Neural activity during a simple reaching task in macaques is counter to gating and rebound in basal ganglia-thalamic communication.

Task-related activity in the ventral thalamus, a major target of basal ganglia output, is often assumed to be permitted or triggered by changes in basal ganglia activity through gating- or rebound-like mechanisms. To test those hypotheses, we sampled single-unit activity from connected basal ganglia output and thalamic nuclei (globus pallidus-internus [GPi] and ventrolateral anterior nucleus [VLa]) in monkeys performing a reaching task. Rate increases were the most common peri-movement change in both nuclei. Moreover, peri-movement changes generally began earlier in VLa than in GPi. Simultaneously recorded GPi-VLa pairs rarely showed short-time-scale spike-to-spike correlations or slow across-trials covariations, and both were equally positive and negative. Finally, spontaneous GPi bursts and pauses were both followed by small, slow reductions in VLa rate. These results appear incompatible with standard gating and rebound models. Still, gating or rebound may be possible in other physiological situations: simulations show how GPi-VLa communication can scale with GPi synchrony and GPi-to-VLa convergence, illuminating how synchrony of basal ganglia output during motor learning or in pathological conditions may render this pathway effective. Thus, in the healthy state, basal ganglia-thalamic communication during learned movement is more subtle than expected, with changes in firing rates possibly being dominated by a common external source.

Subthalamic Nucleus Activity Influences Sensory and Motor Cortex during Force Transduction.

The subthalamic nucleus (STN) is proposed to participate in pausing, or alternately, in dynamic scaling of behavioral responses, roles that have conflicting implications for understanding STN function in the context of deep brain stimulation (DBS) therapy. To examine the nature of event-related STN activity and subthalamic-cortical dynamics, we performed primary motor and somatosensory electrocorticography while subjects (n = 10) performed a grip force task during DBS implantation surgery. Phase-locking analyses demonstrated periods of STN-cortical coherence that bracketed force transduction, in both beta and gamma ranges. Event-related causality measures demonstrated that both STN beta and gamma activity predicted motor cortical beta and gamma activity not only during force generation but also prior to movement onset. These findings are consistent with the idea that the STN participates in motor planning, in addition to the modulation of ongoing movement. We also demonstrated bidirectional information flow between the STN and somatosensory cortex in both beta and gamma range frequencies, suggesting robust STN participation in somatosensory integration. In fact, interactions in beta activity between the STN and somatosensory cortex, and not between STN and motor cortex, predicted PD symptom severity. Thus, the STN contributes to multiple aspects of sensorimotor behavior dynamically across time.

Subthalamic Nucleus and Sensorimotor Cortex Activity During Speech Production.

The sensorimotor cortex is somatotopically organized to represent the vocal tract articulators such as lips, tongue, larynx, and jaw. How speech and articulatory features are encoded at the subcortical level, however, remains largely unknown. We analyzed LFP recordings from the subthalamic nucleus (STN) and simultaneous electrocorticography recordings from the sensorimotor cortex of 11 human subjects (1 female) with Parkinson's disease during implantation of deep-brain stimulation (DBS) electrodes while they read aloud three-phoneme words. The initial phonemes involved either articulation primarily with the tongue (coronal consonants) or the lips (labial consonants). We observed significant increases in high-gamma (60-150 Hz) power in both the STN and the sensorimotor cortex that began before speech onset and persisted for the duration of speech articulation. As expected from previous reports, in the sensorimotor cortex, the primary articulators involved in the production of the initial consonants were topographically represented by high-gamma activity. We found that STN high-gamma activity also demonstrated specificity for the primary articulator, although no clear topography was observed. In general, subthalamic high-gamma activity varied along the ventral-dorsal trajectory of the electrodes, with greater high-gamma power recorded in the dorsal locations of the STN. Interestingly, the majority of significant articulator-discriminative activity in the STN occurred before that in sensorimotor cortex. These results demonstrate that articulator-specific speech information is contained within high-gamma activity of the STN, but with different spatial and temporal organization compared with similar information encoded in the sensorimotor cortex.SIGNIFICANCE STATEMENT Clinical and electrophysiological evidence suggest that the subthalamic nucleus (STN) is involved in speech; however, this important basal ganglia node is ignored in current models of speech production. We previously showed that STN neurons differentially encode early and late aspects of speech production, but no previous studies have examined subthalamic functional organization for speech articulators. Using simultaneous LFP recordings from the sensorimotor cortex and the STN in patients with Parkinson's disease undergoing deep-brain stimulation surgery, we discovered that STN high-gamma activity tracks speech production at the level of vocal tract articulators before the onset of vocalization and often before related cortical encoding.

Subthalamic Nucleus Neurons Differentially Encode Early and Late Aspects of Speech Production.

Basal ganglia-thalamocortical loops mediate all motor behavior, yet little detail is known about the role of basal ganglia nuclei in speech production. Using intracranial recording during deep brain stimulation surgery in humans with Parkinson's disease, we tested the hypothesis that the firing rate of subthalamic nucleus neurons is modulated in sync with motor execution aspects of speech. Nearly half of 79 unit recordings exhibited firing-rate modulation during a syllable reading task across 12 subjects (male and female). Trial-to-trial timing of changes in subthalamic neuronal activity, relative to cue onset versus production onset, revealed that locking to cue presentation was associated more with units that decreased firing rate, whereas locking to speech onset was associated more with units that increased firing rate. These unique data indicate that subthalamic activity is dynamic during the production of speech, reflecting temporally-dependent inhibition and excitation of separate populations of subthalamic neurons.SIGNIFICANCE STATEMENT The basal ganglia are widely assumed to participate in speech production, yet no prior studies have reported detailed examination of speech-related activity in basal ganglia nuclei. Using microelectrode recordings from the subthalamic nucleus during a single-syllable reading task, in awake humans undergoing deep brain stimulation implantation surgery, we show that the firing rate of subthalamic nucleus neurons is modulated in response to motor execution aspects of speech. These results are the first to establish a role for subthalamic nucleus neurons in encoding of aspects of speech production, and they lay the groundwork for launching a modern subfield to explore basal ganglia function in human speech.

Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement.

Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinson's disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate.NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also demonstrate, for the first time in humans, a mechanism through which the premotor and sensory cortices are functionally connected to the STN.

Primary motor cortex of the parkinsonian monkey: altered encoding of active movement.

Abnormalities in the movement-related activation of the primary motor cortex (M1) are thought to be a major contributor to the motor signs of Parkinson's disease. The existing evidence, however, variably indicates that M1 is under-activated with movement, overactivated (due to a loss of functional specificity) or activated with abnormal timing. In addition, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those gaps in knowledge were addressed by studying the extracellular activity of antidromically-identified lamina 5b pyramidal-tract type neurons (n = 153) and intratelencephalic-type corticostriatal neurons (n = 126) in the M1 of two monkeys as they performed a step-tracking arm movement task. We compared movement-related discharge before and after the induction of parkinsonism by administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and quantified the spike rate encoding of specific kinematic parameters of movement using a generalized linear model. The fraction of M1 neurons with movement-related activity declined following MPTP but only marginally. The strength of neuronal encoding of parameters of movement was reduced markedly (mean 29% reduction in the coefficients from the generalized linear model). This relative decoupling of M1 activity from kinematics was attributable to reductions in the coefficients that estimated the spike rate encoding of movement direction (-22%), speed (-40%), acceleration (-49%) and hand position (-33%). After controlling for MPTP-induced changes in motor performance, M1 activity related to movement itself was reduced markedly (mean 36% hypoactivation). This reduced activation was strong in pyramidal tract-type neurons (-50%) but essentially absent in corticostriatal neurons. The timing of M1 activation was also abnormal, with earlier onset times, prolonged response durations, and a 43% reduction in the prevalence of movement-related changes beginning in the 150-ms period that immediately preceded movement. Overall, the results are consistent with proposals that under-activation and abnormal timing of movement-related activity in M1 contribute to parkinsonian motor signs but are not consistent with the idea that a loss of functional specificity plays an important role. Given that pyramidal tract-type neurons form the primary efferent pathway that conveys motor commands to the spinal cord, the dysfunction of movement-related activity in pyramidal tract-type neurons is likely to be a central factor in the pathophysiology of parkinsonian motor signs.

Movement-related dynamics of cortical oscillations in Parkinson's disease and essential tremor.

Recent electrocorticography data have demonstrated excessive coupling of beta-phase to gamma-amplitude in primary motor cortex and that deep brain stimulation facilitates motor improvement by decreasing baseline phase-amplitude coupling. However, both the dynamic modulation of phase-amplitude coupling during movement and the general cortical neurophysiology of other movement disorders, such as essential tremor, are relatively unexplored. To clarify the relationship of these interactions in cortical oscillatory activity to movement and disease state, we recorded local field potentials from hand sensorimotor cortex using subdural electrocorticography during a visually cued, incentivized handgrip task in subjects with Parkinson's disease (n = 11), with essential tremor (n = 9) and without a movement disorder (n = 6). We demonstrate that abnormal coupling of the phase of low frequency oscillations to the amplitude of gamma oscillations is not specific to Parkinson's disease, but also occurs in essential tremor, most prominently for the coupling of alpha to gamma oscillations. Movement kinematics were not significantly different between these groups, allowing us to show for the first time that robust alpha and beta desynchronization is a shared feature of sensorimotor cortical activity in Parkinson's disease and essential tremor, with the greatest high-beta desynchronization occurring in Parkinson's disease and the greatest alpha desynchronization occurring in essential tremor. We also show that the spatial extent of cortical phase-amplitude decoupling during movement is much greater in subjects with Parkinson's disease and essential tremor than in subjects without a movement disorder. These findings suggest that subjects with Parkinson's disease and essential tremor can produce movements that are kinematically similar to those of subjects without a movement disorder by reducing excess sensorimotor cortical phase-amplitude coupling that is characteristic of these diseases.

Movement-related discharge in the macaque globus pallidus during high-frequency stimulation of the subthalamic nucleus.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson's disease. Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an "informational lesion," whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task-related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism.

Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex.

Although there is general consensus that deep brain stimulation (DBS) yields substantial clinical benefit in patients with Parkinson's disease (PD), the therapeutic mechanism of DBS remains a matter of debate. Recent studies demonstrate that DBS targeting the globus pallidus internus (GPi-DBS) suppresses pathological oscillations in firing rate and between-cell spike synchrony in the vicinity of the electrode but has negligible effects on population-level firing rate or the prevalence of burst firing. The present investigation examines the downstream consequences of GPi-DBS at the level of the primary motor cortex (M1). Multielectrode, single cell recordings were conducted in the M1 of two parkinsonian nonhuman primates (Macaca fasicularis). GPi-DBS that induced significant reductions in muscular rigidity also reduced the prevalence of both beta (12-30 Hz) oscillations in single unit firing rates and of coherent spiking between pairs of M1 neurons. In individual neurons, GPi-DBS-induced increases in mean firing rate were three times more common than decreases; however, averaged across the population of M1 neurons, GPi-DBS induced no net change in mean firing rate. The population-level prevalence of burst firing was also not affected by GPi-DBS. The results are consistent with the hypothesis that suppression of both pathological, beta oscillations and synchronous activity throughout the cortico-basal ganglia network is a major therapeutic mechanism of GPi-DBS.

Dopamine neurons encode errors in predicting movement trigger occurrence.

The capacity to anticipate the timing of events in a dynamic environment allows us to optimize the processes necessary for perceiving, attending to, and responding to them. Such anticipation requires neuronal mechanisms that track the passage of time and use this representation, combined with prior experience, to estimate the likelihood that an event will occur (i.e., the event's "hazard rate"). Although hazard-like ramps in activity have been observed in several cortical areas in preparation for movement, it remains unclear how such time-dependent probabilities are estimated to optimize response performance. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys during an arm-reaching task for which the foreperiod preceding the "go" signal varied randomly along a uniform distribution. After extended training, the monkeys' reaction times correlated inversely with foreperiod duration, reflecting a progressive anticipation of the go signal according to its hazard rate. Many dopamine neurons modulated their firing rates as predicted by a succession of hazard-related prediction errors. First, as time passed during the foreperiod, slowly decreasing anticipatory activity tracked the elapsed time as if encoding negative prediction errors. Then, when the go signal appeared, a phasic response encoded the temporal unpredictability of the event, consistent with a positive prediction error. Neither the anticipatory nor the phasic signals were affected by the anticipated magnitudes of future reward or effort, or by parameters of the subsequent movement. These results are consistent with the notion that dopamine neurons encode hazard-related prediction errors independently of other information.

Limited encoding of effort by dopamine neurons in a cost-benefit trade-off task.

Animals are thought to evaluate the desirability of action options using a unified scale that combines predicted benefits ("rewards"), costs, and the animal's internal motivational state. Midbrain dopamine neurons have long been associated with the reward part of this equation, but it is unclear whether these neurons also estimate the costs of taking an action. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys (Macaca mulatta) during a reaching task in which the energetic costs incurred (friction loads) and the benefits gained (drops of food) were manipulated independently. Although the majority of dopamine neurons encoded the upcoming reward alone, a subset predicted net utility of a course of action by signaling the expected reward magnitude discounted by the invested cost in terms of physical effort. In addition, the tonic activity of some dopamine neurons was slowly reduced in conjunction with the accumulated trials, which is consistent with the hypothesized role for tonic dopamine in the invigoration or motivation of instrumental responding. The present results shed light on an often-hypothesized role for dopamine in the regulation of the balance in natural behaviors between the energy expended and the benefits gained, which could explain why dopamine disorders, such as Parkinson's disease, lead to a breakdown of that balance.

Multifaceted aspects of chunking enable robust algorithms.

Sequence production tasks are a standard tool to analyze motor learning, consolidation, and habituation. As sequences are learned, movements are typically grouped into subsets or chunks. For example, most Americans memorize telephone numbers in two chunks of three digits, and one chunk of four. Studies generally use response times or error rates to estimate how subjects chunk, and these estimates are often related to physiological data. Here we show that chunking is simultaneously reflected in reaction times, errors, and their correlations. This multimodal structure enables us to propose a Bayesian algorithm that better estimates chunks while avoiding overfitting. Our algorithm reveals previously unknown behavioral structure, such as an increased error correlations with training, and promises a useful tool for the characterization of many forms of sequential motor behavior.

Axonal and synaptic failure suppress the transfer of firing rate oscillations, synchrony and information during high frequency deep brain stimulation.

High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for Parkinson's disease, but its effects on neural activity in basal ganglia circuits are not fully understood. DBS increases the excitation of STN efferents yet decouples STN spiking patterns from the spiking patterns of STN synaptic targets. We propose that this apparent paradox is resolved by recent studies showing an increased rate of axonal and synaptic failures in STN projections during DBS. To investigate this hypothesis, we combine in vitro and in vivo recordings to derive a computational model of axonal and synaptic failure during DBS. Our model shows that these failures induce a short term depression that suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information from STN to its synaptic targets. In particular, our computational model reproduces the widely reported suppression of parkinsonian ß oscillations and synchrony during DBS. Our results support the idea that short term depression is a therapeutic mechanism of STN DBS that works as a functional lesion by decoupling the somatic spiking patterns of STN neurons from spiking activity in basal ganglia output nuclei.

Detecting rhythmic spiking through the power spectra of point process model residuals.

Objective: Oscillations figure prominently as neurological disease hallmarks and neuromodulation targets. To detect oscillations in a neuron's spiking, one might attempt to seek peaks in the spike train's power spectral density (PSD) which exceed a flat baseline. Yet for a non-oscillating neuron, the PSD is not flat: The recovery period ("RP", the post-spike drop in spike probability, starting with the refractory period) introduces global spectral distortion. An established "shuffling" procedure corrects for RP distortion by removing the spectral component explained by the inter-spike interval (ISI) distribution. However, this procedure sacrifices oscillation-related information present in the ISIs, and therefore in the PSD. We asked whether point process models (PPMs) might achieve more selective RP distortion removal, thereby enabling improved oscillation detection. Approach: In a novel "residuals" method, we first estimate the RP duration (nr) from the ISI distribution. We then fit the spike train with a PPM that predicts spike likelihood based on the time elapsed since the most recent of any spikes falling within the preceding nr milliseconds. Finally, we compute the PSD of the model's residuals. Main results: We compared the residuals and shuffling methods' ability to enable accurate oscillation detection with flat baseline-assuming tests. Over synthetic data, the residuals method generally outperformed the shuffling method in classification of true- versus false-positive oscillatory power, principally due to enhanced sensitivity in sparse spike trains. In single-unit data from the internal globus pallidus (GPi) and ventrolateral anterior thalamus (VLa) of a parkinsonian monkey -- in which alpha-beta oscillations (8-30 Hz) were anticipated -- the residuals method reported the greatest incidence of significant alpha-beta power, with low firing rates predicting residuals-selective oscillation detection. Significance: These results encourage continued development of the residuals approach, to support more accurate oscillation detection. Improved identification of oscillations could promote improved disease models and therapeutic technologies.

A neurocomputational view of the effects of Parkinson's disease on speech production.

The purpose of this article is to review the scientific literature concerning speech in Parkinson's disease (PD) with reference to the DIVA/GODIVA neurocomputational modeling framework. Within this theoretical view, the basal ganglia (BG) contribute to several different aspects of speech motor learning and execution. First, the BG are posited to play a role in the initiation and scaling of speech movements. Within the DIVA/GODIVA framework, initiation and scaling are carried out by initiation map nodes in the supplementary motor area acting in concert with the BG. Reduced support of the initiation map from the BG in PD would result in reduced movement intensity as well as susceptibility to early termination of movement. A second proposed role concerns the learning of common speech sequences, such as phoneme sequences comprising words; this view receives support from the animal literature as well as studies identifying speech sequence learning deficits in PD. Third, the BG may play a role in the temporary buffering and sequencing of longer speech utterances such as phrases during conversational speech. Although the literature does not support a critical role for the BG in representing sequence order (since incorrectly ordered speech is not characteristic of PD), the BG are posited to contribute to the scaling of individual movements in the sequence, including increasing movement intensity for emphatic stress on key words. Therapeutic interventions for PD have inconsistent effects on speech. In contrast to dopaminergic treatments, which typically either leave speech unchanged or lead to minor improvements, deep brain stimulation (DBS) can degrade speech in some cases and improve it in others. However, cases of degradation may be due to unintended stimulation of efferent motor projections to the speech articulators. Findings of spared speech after bilateral pallidotomy appear to indicate that any role played by the BG in adult speech must be supplementary rather than mandatory, with the sequential order of well-learned sequences apparently represented elsewhere (e.g., in cortico-cortical projections).

Spatiotemporally-specific cortical-subthalamic coupling differentiates aspects of speech performance.

Speech provides a rich context for exploring human cortical-basal ganglia circuit function, but direct intracranial recordings are rare. We recorded electrocorticographic signals in the cortex synchronously with single units in the subthalamic nucleus (STN), a basal ganglia node that receives direct input from widespread cortical regions, while participants performed a syllable repetition task during deep brain stimulation (DBS) surgery. We discovered that STN neurons exhibited spike-phase coupling (SPC) events with distinct combinations of frequency, location, and timing that indexed specific aspects of speech. The strength of SPC to posterior perisylvian cortex predicted phoneme production accuracy, while that of SPC to perirolandic cortex predicted time taken for articulation Thus, STN-cortical interactions are coordinated via transient bursts of behavior-specific synchronization that involves multiple neuronal populations and timescales. These results both suggest mechanisms that support auditory-sensorimotor integration during speech and explain why firing-rate based models are insufficient for explaining basal ganglia circuit behavior.

Neural dynamics underlying self-control in the primate subthalamic nucleus.

The subthalamic nucleus (STN) is hypothesized to play a central role in neural processes that regulate self-control. Still uncertain, however, is how that brain structure participates in the dynamically evolving estimation of value that underlies the ability to delay gratification and wait patiently for a gain. To address that gap in knowledge, we studied the spiking activity of neurons in the STN of monkeys during a task in which animals were required to remain motionless for varying periods of time in order to obtain food reward. At the single-neuron and population levels, we found a cost-benefit integration between the desirability of the expected reward and the imposed delay to reward delivery, with STN signals that dynamically combined both attributes of the reward to form a single integrated estimate of value. This neural encoding of subjective value evolved dynamically across the waiting period that intervened after instruction cue. Moreover, this encoding was distributed inhomogeneously along the antero-posterior axis of the STN such that the most dorso-posterior-placed neurons represented the temporal discounted value most strongly. These findings highlight the selective involvement of the dorso-posterior STN in the representation of temporally discounted rewards. The combination of rewards and time delays into an integrated representation is essential for self-control, the promotion of goal pursuit, and the willingness to bear the costs of time delays.

Testing the contributions of striatal dopamine loss to the genesis of parkinsonian signs.

The diverse and independently-varying signs of Parkinson's disease (PD) are often attributed to one simple mechanism: degeneration of the dopaminergic innervation of the posterolateral striatum. However, growing recognition of the dopamine (DA) loss and other pathology in extra-striatal brain regions has led to uncertainty whether loss of DA in the striatum is sufficient to cause parkinsonian signs. We tested this hypothesis by infusing cis-flupenthixol (cis-flu; a broad-spectrum D1/D2 receptor antagonist) into different regions of the macaque putamen (3 hemispheres of 2 monkeys) while the animal performed a visually-cued choice reaction time task in which visual cues indicated the arm to reach with and the peripheral target to contact to obtain food reward. Following reward delivery, the animal was required to self-initiate release of the peripheral target and return of the chosen hand to its home position (i.e., without the benefit of external sensory cues or immediate rewards). Infusions of cis-flu at 15 of 26 sites induced prolongations of reaction time (9 of 15 cases), movement duration (6 cases), and/or dwell time of the hand at the peripheral target (8 cases). Dwell times were affected more severely (+95%) than visually-triggered reaction times or movement durations (+25% and +15%, respectively). Specifically, the animal's hand often 'froze' at the peripheral target for up to 25-s, similar to the akinetic freezing episodes observed in PD patients. Across injections, slowing of self-initiation did not correlate in severity with prolongations of visually-triggered reaction time or movement duration, although the latter two were correlated with each other. Episodes of slowed self-initiation appeared primarily in the arm contralateral to the injected hemisphere and were not associated with increased muscle co-contraction or global alterations in behavioral state (i.e., inattention or reduced motivation), consistent with the idea that these episodes reflected a fundamental impairment of movement initiation. We found no evidence for an anatomic topography within the putamen for the effects elicited. We conclude that acute focal blockade of DA transmission in the putamen is sufficient to induce marked akinesia-like impairments. Furthermore, different classes of impairments can be induced independently, suggesting that specific parkinsonian signs have unique pathophysiologic substrates.

Basal ganglia activity patterns in parkinsonism and computational modeling of their downstream effects.

The availability of suitable animal models and the opportunity to record electrophysiologic data in movement disorder patients undergoing neurosurgical procedures has allowed researchers to investigate parkinsonism-related changes in neuronal firing patterns in the basal ganglia and associated areas of the thalamus and cortex. These studies have shown that parkinsonism is associated with increased activity in the basal ganglia output nuclei, along with increases in burst discharges, oscillatory firing and synchronous firing patterns throughout the basal ganglia. Computational approaches have the potential to play an important role in the interpretation of these data. Such efforts can provide a formalized view of neuronal interactions in the network of connections between the basal ganglia, thalamus, and cortex, allow for the exploration of possible contributions of particular network components to parkinsonism, and potentially result in new conceptual frameworks and hypotheses that can be subjected to biological testing. It has proven very difficult, however, to integrate the wealth of the experimental findings into coherent models of the disease. In this review, we provide an overview of the abnormalities in neuronal activity that have been associated with parkinsonism. Subsequently, we discuss some particular efforts to model the pathophysiologic mechanisms that may link abnormal basal ganglia activity to the cardinal parkinsonian motor signs and may help to explain the mechanisms underlying the therapeutic efficacy of deep brain stimulation for Parkinson's disease. We emphasize the logical structure of these computational studies, making clear the assumptions from which they proceed and the consequences and predictions that follow from these assumptions.

Primary motor cortex of the parkinsonian monkey: differential effects on the spontaneous activity of pyramidal tract-type neurons.

Dysfunction of primary motor cortex (M1) is thought to contribute to the pathophysiology of parkinsonism. What specific aspects of M1 function are abnormal remains uncertain, however. Moreover, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those questions were addressed by studying the resting activity of intratelencephalic-type corticostriatal neurons (CSNs) and distant-projecting lamina 5b pyramidal-tract type neurons (PTNs) in the macaque M1 before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Contrary to previous reports, the general population of M1 neurons (i.e., PTNs, CSNs, and unidentified neurons) showed reduced baseline firing rates following MPTP, attributable largely to a marked decrease in PTN firing rates. CSN firing rates were unmodified. Although burstiness and firing patterns remained constant in M1 neurons as a whole and CSNs in particular, PTNs became more bursty post-MPTP and less likely to fire in a regular-spiking pattern. Rhythmic spiking (found in PTNs predominantly) occurred at beta frequencies (14-32 Hz) more frequently following MPTP. These results indicate that MPTP intoxication induced distinct modifications in the activity of different M1 neuronal subtypes. The particular susceptibility of PTNs suggests that PTN dysfunction may be an important contributor to the pathophysiology of parkinsonian motor signs.