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Hagai Bergman

Publications and source records attributed to Hagai Bergman.

At least 19 recordsLinked to original sources
PubMed2006

Basal ganglia oscillations and pathophysiology of movement disorders.

Low frequency rest tremor is one of the cardinal signs of Parkinson's disease and some of its animal models. Current physiological studies and models of the basal ganglia differ as to which aspects of neuronal activity are crucial to the pathophysiology of Parkinson's disease. There is evidence that neural oscillations and synchronization play a central role in the generation of the disease. However, parkinsonian tremor is not strictly correlated with the synchronous oscillations in the basal ganglia networks. Rather, abnormal basal ganglia output enforces abnormal thalamo-cortical processing leading to akinesia, the main negative symptom of Parkinson's disease. Parkinsonian tremor has probably evolved as a downstream compensatory mechanism.

Animals↗
PubMed2006

Dopamine replacement therapy does not restore the full spectrum of normal pallidal activity in the 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine primate model of Parkinsonism.

Current physiological studies emphasize the role of neuronal oscillations and synchronization in the pathophysiology of Parkinson's disease; however, little is known about their specific roles in the neuronal substrate of dopamine replacement therapy (DRT). We investigated oscillatory activity and correlations throughout the different states of levodopa-naive parkinsonism as well as "Off-On" and dyskinetic states of DRT in the external globus pallidum (GPe) of tremulous (vervet) and rigid-akinetic (macaque) monkeys and in the internal globus pallidum (GPi) of the vervet monkey. We found that, although oscillatory activity of cells and interneuronal correlation in both pallidal segments increases after induction of parkinsonism with 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) and decreases in response to DRT, important differences exist between the two pallidal segments. In the GPi, the fraction of oscillatory cells and relative power of oscillations were significantly higher than in the GPe, and the dominant frequency was within the range of 7.5-13.5 Hz compared with a range of 4.5-7.5 Hz within the GPe. The interneuronal correlations were mostly oscillatory in the GPi, whereas at least half are non-oscillatory in the GPe. We demonstrate that the tremor characteristics after exposure to DRT do not resemble those of the normal or the levodopa-naive state. Moreover, although DRT reverses the MPTP-induced neuronal changes (rate, pattern, and pairwise correlations), the balance between GPe and GPi fails to restore. We therefore suggest that this imbalance reflects additional abnormal organization of the basal ganglia networks in response to dopamine replacement and may constitute the physiological substrate of the limitations and side effects of chronic DRT.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Midbrain dopamine neurons encode decisions for future action.

Current models of the basal ganglia and dopamine neurons emphasize their role in reinforcement learning. However, the role of dopamine neurons in decision making is still unclear. We recorded from dopamine neurons in monkeys engaged in two types of trial: reference trials in an instructed-choice task and decision trials in a two-armed bandit decision task. We show that the activity of dopamine neurons in the decision setting is modulated according to the value of the upcoming action. Moreover, analysis of the probability matching strategy in the decision trials revealed that the dopamine population activity and not the reward during reference trials determines choice behavior. Because dopamine neurons do not have spatial or motor properties, we conclude that immediate decisions are likely to be generated elsewhere and conveyed to the dopamine neurons, which play a role in shaping long-term decision policy through dynamic modulation of the efficacy of basal ganglia synapses.

Animals↗
PubMed2006

Competition between feedback loops underlies normal and pathological dynamics in the basal ganglia.

Experiments performed in normal animals suggest that the basal ganglia (BG) are crucial in motor program selection. BG are also involved in movement disorders. In particular, BG neuronal activity in parkinsonian animals and patients is more oscillatory and more synchronous than in normal individuals. We propose a new model for the function and dysfunction of the motor part of BG. We hypothesize that the striatum, the subthalamic nucleus, the internal pallidum (GPi), the thalamus, and the cortex are involved in closed feedback loops. The direct (cortex-striatum-GPi-thalamus-cortex) and the hyperdirect loops (cortex-subthalamic nucleus-GPi-thalamus-cortex), which have different polarities, play a key role in the model. We show that the competition between these two loops provides the BG-cortex system with the ability to perform motor program selection. Under the assumption that dopamine potentiates corticostriatal synaptic transmission, we demonstrate that, in our model, moderate dopamine depletion leads to a complete loss of action selection ability. High depletion can lead to synchronous oscillations. These modifications of the network dynamical state stem from an imbalance between the feedback in the direct and hyperdirect loops when dopamine is depleted. Our model predicts that the loss of selection ability occurs before the appearance of oscillations, suggesting that Parkinson's disease motor impairments are not directly related to abnormal oscillatory activity. Another major prediction of our model is that synchronous oscillations driven by the hyperdirect loop appear in BG after inactivation of the striatum.

Action Potentials↗
PubMed2006

Local shuffling of spike trains boosts the accuracy of spike train spectral analysis.

Spectral analysis of neuronal spike trains is an important tool in understanding the characteristics of neuronal activity by providing insights into normal and pathological periodic oscillatory phenomena. However, the refractory period creates high-frequency modulations in spike-train firing rate because any rise in the discharge rate causes a descent in subsequent time bins, leading to multifaceted modifications in the structure of the spectrum. Thus the power spectrum of the spiking activity (autospectrum) displays elevated energy in high frequencies relative to the lower frequencies. The spectral distortion is more dominant in neurons with high firing rates and long refractory periods and can lead to reduced identification of low-frequency oscillations (such as the 5- to 10-Hz burst oscillations typical of Parkinsonian basal ganglia and thalamus). We propose a compensation process that uses shuffling of interspike intervals (ISIs) for reliable identification of oscillations in the entire frequency range. This compensation is further improved by local shuffling, which preserves the slow changes in the discharge rate that may be lost in global shuffling. Cross-spectra of pairs of neurons are similarly distorted regardless of their correlation level. Consequently, identification of low-frequency synchronous oscillations, even for two neurons recorded by a single electrode, is improved by ISI shuffling. The ISI local shuffling is computed with confidence limits that are based on the first-order statistics of the spike trains, thus providing a reliable estimation of auto- and cross-spectra of spike trains and making it an optimal tool for physiological studies of oscillatory neuronal phenomena.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Real-time refinement of subthalamic nucleus targeting using Bayesian decision-making on the root mean square measure.

The subthalamic nucleus (STN) is a major target for treatment of advanced Parkinson's disease patients undergoing deep brain stimulation surgery. Microelectrode recording (MER) is used in many cases to identify the target nucleus. A real-time procedure for identifying the entry and exit points of the STN would improve the outcome of this targeting procedure. We used the normalized root mean square (NRMS) of a short (5 seconds) MER sampled signal and the estimated anatomical distance to target (EDT) as the basis for this procedure. Electrode tip location was defined intraoperatively by an expert neurophysiologist to be before, within, or after the STN. Data from 46 trajectories of 27 patients were used to calculate the Bayesian posterior probability of being in each of these locations, given RMS-EDT pair values. We tested our predictions on each trajectory using a bootstrapping technique, with the rest of the trajectories serving as a training set and found the error in predicting the STN entry to be (mean +/- SD) 0.18 +/- 0.84, and 0.50 +/- 0.59 mm for STN exit point, which yields a 0.30 +/- 0.28 mm deviation from the expert's target center. The simplicity and computational ease of RMS calculation, its spike sorting-independent nature and tolerance to electrode parameters of this Bayesian predictor, can lead directly to the development of a fully automated intraoperative physiological procedure for the refinement of imaging estimates of STN borders.

Bayes Theorem↗
PubMed2005

Emerging patterns of neuronal responses in supplementary and primary motor areas during sensorimotor adaptation.

Acquisition and retention of sensorimotor skills have been extensively investigated psychophysically, but little is known about the underlying neuronal mechanisms. Here we examine the evolution of neural activity associated with adaptation to new kinematic tasks in two cortical areas: the caudal supplementary motor area (SMA proper), and the primary motor cortex (MI). We investigate the hypothesis that adaptation starts at premotor areas, i.e., higher in the hierarchy of computation, until a stable representation is formed in primary areas. In accordance with previous studies, we found that adaptation can be characterized by two phases: an early phase that is accompanied by fast and substantial reduction of errors, followed by a late phase with slower and more moderate improvements in behavior. We used unsupervised clustering to separate the activity of the single cells into groups of cells with similar response patterns, under the assumption that each such subpopulation forms a functional unit. We specifically observed the number of clusters in each cortical area during early and late phases of the adaptation and found that the number of clusters is higher in the SMA during early phases of adaptation. In contrast, a higher number of clusters was observed in MI only during late phases. Our results suggest a new approach to analyze responses of large populations of neurons and use it to show a hierarchy of dynamic reorganization of functional groups during adaptation.

Adaptation, Physiological↗
PubMed2005

Age and medication effects on rhythmic responses in ADHD: possible oscillatory mechanisms?

Voluntary motor responses in children with attention-deficit hyperactivity disorder (ADHD) may reflect underlying neuronal oscillatory mechanisms. The aims of this study were: (1) to corroborate the presence of rhythmic motor abnormalities on tapping test in children with attention-deficit hyperactivity disorder, shown in previous studies; (2) to delineate the characteristics of ADHD children demonstrating these rhythmic abnormalities; (3) to assess the impact of methylphenidate (Ritalin) on this abnormal motor phenomenon. The study was designed in a double blind manner. Sixty-four ADHD children aged 6-12 years and 60 matched controls underwent a finger tapping test (1-5 Hz). We measured the abnormal rhythmic tapping with and without methylphenidate treatment in a double blind design. Conventional statistical analysis was used to assess the correlation of the presence of motor abnormality with various clinical characteristics (such as degree of hyperactivity/impulsivity). Fifty-six percent of children with ADHD compared to 8% of controls demonstrated abnormal rhythmic responses at a mean frequency of 3.1+/-0.9 Hz. These erroneous voluntary movements were more common in children with a greater degree of hyperactivity, in younger children but not significantly altered by methylphenidate treatment. Surprisingly, abnormal rhythmic responses showed less variability than found for responses for which the tapping was adequately paced, suggesting different motor control processes for normal and abnormal paced tapping. We speculate that rhythmic tapping responses reflect abnormal oscillatory mechanisms involved in ADHD, exacerbated in younger children with ADHD and in those in whom the hyperactivity/impulsivity is more pronounced.

Age Factors↗
PubMed2005

Physiological studies of information processing in the normal and Parkinsonian basal ganglia: pallidal activity in Go/No-Go task and following MPTP treatment.

Understanding the role of the basal ganglia in day to day behavior is critical for a better understanding of the role of these structures in pathological states--such as Parkinson's disease. To elucidate this connection, we studied pallidal activity in a monkey performing a delayed release Go/No-Go task and in monkeys treated with the dopaminergic neurotoxin--MPTP. We compared the results with the predictions of the action selection and reinforcement driven dimensionality reduction models of the basal ganglia. The fraction of responding pallidal neurons, as well as the ratio of positive to negative responses, were equal in the Go and the No-Go modes. The fraction of pallidal neurons with significant responses following the trigger signal (19/26) was higher than that following the visual cue (11/26); however, the fraction of negative responses was significantly higher following the cue signal (47%) than that following the trigger signal (22%). Most (80%) of the cue responses were sensitive to the laterality of the cue, whereas only 25% of the responses following the trigger signal were sensitive to the cue or movement direction. Finally, pallidal spiking activity was not correlated in the normal behaving monkey, and became highly synchronized following MPTP treatment. We conclude that pallidal activity in the normal monkey is consistent with the model of action selection, assuming that action is selected following the visual cue. However, the reinforcement driven dimensionality reduction model is consistent with both the Go/No-Go responses and the normal/MPTP correlation studies.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Reduced basal activity and increased functional homogeneity in sensorimotor and striatum of a Parkinson's disease rat model: a functional MRI study.

Functional neuro-imaging studies of Parkinson's disease (PD) patients and animal models show inconsistent cortical responses to sensory stimulation: some present increased sensorimotor cortex activation contradicting classical basal ganglia-cortex circuitry models, whereas others show decreased activation. As functional neuro-imaging activation is defined as the signal difference between stimulation ON and stimulation OFF, reduced 'activation' can point to either increased neuronal activity during stimulation ON or to decreased basal neuronal activity during stimulation OFF. A unique non-invasive method that uses the temporal and the spatial variances of functional magnetic resonance imaging signal is employed here to compare basal neuronal activity levels and 'functional homogeneity' between groups. Based on the assumption that the temporal variance reflects average neuronal activity, the variance of activity within a predefined region is defined as the region's 'functional homogeneity', which is assumed to estimate neuronal synchronization. Comparison of temporal and spatial variances of the sensorimotor cortex and the striatum in the 6-hydroxydopamine (6-OHDA) PD rat model and a control rat group show bilaterally decreased temporal and spatial variances in the 6-OHDA rat group, suggesting bilateral reduction of basal neuronal activity levels together with an increase in local neuronal synchronization in line with classical basal ganglia-cortex circuit models.

Adrenergic Agents↗
PubMed2004

Identifying subtle interrelated changes in functional gene categories using continuous measures of gene expression.

MOTIVATION: Analysis of large-scale expression data is greatly facilitated by the availability of gene ontologies (GOs). Many current methods test whether sets of transcripts annotated with specific ontology terms contain an excess of 'changed' transcripts. This approach suffers from two main limitations. First, since gene expression is continuous rather than discrete, designating a gene as changed or unchanged is arbitrary and oblivious to the actual magnitude of the change. Second, by considering only the number of changed genes, finer changes in expression patterns associated with the category may be ignored. Since genes generally participate in multiple networks, widespread and subtle modifications in expression patterns are at least as important as extreme increases/decreases of a few genes. RESULTS: Numerical simulations confirm that incorporating continuous measures of gene expression for all measured transcripts yields detection of considerably more subtle changes. Applying continuous measures to microarray data from brains of mice injected with the Parkinsonian neurotoxin, MPTP, enables detection of changes in various biologically relevant GO terms, many of which are overlooked by discrete approaches.

Algorithms↗
PubMed2004

Independent coding of movement direction and reward prediction by single pallidal neurons.

Associating action with its reward value is a basic ability needed by adaptive organisms and requires the convergence of limbic, motor, and associative information. To chart the basal ganglia (BG) involvement in this association, we recorded the activity of 61 well isolated neurons in the external segment of the globus pallidus (GPe) of two monkeys performing a probabilistic visuomotor task. Our results indicate that most (96%) neurons responded to multiple phases of the task. The activity of many (34%) pallidal neurons was modulated solely by direction of movement, and the activity of only a few (3%) pallidal neurons was modulated exclusively by reward prediction. However, the activity of a large number (41%) of single pallidal neurons was comodulated by both expected trial outcome and direction of arm movement. The information carried by the neuronal activity of single pallidal neurons dynamically changed as the trial progressed. The activity was predominantly modulated by both outcome prediction and future movement direction at the beginning of trials and became modulated mainly by movement-direction toward the end of trials. GPe neurons can either increase or decrease their discharge rate in response to predicted future reward. The effects of movement-direction and reward probability on neural activity are linearly summed and thus reflect two independent modulations of pallidal activity. We propose that GPe neurons are uniquely suited for independent processing of a multitude of parameters. This is enabled by the funnel-structure characteristic of the BG architecture, as well as by the anatomical and physiological properties of GPe neurons.

Action Potentials↗
PubMed2004

Acquisition and generalization of visuomotor transformations by nonhuman primates.

The kinematics of straight reaching movements can be specified vectorially by the direction of the movement and its extent. To explore the representation in the brain of these two properties, psychophysical studies have examined learning of visuomotor transformations of either rotation or gain and their generalization. However, the neuronal substrates of such complex learning are only beginning to be addressed. As an initial step in ensuring the validity of such investigations, it must be shown that monkeys indeed learn and generalize visuomotor transformations in the same manner as humans. Here, we analyze trajectories and velocities of movements as monkeys adapt to either rotational or gain transformations. We used rotations with different signs and magnitudes, and gains with different signs, and analyzed transfer of learning to untrained movements. The results show that monkeys can adapt to both types of transformation with a time course that resembles human learning. Analysis of the aftereffects reveals that rotation is learned locally and generalizes poorly to untrained directions, whereas gain is learned more globally and can be transferred to other amplitudes. The results lend additional support to the hypothesis that reaching movements are learned locally but can be easily rescaled to other magnitudes by scaling the peak velocity. The findings also indicate that reaching movements in monkeys are planned and executed very similarly to those in humans. This validates the underlying presumption that neuronal recordings in primates can help elucidate the mechanisms of motor learning in particular and motor planning in general.

Animals↗
PubMed2004

Complex locking rather than complete cessation of neuronal activity in the globus pallidus of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primate in response to pallidal microstimulation.

High-frequency stimulation of the globus pallidus (GP) has emerged as a successful tool for treating Parkinson's disease and other motor disorders. However, the mechanism governing its therapeutic effect is still under debate. To shed light on the basic mechanism of deep brain stimulation (DBS), we performed microstimulation in the GP of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkey while recording with other microelectrodes in the same nucleus. We used robust methods to reduce the stimulus artifact, and 600-3000 repetitions of a single stimulus and of high-frequency short trains (10-40 stimuli), enabling high temporal resolution analysis of neural responses. Low-frequency stimulation yielded a typical three-stage response: short-term (2-3 msec duration) activity, followed by mid-term (15-25 msec) inhibition, and occasionally longer-term (30-40 msec) excitation. Trains of high-frequency stimuli elicited complex locking of the response to the stimuli in most neurons. The locking displayed a stereotypic temporal structure consisting of three short-duration (1-2 msec) phases: an initial (mean latency = 2.9 msec) excitation followed by an inhibition (4.6 msec) and a second excitation (6.3 msec). The change in the mean firing rate was mixed; the majority of the neurons displayed partial inhibition during the stimulus train. Slow inhibitory and excitatory multiphase changes in the firing rate were observed after the stimulus trains. The activity of neurons recorded simultaneously displayed rate correlations but no spike-to-spike correlations. Our results suggest that the effect of DBS on the GP is not complete inhibition but rather a complex reshaping of the temporal structure of the neuronal activity within that nucleus.

Animals↗
PubMed2004

Coincident but distinct messages of midbrain dopamine and striatal tonically active neurons.

Midbrain dopamine and striatal tonically active neurons (TANs, presumed acetylcholine interneurons) signal behavioral significance of environmental events. Since striatal dopamine and acetylcholine affect plasticity of cortico-striatal transmission and are both crucial to learning, they may serve as teachers in the basal ganglia circuits. We recorded from both neuronal populations in monkeys performing a probabilistic instrumental conditioning task. Both neuronal types respond robustly to reward-related events. Although different events yielded responses with different latencies, the responses of the two populations coincided, indicating integration at the target level. Yet, while the dopamine neurons' response reflects mismatch between expectation and outcome in the positive domain, the TANs are invariant to reward predictability. Finally, TAN pairs are synchronized, compared to a minority of dopamine neuron pairs. We conclude that the striatal cholinergic and dopaminergic systems carry distinct messages by different means, which can be integrated differently to shape the basal ganglia responses to reward-related events.

Acetylcholine↗
PubMed2004

Spike synchronization in the cortex/basal-ganglia networks of Parkinsonian primates reflects global dynamics of the local field potentials.

Cortical local field potentials (LFPs) reflect synaptic potentials and accordingly correlate with neuronal discharge. Because LFPs are coherent across substantial cortical areas, we hypothesized that cortical spike correlations could be predicted from them. Because LFPs recorded in the basal ganglia (BG) are also correlated with neuronal discharge and are clinically accessible in Parkinson's disease patients, we were interested in testing this hypothesis in the BG, as well. We recorded LFPs and unit discharge from multiple electrodes, which were placed in primary motor cortex or in the basal ganglia (striatum and pallidum) of two monkeys before and after rendering them parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We used the method of partial spectra to construct LFP predictors of the spike cross-correlation functions (CCFs). The predicted CCF is an estimate of the correlation between two neurons under the assumption that their association is explained solely by the association of each with the LFP recorded on a third electrode. In the normal condition, the predictors account for cortical rate covariations but not for the association among the tonically active neurons of the striatum. In the parkinsonian condition, with the appearance of 10 Hz oscillations throughout the cortex-basal ganglia networks, the LFP predictors account remarkably better for the CCFs in both the cortex and the basal ganglia. We propose that, in the parkinsonian condition, the cortex-basal ganglia networks are more tightly related to global modes of brain dynamics that are echoed in the LFP.

Action Potentials↗
PubMed2004

Discharge rate of substantia nigra pars reticulata neurons is reduced in non-parkinsonian monkeys with apomorphine-induced orofacial dyskinesia.

Involuntary movements (dyskinesia) are a common symptom of dopamine-replacement therapy in parkinsonian patients, neuroleptic drug treatment of mental patients, and tic disorders. Levodopa-induced dyskinesia has been shown to be associated with substantial reduction of firing rate in the internal part of the globus pallidus. This study characterizes the changes that occur in the activity of the substantia nigra pars reticulata (SNr) of non-parkinsonian (normal) monkeys with apomorphine (APO)-induced orofacial dyskinesia. We conducted extracellular recordings of SNr neurons of two monkeys before and after induction of orofacial dyskinesia by systemic administration of APO. Involuntary orofacial movements appeared a few minutes after the injections and lasted 20-40 min. Almost all recorded neurons changed their firing rate after APO injection (96%), and most declined (70%). The mean amplitude of decreases was also larger than that of increases (40 vs. 21% of the control rate). Changes in firing pattern were not significant on average. Pairs of SNr neurons were uncorrelated before APO injection, similar to the normal pallidum. However, unlike the increased correlations in the pallidum that accompany parkinsonism, orofacilal dyskinesia in non-parkinsonian monkeys was not associated with changes in correlation between SNr neurons. We conclude that normal monkeys treated with APO can model orofacial dyskinesia and tic disorders that are a consequence of dopaminergic over-activity. These symptoms appear to be more related to reduced firing rate of SNr neurons and thus to disinhibition of their targets, than to changes in pattern and synchronization.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗