Projections from basal ganglia to tegmentum: a subcortical route for explaining the pathophysiology of Parkinson’s disease signs?

Functional changes in the organisation of neuronal circuitries are generally used to explain parkinsonian motor symptoms and levodopa-induced dyskinesias. Based on information from histology and neurophysiological microrecordings of specific basal ganglia nuclei, the most widely accepted scheme is based on a central loop which starts in the cerebral cortex, makes multiple relays in the basal ganglia, and returns to the cerebral cortex. Transcranial magnetic stimulation studies, however, reveal no significant differences in the excitability of the motor cortex between normal subjects and patients with Parkinson’s disease. Furthermore, electrophysiological and audiospinal facilitation studies indicate that the activity of reticular nuclei is altered in Parkinson’s disease. It therefore appears that a circuit with the cortex as the only recipient of basal ganglia output is an oversimplification. This paper explores the relationships between various basal ganglia nuclei and proposes a subcortical pathway via which modifications in the basal ganglia may influence motor function.

     

Late emergence of synchronized oscillatory activity in the pallidum during progressive Parkinsonism

Parkinson's disease is known to result from basal ganglia dysfunction. Electrophysiological recordings in parkinsonian patients and animals have shown the emergence of abnormal synchronous oscillatory activity in the cortico-basal ganglia network in the pathological condition. In addition, previous studies pointed out an altered response pattern during movement execution in the pallidum of parkinsonian animals. To investigate the dynamics of these changes during disease progression and to relate them to the onset of the motor symptoms, we recorded spontaneous and movement-related neuronal activity in the internal pallidum of nonhuman primates during a progressive dopamine depletion process. Parkinsonian motor symptoms appeared progressively during the intoxication protocol, at the end of which both animals displayed severe akinesia, rigidity and postural abnormalities. Spontaneous firing rates did not vary significantly after intoxication. During the early phase of the protocol, voluntary movements were significantly slowed down and delayed. At the same time, the neuronal response to movement execution was modified and inhibitory responses disappeared. In contrast, the unitary and collective dynamic properties of spontaneous neuronal activity, as revealed by spectral and correlation analysis, remained unchanged during this period. Spontaneous correlated activity increased later, after animals became severely bradykinetic, whereas synchronous oscillatory activity appeared only after major motor symptoms developed. Thus, a causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely. The pathological disruption of movement-related activity in the basal ganglia appears to be a better correlate at least to bradykinesia and stands as the best candidate to account for this motor symptom.     

Repetitive transcranial magnetic stimulation (rTMS): insights into the treatment of Parkinson's disease by cortical stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a potent tool that can be used to modify activity of targeted cortical areas. Significant clinical effects have been obtained in patients with Parkinson's disease (PD) by stimulating different cortical regions with rTMS at inhibitory (low) or excitatory (high) frequency. These effects were thought to result from plastic changes in motor cortical networks. Actually cortical dysfunction has been documented in PD by neuroimaging and neurophysiologic studies showing either hypo- or hyper-activation of various brain areas. In addition, cortical excitability studies using transcranial magnetic stimulation disclosed significant alterations in intracortical facilitatory or inhibitory processes according to the resting state or to phases of movement preparation or execution. These observations clearly support the therapeutic potential of cortical neuromodulation in PD. Motor cortex stimulation could impact on any station within the cortico-basal ganglia-thalamo-cortical loops that are involved in motor control, providing alleviation of parkinsonian symptoms. Depending on the target, cortical stimulation might improve motor performance or other symptoms associated with PD, like depression. Clinical application of rTMS to treat PD patients is limited by the short duration of the effects beyond the time of stimulation, even if long-lasting improvements have been observed after repeated rTMS sessions. In any case, the place of cortical stimulation in the therapeutic management of PD patients remains to be determined, as an alternative or a complementary technique to deep brain stimulation. The rTMS technique could be used to better define the targets and the parameters of stimulation subsequently applied in chronic epidural stimulation.     

Dopamine depletion increases the power and coherence of beta-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat

Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) of untreated patients implanted with stimulation electrodes for the treatment of Parkinson's disease (PD) demonstrate strong coherence with the cortical electroencephalogram over the beta-frequency range (15-30 Hz). However, studies in animal models of PD emphasize increased temporal coupling in cortico-basal ganglia circuits at substantially lower frequencies, undermining the potential usefulness of these models. Here we show that 6-hydroxydopamine (6-OHDA) lesions of midbrain dopamine neurons are associated with significant increases in the power and coherence of beta-frequency oscillatory activity present in LFPs recorded from frontal cortex and STN of awake rats, as compared with the healthy animal. Thus, the pattern of synchronization between population activity in the STN and cortex in the 6-OHDA-lesioned rodent model of PD closely parallels that seen in the parkinsonian human. The peak frequency of coherent activity in the beta-frequency range was increased in lesioned animals during periods of spontaneous and sustained movement. Furthermore, administration of the dopamine receptor agonist apomorphine to lesioned animals suppressed beta-frequency oscillations, and increased coherent activity at higher frequencies in the cortex and STN, before producing the rotational behaviour indicative of successful lesion. Taken together, these results support a crucial role for dopamine in the modulation of population activity in cortico-basal ganglia circuits, whereby dopaminergic mechanisms effectively filter out synchronized, rhythmic activity at beta-frequencies at the systems level, and shift temporal couplings in these circuits to higher frequencies. These changes may be important in regulating movement.     

A new approach to understand the pathophysiology of Parkinson’s disease

Journal of Neurology - Here I introduce a dynamic model of the basal ganglia functions for the control of voluntary movement: information through major pathways in the cortico-basal ganglia loop,...     

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.     

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.     

The role of motor cortex in the pathophysiology of voluntary movement deficits associated with parkinsonism.

The characteristic motor deficits of parkinsonism result from dysfunction of the nigrostriatal dopaminergic system of the basal ganglia. These subcortical deficits must ultimately be expressed at the cortical and spinal motoneuron levels to result in the difficulty with initiation and execution of movements seen in parkinsonism. This article describes the neuronal activity of two motor cortical regions, the primary motor cortex (MI) and supplementary motor area (SMA), which receive the majority of basal ganglia outputs related to movement control through the ventral lateral thalamus. The kinematics and electromyographic characteristics of stimulus-initiated and self-initiated normal and parkinsonian movements are described, and the possible relation of SMA and MI task-related neuronal activity to the parkinsonian movement deficits is reviewed.     

Somatotopy in the basal ganglia: experimental and clinical evidence for segregated sensorimotor channels

Growing experimental and clinical evidence supports the notion that the cortico-basal ganglia–thalamo-cortical loops proceed along parallel circuits linking cortical and subcortical regions subserving the processing of sensorimotor, associative and affective tasks. In particular, there is evidence that a strict topographic segregation is maintained during the processing of sensorimotor information flowing from cortical motor areas to the sensorimotor areas of the basal ganglia. The output from the basal ganglia to the motor thalamus, which projects back to neocortical motor areas, is also organized into topographically segregated channels. This high degree of topographic segregation is demonstrated by the presence of a well-defined somatotopic organization in the sensorimotor areas of the basal ganglia. The presence of body maps in the basal ganglia has become clinically relevant with the increasing use of surgical procedures, such as lesioning or deep brain stimulation, which are selectively aimed at restricted subcortical targets in the sensorimotor loop such as the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi). The ability to ameliorate the motor control dysfunction without producing side effects related to interference with non-motor circuits subserving associative or affective processing requires the ability to target subcortical areas particularly involved in sensorimotor processing (currently achieved only by careful intraoperative microelectrode mapping). The goal of this article is to review current knowledge about the somatotopic segregation of basal ganglia sensorimotor areas and outline in detail what is known about their body maps.     

Facing the lack of anti-phase oscillation in the parafascicular nucleus after dopamine depletion

There is a large body of literature establishing that excessive neuronal synchronization and a shift in firing pattern within the cortico-basal ganglia circuit is implicated in Parkinson's disease (PD), yet a causal link between abnormal network oscillation and specific deficits in PD is lacking. It is proposed that enhanced (inhibitory) synchronous basal ganglia output could trigger anti-phase oscillatory activity in target thalamic nuclei, and entrain this abnormal synchronization within the cortico-basal ganglia loop through a reciprocal resonance mechanism. In a recent Experimental Neurology paper (2009), Parr-Brownlie et al. addressed this issue by assessing electrophysiological recordings in vivo in anesthetized control and dopamine-depleted rats induced by unilateral injection of 6-hydroxydopamine. Results from this study demonstrate that a shift in firing pattern in basal ganglia output neurons does not directly drive the distinctive oscillatory activity observed in the parafascicular nucleus after dopamine depletion. This commentary discusses possible mechanisms mediating the altered oscillatory activity found in the parafascicular nucleus after dopamine depletion and its link to the increased in-phase oscillations with synchronous firing in the subthalamic nucleus.     

Closed-loop cortical neuromodulation in Parkinson’s disease: An alternative to deep brain stimulation?

Deep brain stimulation (DBS) is usually performed to treat advanced Parkinson’s disease (PD) patients with electrodes permanently implanted in basal ganglia while the stimulator delivers electrical impulses continuously and independently of any feedback (open-loop stimulation). Conversely, in closed-loop stimulation, electrical stimulation is delivered as a function of neuronal activities recorded and analyzed online. There is an emerging development of closed-loop DBS in the treatment of PD and a growing discussion about proposing cortical stimulation rather than DBS for this purpose. Why does it make sense to “close the loop” to treat parkinsonian symptoms? Could closed-loop stimulation applied to the cortex become a valuable therapeutic strategy for PD? Can mathematical modeling contribute to the development of this technique? We review the various evidences in favor of the use of closed-loop cortical stimulation for the treatment of advanced PD, as an emerging technique which might offer substantial clinical benefits for PD patients.     

Temporal and spatial alterations in GPi neuronal encoding might contribute to slow down movement in Parkinsonian monkeys

Although widely investigated, the exact relationship between changes in basal ganglia neuronal activity and parkinsonian symptoms has not yet been deciphered. It has been proposed that bradykinesia (motor slowness) is related either to a modification of the activity of the globus pallidus internalis (GPi), the main output structure, or to a loss of spatial selectivity of the extrapyramidal motor system. Here we investigate the relationship between movement initiation and GPi activity in parkinsonian non-human primates. We compare neuronal encoding of movement in the normal and pathological conditions. After dopamine depletion, we observe an increased number of neurons responding to movement, with a less specific somato-sensory receptive field and a disruption of the selection mechanism. Moreover, the temporal order of the response of GPi neurons in parkinsonian animals is reversed. Indeed, whereas muscle activity and movement are delayed in parkinsonian animals, GPi neuronal responses to movement occur earlier and are prolonged, compared with normal conditions. Parkinsonian bradykinesia could thus result from an impairment of both temporal and spatial specificity of the GPi response to movement.     

Cortical stimulation relieves parkinsonian pathological activity in vitro

Previously, we have shown that chemical excitatory drives such as N‐methyl‐d ‐aspartate (NMDA) are capable of activating the striatal microcircuit exhibiting neuronal ensembles that alternate their activity producing temporal sequences. One aim of this work was to demonstrate whether similar activity could be evoked by delivering cortical stimulation. Dynamic calcium imaging allowed us to follow the activity of dozens of neurons with single‐cell resolution in mus musculus brain slices. A train of electrical stimuli in the cortex evoked network activity similar to the one induced by bath application of NMDA. Previously, we have also shown that the dopamine‐depleted striatal microcircuit increases its spontaneous activity generating dominant recurrent ensembles that interrupt the temporal sequences found in control microcircuits. This activity correlates with parkinsonian pathological activity. Several cortical stimulation protocols such as transcranial magnetic stimulation reduce motor signs of Parkinsonism. Here, we show that cortical stimulation in vitro temporarily eliminates the pathological activity from the dopamine‐depleted striatal microcircuit by turning off some neurons that sustain this activity and recruiting new ones that allow transitions between network states, similar to the control circuit. When cortical stimulation is given in the presence of L‐DOPA, parkinsonian activity is eliminated during the whole recording period. The present experimental evidence suggests that cortical stimulation such as that generated by transcranial magnetic stimulation, or otherwise, may allow reduce L‐DOPA dosage.     

Network-level neuroplasticity in cortico-basal ganglia pathways

The striatum, the largest input nucleus of the basal ganglia, receives massive inputs from the neocortex and thalamus, and gives rise to the direct, indirect and striosomal pathways of the basal ganglia. Here, the view is developed that the striatum is a major site for adaptive plasticity in cortico-basal ganglia circuits, affecting in the normal state a broad range of behaviours. This plasticity can become a major source of maladaptive responses in disease states affecting the basal ganglia.     

Task-related differential dynamics of EEG alpha- and beta-band synchronization in cortico-basal motor structures

Movement-related processing results in the modulation of neuronal synchronization over several electroencephalography (EEG) frequency ranges, including alpha- (8–12 Hz) and beta-band (14–30 Hz). Whether modulation patterns differ across sites within the motor system remains unclear, but could denote how information is conveyed across the cortico-basal network. We therefore compared the event-related synchronization/desynchronization (ERS/ERD) in recordings from the scalp, basal ganglia and thalamic structures during a motor task.
Simultaneous depth and scalp EEG were recorded in 13 patients, undergoing deep brain stimulation of the thalamic ventral intermediate nucleus (VIM) or the subthalamic nucleus (STN). They performed a choice-reaction task with pre-cued Go-signals, instructive for either left- or right-sided button presses.
In the beta-band, pre-cues and Go-signals were followed by ERD starting well before and peaking at task execution, uniformly in all cortical and subcortical recordings. In contrast, a comparable alpha-band ERD was only seen at the scalp, whereas mirror-like ERS were observed in the motor-inhibitory STN. In VIM, which receives strong somatosensory afferences, a major alpha-ERD upon the Go-signal did not start until the motor response.
These dissociations of task-related Alpha- and Beta-band dynamics tag a functional diversity in cortico-basal networks, which are simultaneously active in motor processing. Whereas the uniform downregulation of Beta-activity points to an anti-kinetic operation mode throughout the motor system, site-dependent courses of Alpha-synchronization rather reflect the coordination of activity levels in functionally divergent motor structures during the preparation and execution of movements.     

Upregulation of striatal preproenkephalin gene expression occurs before the appearance of parkinsonian signs in 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine monkeys

GABA and enkephalin-utilizing efferents from the striatum to the external segment of the pallidal complex (GPe) are thought to be overactive in Parkinson's disease (PD). This overactivity is generally held to play a major role in the genesis of parkinsonian symptoms, which are thought to appear when dopaminergic neuronal death exceeds a critical threshold. Little is known, however, regarding the activity of this pathway during disease progression and more particularly, prior to the emergence of parkinsonian symptoms. In order to test the hypothesis that an upregulation of striatal preproenkephalin-A (PPE-A) mRNA levels occurs before the appearance of parkinsonian motor disabilities, the present study assessed PPE-A mRNA expression and striatal dopamine (DA) content following a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration protocol in monkeys that produces a progressive parkinsonian state. Groups ranged from normal to full parkinsonian through asymptomatic lesioned monkeys. The key finding of this study is that PPE-A expression is already upregulated in asymptomatic-lesioned monkeys showing a marked DA depletion (56%). Importantly, this up-regulation is restricted to motor regions of the basal ganglia circuitry. The increased PPE-A mRNA expression observed in asymptomatic, but DA-depleted animals, supports our initial hypothesis of such an upregulation occurring before the appearance of parkinsonian motor disabilities. Furthermore, when considered with recent electrophysiological and histochemical data, these findings question the functional significance of upregulated enkephalin transmission in the indirect striatopallidal pathway.     

Changes in neuronal activity of cortico‐basal ganglia–thalamic networks induced by acute dopaminergic manipulations in rats

The basal ganglia are thought to be particularly sensitive to changes in dopaminergic tone, and the realization that reduced dopaminergic signaling causes pronounced motor dysfunction is the rationale behind dopamine replacement therapy in Parkinson's disease. It has, however, proven difficult to identify which neurophysiological changes that ultimately lead to motor dysfunctions. To clarify this, we have here recorded neuronal activity throughout the cortico‐basal ganglia–thalamic circuits in freely behaving rats during periods of immobility following acute dopaminergic manipulations, involving both vesicular dopamine depletion and antagonism of D1 and D2 type dopamine receptors. Synchronized and rhythmic activities were detected in the form of betaband oscillations in local field potentials and as cortical entrainment of action potentials in several basal ganglia structures. Analyses of the temporal development of synchronized oscillations revealed a spread from cortex to gradually also include deeper structures. In addition, firing rate changes involving neurons in all parts of the network were observed. These changes were typically relatively balanced within each structure, resulting in negligible net rate changes. Animals treated with D1 receptor antagonist showed a rapid onset of hypokinesia that preceded most of the neurophysiological changes, with the exception of these balanced rate changes. Parallel rate changes in functionally coupled ensembles of neurons in different structures may therefore be the first step in a cascade of neurophysiological changes underlying motor symptoms in the parkinsonian state. We suggest that balanced rate changes in distributed networks are possible mechanism of disease that should be further investigated in conditions involving dopaminergic dysfunction.     

Effects of deep brain stimulation on the primary motor cortex: Insights from transcranial magnetic stimulation studies

Deep brain stimulation (DBS) implanted in different basal ganglia nuclei regulates the dysfunctional neuronal circuits and improves symptoms in movement disorders. However, the understanding of the neurophysiological mechanism of DBS is at an early stage. Transcranial magnetic stimulation (TMS) can be used safely in movement disorder patients with DBS, and can shed light on how DBS works. DBS at a therapeutic setting normalizes the abnormal motor cortical excitability measured with motor evoked potentials (MEP) produced by primary motor cortical TMS. Abnormal intracortical circuits in the motor cortex tested with paired-pulse TMS paradigm also show normalization with DBS. These changes are accompanied with improvements in symptoms after chronic DBS. Single-pulse DBS produces cortical evoked potentials recorded by electroencephalography at specific latencies and modulates motor cortical excitability at certain time intervals measured with MEP. Combination of basal ganglia DBS with motor cortical TMS at stimulus intervals consistent with the latency of cortical evoked potentials delivered in a repetitive mode produces plastic changes in the primary motor cortex. TMS can be used to examine the effects of open and closed loop DBS. Patterned DBS and TMS delivered in a repetitive mode may be developed as a new therapeutic method for movement disorder patients.     

Pathophysiology of pain and fatigue in Parkinson's disease

In Parkinson's disease (PD), nigral degeneration determines an altered neuronal ouput from the subthalamic nucleus and globus pallidus, and as a consequence functional changes in the motor circuits linking basal ganglia to the motor cortical areas. Movement slowness, rigidity and tremor are among the principal motor symptoms of PD. Studies of movement execution have shown that PD patients have difficulty in performing simultaneous and sequential movements. In executing sequential movements the abnormalities of PD patients worsen as the sequence progresses. This phenomenon, called sequential effect, may be one of the mechanisms underlying the fatigue of PD patients. Cortical deafferentation is thought to be responsible for the motor disturbances of PD and studies using transcranial magnetic stimulation showed that in PD patients there are abnormalities in cortical plasticity and in cortical connectivity. Sensorimotor integration refers to the processes that link sensory input to motor output to produce appropriate voluntary movements. Sensory information is important for motor preparation and execution in parkinsonian patients, and PD patients have greater difficulty in performing movements when no external cues are provided. Investigating the role of sensory information, several studies provided evidence that PD patients have numerous somatosensory deficits, including tactile temporal discrimination threshold. Neurophysiological testing in PD has also found altered central somatosensory processing. Finally PD patients may experience painful sensations after the onset of the disease and various evidence suggests an abnormal nociceptive input processing in the central nervous system that might predispose PD patients to developing pain.