Dopamine-depleted Basal Ganglia Research Articles

Tremor in Parkinson's Disease May Arise from Interactions of Central Rhythms with Spinal Reflex Loop Oscillations.

It is commonly believed that tremor, one of the cardinal signs of Parkinson’s disease, is associated with cerebello-thalamo-cortical oscillations set off by the dopamine-depleted basal ganglia networks. The triggering mechanism has been, however, not entirely delineated. Several reports have pointed to the relevance of interactions with peripheral/spinal mechanisms to tremor generation. Investigations of motor unit synchronization and discharge patterns suggested that exaggerated beta-band oscillations may intermittently reach alpha-motoneurons and modulate low-amplitude membrane oscillations due to spinal loop transmission delays. As a result, the spinal reflex loop will oscillate more vigorously and at a lower frequency and, in turn, entrain larger transcortical loops. Motoneurons may thus represent the specific generator “node” in a tremor network encompassing both cerebral and peripheral/spinal recurrent circuits.

Long‐range temporal correlations in the subthalamic nucleus of patients with Parkinson’s disease

Neuronal activity in the subthalamic nucleus (STN) of patients with Parkinson's disease (PD) is characterised by excessive neuronal synchronization, particularly in the beta frequency range. However, less is known about the temporal dynamics of neuronal oscillations in PD. In this respect long-range temporal correlations (LRTC) are of special interest as they quantify the neuronal dynamics on different timescales and have been shown to be relevant for optimal information processing in the brain. While the presence of LRTC has been demonstrated in cortical data, their existence in deep brain structures remains an open question. We investigated (i) whether LRTC are present in local field potentials (LFP) recorded bilaterally from the STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF) and (ii) whether LRTC can be modulated by levodopa treatment (ON). Detrended fluctuation analysis was utilised in order to quantify the temporal dynamics in the amplitude fluctuations of LFP oscillations. We demonstrated for the first time the presence of LRTC (extending up to 50 s) in the STN. Importantly, the ON state was characterised by significantly stronger LRTC than the OFF state, both in beta (13-35 Hz) and high-frequency (> 200 Hz) oscillations. The existence of LRTC in subcortical structures such as STN provides further evidence for their ubiquitous nature in the brain. The weaker LRTC in the OFF state might indicate limited information processing in the dopamine-depleted basal ganglia. The present results implicate LRTC as a potential biomarker of pathological neuronal processes in PD.

Long-range temporal correlations in the subthalamic nucleus of patients with Parkinson's Disease

Neuronal activity in the subthalamic nucleus (STN) of untreated patients with Parkinson’s disease (PD) is characterized by excessive neuronal synchronization, particularly in the beta frequency range. However, less is known about the temporal dynamics of neuronal oscillations in PD. In this respect long-range temporal correlations (LRTC) are of special interest since they quantify neuronal dynamics on different time scales and were shown to be relevant for optimal information processing in the brain. While the presence of LRTC was demonstrated in cortical data, their existence in deep brain structures remains an open question. We investigated (1) whether LRTC are present in local field potentials (LFP) recorded from bilateral STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF), and (2) whether LRTC can be modulated by acute levodopa treatment (ON). Detrended Fluctuation Analysis was utilized in order to quantify the temporal dynamics in amplitude fluctuations of neuronal oscillations. We demonstrated for the first time the presence of LRTC (extending up to 50 sec) in STN. Importantly, the ON state was characterized by significantly stronger LRTC compared to the OFF state, both in beta (13–35 Hz) and high-frequency (> 200 Hz) oscillations. On the other hand, spectral power decreased in the beta band and increased in the high-frequency band during ON medication. The existence of LRTC in subcortical STN provides further evidence for their ubiquitous nature in the brain. The weaker LRTC in the OFF state might indicate limited information processing in the dopamine-depleted basal ganglia. The present results implicate LRTC as a potential biomarker of pathological neuronal processes in PD that may be used for diagnosis and treatment strategies. Supported by DFG KFO 247.

Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor

Parkinson disease (PD) is characterized by striatal dopamine depletion, which explains clinical symptoms such as bradykinesia and rigidity, but not resting tremor. Instead, resting tremor is associated with increased activity in a distinct cerebellothalamic circuit. To date, it remains unknown how the interplay between basal ganglia and the cerebellothalamic circuit can result in resting tremor. We studied 21 tremor-dominant PD patients, 23 nontremor PD patients, and 36 controls. Using functional magnetic resonance imaging, we measured functional connectivity between basal ganglia nuclei (globus pallidus internus [GPi], globus pallidus externus [GPe], putamen, caudate) and the cerebellothalamic circuit. Using electromyography during scanning, we measured tremor-related activity in the basal ganglia and cerebellothalamic circuit. We also quantified striatopallidal dopamine depletion using iodine-123-N-omega-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)tropane [[I-123]FP-CIT] single photon emission computed tomography. Pallidal (but not striatal) dopamine depletion correlated with clinical tremor severity. The GPi, GPe, and putamen were transiently activated at the onset of tremor episodes, whereas activity in the cerebellothalamic circuit cofluctuated with tremor amplitude. The GPi and putamen of tremor-dominant PD patients had increased functional connectivity with the cerebellothalamic circuit, which was relegated through the motor cortex. Resting tremor may result from a pathological interaction between the basal ganglia and the cerebellothalamic circuit. The cerebellothalamic circuit, which controls tremor amplitude, appears to be driven into tremor generation when receiving transient signals from the dopamine-depleted basal ganglia. This may explain why basal ganglia dysfunction is required for developing resting tremor, although a cerebellothalamic circuit produces it. Our model also clarifies why neurosurgical interventions targeted at either the basal ganglia or the cerebellothalamic circuit can both suppress tremor.

The Subthalamic Nucleus becomes a Generator of Bursts in the Dopamine-Depleted State. Its High Frequency Stimulation Dramatically Weakens Transmission to the Globus Pallidus

Excessive burst firing in the dopamine-depleted basal ganglia correlates with severe motor symptoms of Parkinson's disease that are attenuated by high frequency electrical stimulation of the subthalamic nucleus (STN). Here we test the hypothesis that pathological bursts in dopamine-deprived basal ganglia are generated within the STN and transmitted to globus pallidus neurons. To answer this question we recorded excitatory synaptic currents and potentials from subthalamic and pallidal neurons in the basal ganglia slice (BGS) from dopamine-depleted mice while continuously blocking GABAA receptors. In control mice, a single electrical stimulus delivered to the internal capsule or the rostral pole of the STN evoked a short duration, small amplitude, monosynaptic EPSC in subthalamic neurons. In contrast, in the dopamine-depleted BGS, this monosynaptic EPSC was amplified and followed by a burst of polysynaptic EPSCs that eventually reverberated three to seven times, providing a long lasting response that gave rise to bursts of EPSCs and spikes in GP neurons. Repetitive (10–120 Hz) stimulation delivered to the STN in the dopamine-depleted BGS attenuated STN-evoked bursts of EPSCs in pallidal neurons after several minutes of stimulation but only high frequency (90–120 Hz) stimulation replaced them with small amplitude EPSCs at 20 Hz. We propose that the polysynaptic pathway within the STN amplifies subthalamic responses to incoming excitation in the dopamine-depleted basal ganglia, thereby transforming the STN into a burst generator and entraining pallidal neurons in pathogenic bursting activities. High frequency stimulation of the STN prevents the transmission of this pathological activity to globus pallidus and imposes a new glutamatergic synaptic noise on pallidal neurons.

Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: In vivo imaging with [18F]fallypride

The purpose of the current study was to examine changes in dopamine D2 receptor (DA-D2R) expression within the basal ganglia of MPTP mice subjected to intensive treadmill exercise. Using Western immunoblotting analysis of synaptoneurosomes and in vivo positron emission tomography (PET) imaging employing the DA-D2R specific ligand [¹⁸F]fallypride, we found that high intensity treadmill exercise led to an increase in striatal DA-D2R expression that was most pronounced in MPTP compared to saline treated mice. Exercise-induced changes in the DA-D2R in the dopamine-depleted basal ganglia are consistent with the potential role of this receptor in modulating medium spiny neurons (MSNs) function and behavioral recovery. Importantly, findings from this study support the rationale for using PET imaging with [¹⁸F]fallypride to examine DA-D2R changes in individuals with Parkinson's Disease (PD) undergoing high-intensity treadmill training.

Physiology of the normal and dopamine-depleted basal ganglia: Insights into levodopa pharmacotherapy

Dopamine (DA) neurons exist in two activity states; either spontaneously firing or quiescent and nonfiring. When faced with a behavioral demand, the quiescent DA neurons can be activated to facilitate normal motor output. Levodopa appears to increase DA output by activating these nonfiring neurons; as a consequence, DA release is increased, but behavioral demand can now overwhelm the system, potentially leading to the inactivation and on/off phenomena. Levodopa administered in a pulsatile manner may also lead to the induction of synaptic plasticity within the DA systems. In the ventral mesolimbic system, this could lead to the loss of behavioral flexibility, impulsive behavior, and cognitive impairment, whereas in the dorsal nigrostriatal system, this may underlie Levodopa-induced dyskinesia. Continuous administration of Levodopa may circumvent this sensitization process, enabling a therapeutic response without limbic and motor side effects.

NMDA receptor antagonism modifies the synergistic regulation of striatal tachykinin gene expression induced by dopamine D 1 and serotonin 2 receptor stimulation following neonatal dopamine depletion

Co-application of SKF-38393 (dopamine D 1 agonist; 1 mg/kg) and DOI (serotonin 2 agonist; 1 mg/kg) induced a synergistic increase in striatal preprotachykinin (PPT) mRNA levels in adult rats 60 days after neonatal intracerebroventricular injection of 6-hydroxydopamine. This magnitude of response was not observed in intact (vehicle-injected) rats and was restricted to the dorsomedial (DM, 333±25% of lesion) subregion of the anterior striatum, with smaller increases observed in the dorsolateral striatum (DL, 206±26% of lesion). A single i.p. injection of MK-801 (NMDA antagonist; 0.1 mg/kg) administered prior to dopamine D 1 (D 1) and serotonin 2 (5-HT 2) receptor co-stimulation suppressed the synergistic regulation of PPT mRNA expression in the DM striatum, but also produced a large increase in PPT message levels within the DL striatum (321±17% of lesion). These data suggest that the synergistic regulation of PPT mRNA within the DM striatum induced by D 1/5-HT 2 receptor co-stimulation in the dopamine lesioned rat is dependent on NMDA receptor activity. However, MK-801 may simultaneously potentiate striatal PPT mRNA expression by a separate mechanism due to the changed environment of the dopamine-depleted basal ganglia.

The accumbens: beyond the core-shell dichotomy.

This article highlights recent discoveries related to the accumbens and closely associated structures, with special reference to their importance in neuropsychiatry. The development of "striatal patches" in the accumbens is reviewed in a series of pictures. Neuronal ensembles are discussed as potentially important functional-anatomical units. Attention is also drawn to recent discoveries related to the neuronal circuits that the primate accumbens establishes with the mesencephalic dopamine system. On the basis of histological and neurochemical differences, the accumbens has been divided into core and shell compartments. In the context of this article, the shell, which is an especially diversified part of the accumbens, is the subject of special attention because of its close relation to the extended amygdala and distinctive response to antipsychotic and psychoactive drugs.

Reinstatement of synaptic connectivity in the striatum of weaver mutant mice following transplantation of ventral mesencephalic anlagen.

Ventral mesencephalic anlagen survive following grafting to the striatum of weaver mutant mice and reinnervate the dopamine-depleted basal ganglia of the recipients. The aim of the present study was to examine the pattern of connectivity established by graft-deriving dopamine afferents in the host striatum. Grafts were obtained from normal embryos at a gestational age of 14-15 days and implanted into a surgical cavity overlying the dorsal striatum of adult weaver recipients. Tissue was processed for electron microscopic immunocytochemistry using a primary antiserum against tyrosine hydroxylase. At the time of examination, recipient weaver mutants were 8.5 months old and the grafts had survived for 4.5 months. Grafts were found to contain an estimated 100-1000 tyrosine hydroxylase immunoreactive neurons. Tyrosine hydroxylase immunoreactive fibres, displaying characteristic varicosities, innervated the dorsal striatum to a depth of 1000 micron. In the non-grafted striatum, 8% of the contacts of tyrosine hydroxylase immunoreactive nerve terminals were junctional. That proportion contrasted with the corresponding value of normal animals, which is 27%. In the grafted striatum, 29% of the contacts were junctional. That percentage approximated the value found in normal animals. By applying a stereological correction, it can be estimated from those numbers that the true proportion of junctional contacts in the non-grafted striatum of 8.5-month-old mutants may be 26%, whereas that in the grafted side may be 91%, which is close to the normal situation. The majority of contacts in the reinnervated striatum (84%) were made with dendrites and spines. However, the proportion of total axosomatic contacts in the reinnervated striatum was twice as high as that found in the striatum of normal animals, and the proportion of junctional synapses was three times higher than that found normally. We conclude that: (1) in spite of a genetically determined degenerative process, the dorsal neostriatum of weaver mutant mice is receptive to synaptic investment by dopamine afferents originating in normal donor tissue. (2) In repopulating the denervated weaver striatum, graft-deriving dopamine afferents display a connectional selectivity, i.e. they establish synaptic relations preferentially with those cellular domains that are normally innervated by dopamine nerve terminals. In this context, it is possible that dopamine fibres originating in the grafts invest postsynaptic sites that had either been vacated from the intrinsic dopamine input or had never received such an input. (3) The striatal connectivity following transplantation may retain features of immaturity as suggested by t