and cerebellum and less clear in the cerebral cortex. We describe here a compensation factor that can be calculated from the neuron's hazard function. This factor can be removed from the original autocorrelation function to reveal the underlying firing pattern of the cell.

Failure in identification of overlapping spikes from multiple neuron activity causes artificial correlations.

Recording of multiple neurons from a single electrode is common practice during extra-cellular recordings. Separation and sorting of spikes originating from the different neurons can be performed either on-line or off-line using multiple methods for pattern matching. However, all spike sorting techniques fail either fully or partially in identifying spikes from multiple neurons when they overlap due to occurrence within a short time interval. This failure, that we termed the 'shadowing effect', causes the well-known phenomenon of decreased cross-correlation at zero offset. However, the shadowing effect also causes other artifacts in the auto and cross-correlation of the recorded neurons. These artifacts are significant mainly in brain areas with high firing rate or increased firing synchrony leading to a high probability of spike overlap. Cross correlation of cells recorded from the same electrodes tends to reflect the autocorrelation functions of the two cells, even when there are no functional interactions between the cells. Therefore, the cross-correlation function tends to have a short-term (about the length of the refractory period) peak. A long-term (hundreds of milliseconds to a few seconds) trough in the cross-correlation can be seen in cells with bursting and pausing activities recorded from the same electrode. Even the autocorrelation functions of the recorded neurons feature firing properties of other neurons recorded from the same electrode. Examples of these effects are given from our recordings in the globus pallidus of behaving primates and from the literature. Results of simulations of independent simple model neurons exhibit the same properties as the recorded neurons. The effect is analyzed and can be estimated to enable better evaluation of the underlying firing patterns and the actual synchronization of neighboring neurons recorded by a single electrode.

Acute phase proteins and clinical synovitis activity in patients with rheumatoid arthritis.

A number of laboratory variables, including Hb., ESR and several phase proteins, fluctuated in concord with the clinical signs of synovitis activity in patients with rheumatoid arthritis during a controlled study of 3 disease-modifying anti-rheumatic drugs (DMARD). The correlation between laboratory variables and clinical synovitis was significant in a large patient population but the correlation coefficients were not of such magnitude that any of the laboratory variables reflected clinical synovitis activity in a reliable manner in the individual patients. In patients treated with azathioprine, the response of the Hb, (and consequently of the ESR), was reduced compared to patients given other DMARD. This phenomenon was caused by the bone marrow suppressing effect of azathioprine. However, the effect of azathioprine on the clinical synovitis activity did not differ from that of the 2 other drugs. Similar results were found by reviewing the literature about controlled trials of DMARD. In the present trial the clinical evaluation was performed under optimal conditions. In daily clinical practice the evaluations of the joints may be less than optimal since they may be performed by different rheumatologists with varying experience. Consequently, it may be difficult to do without the unreliable laboratory variables mentioned in the routine assessments of disease activity, unless the quality of routine evaluations of synovitis activity is improved considerably.

Influence of previous gold treatment and other patient variables on outcome of treatment with disease modifying anti-rheumatic drugs (DMARD) in patients with rheumatoid arthritis.

Based on a 2-year controlled double-blind trial of levamisole, penicillamine, and azathioprine (L, P, and A), a computer aided search for predictive factors of outcome was instituted. Already at month 4 several indicators of synovitis activity were able to discriminate between patients staying in the trial for 24 months and patients whose treatment was discontinued before that time. Patients who had previously received gold therapy responded less favourably to L, P, and A than those who had not received gold. This reduction of response was more pronounced in gold resistant patients than in patients whose gold treatment had been discontinued for other reasons. The only phase protein (of several) with a predictive value was haptoglobin. If, after 4 months of treatment, haptoglobin did not normalize, this finding indicated a lack of response to treatment or a deterioration of synovitis activity during the following 4 months. The response to treatment was not influenced by HLA-types, sex, age, or clinical synovitis, disease duration, functional or anatomical aberrations at the start of treatment. The shape of the response curve as reflected by means of monthly measurements of serum-albumin and ESR was not related to disease duration, HLA-types, or previous gold treatment.

Reinforcement-driven dimensionality reduction--a model for information processing in the basal ganglia.

Although anatomical studies of the basal ganglia show the existence of extensive convergence and lateral inhibitory connections, physiological studies failed to show correlated neural activity or lateral interaction in these nuclei. These seemingly contradictory results could be explained with a model in which the basal ganglia reduce the dimensionality of cortical information using optimal extraction methods. Simulations of this model predict a transient change in the efficacy of the feed-forward and lateral synapses following changes in reinforcement signal, causing an increase in correlated firing rates. This process ultimately restores the steady-state situation with diminished efficacy of lateral inhibition and no correlation of firing. Our experimental results confirm the model's predictions: rate correlations show a drastic decrease between the input stage (cortex) and output stage (pallidum). Moreover, preliminary analysis revealed that pallidal correlations show a transient increase following discrepancies between the animal's predictions and reality. We therefore propose that by using a reinforcement-driven dimensionality reduction process the basal ganglia achieve efficient extraction of cortical salient information that may then be used by the frontal cortex for execution and planning of forthcoming actions.

Magnetic stimulation intensity modulates motor inhibition.

Repetitive transcranial magnetic stimulation (rTMS) is a standard tool in neuroscience research and therapy. Here we study one rTMS property that has not received adequate attention, the interaction of subthreshold intensity stimulation and low frequencies. We applied 1Hz rTMS over the motor cortex at three intensities, 40%, 80% and 100% of the resting motor threshold (rMT), and measured cortical excitability before and after the stimulation sessions. When comparing motor evoked potential (MEP) measured from the abductor pollicis brevis (APB) muscle before and after rTMS stimulation, we found that low intensity (40% MT) stimulation significantly decreased MEP magnitude, some smaller (non-significant) inhibition was found for the 80% MT intensity and increased MEP was found for the high intensity (100% MT) stimulation. Our results indicate that when explaining the input-output relationship of motor cortex induced activation as an intensity-dependent function, there might be a need to split it into separate functions associated with separate processes mediated by different cell types such as interneurons, pyramidal neurons and others.

Revealing neuronal functional organization through the relation between multi-scale oscillatory extracellular signals.

The spatial organization of neuronal elements and their connectivity make up the substrate underlying the information processing carried out in the networks they form. Conventionally, anatomical findings make the initial structure which later combines with superimposed neurophysiological information to create a functional organization map. The most common neurophysiological measure is the single neuron spike train extracted from an extracellular recording. This single neuron firing pattern provides valuable clues on information processing in a given brain area; however, it only gives a sparse and focal view of this process. Even with the increase in number of simultaneously recorded neurons, inference on their large-scale functional organization remains problematic. We propose a method of utilizing additional information derived from the same extracellular recording to generate a more comprehensive picture of neuronal functional organization. This analysis is based on the relationship between the oscillatory activity of single neurons and their neighboring neuronal populations. Two signals that reflect the multiple scales of neuronal populations are used to complement the single neuron spike train: (1) the high-frequency background unit activity representing the spiking activity of small localized sub-populations and (2) the low-frequency local field potential that represents the synaptic input to a larger global population. The three coherences calculated between pairs of these three signals arising from a single source of extracellular recording are then used to infer mosaic representations of the functional neuronal organization. We demonstrate this methodology on experimental data and on simulated leaky integrate-and-fire neurons.

On individual reference intervals based on a longitudinal study of plasma proteins and lipids in healthy subjects, and their possible clinical application.

In a longitudinal study, we determined interindividual and intra-individual variation in 20 plasma proteins and lipids and in other blood constituents by analysis of variance. Blood from 20 healthy subjects was sampled monthly for six months, a rigorous blood-sampling technique being applied. The mean proportion of interindividual variation differed for each blood constituent, ranging from 22 to 91% of the total variation. The possible clinical application of individual reference intervals of this homeostatic model was demonstrated by the fact that they were exceeded in individual cases of upper respiratory tract infection. Concordance between individual reference intervals in healthy controls and in patients--as exemplified in two chronic diseases, multiple sclerosis and chronic inactive pyelonephritis--suggests that the use of individual intervals in (chronic) disease is valid, even when derived from healthy persons. Additionally, sex- and age-related differences were significant for some constituents.

The diagnostic value of alpha 1-antitrypsin globules in liver cells as a morphological marker of alpha 1-antitrypsin deficiency.

In order to determine the diagnostic value of alpha 1-antitrypsin (AAT) globules as a morphological marker of AAT-deficiency of the Pi-Z type, liver needle biopsies from a prospective series of 600 patients were stained with PAS after pretreatment with diastase and by indirect immunoperoxidase staining for AAT deposits. Serum AAT phenotypes of the patients were determined by means of isoelectric focusing. Thirty-two biopsies were from patients with the Pi-Z allele (31 MZ, 1 Z), and 568 biopsies from patients without the Pi-Z allele. AAT globules larger than 3 micron were found in 16 biopsies of which 15 were from patients with the Pi-Z allele (diagnostic specificity 0.94), whereas 20 of 26 biopsies with AAT globules larger than 1 micron were from Pi-Z patients (diagnostic specificity 0.77). Only 47% of the biopsies from patients with the Pi-Z allele contained AAT globules larger than 3 micron. Thus, although AAT globules larger than 3 micron are highly specific as a morphological marker of the Pi-Z allele, their rather infrequent occurrence in carriers of the Pi-Z allele indicates that all investigations concerning the correlation between AAT deficiency of the Pi-Z type and liver disease should be based on phenotyping of sera from all the patients.