Input Zone-Selective Dysrhythmia in Motor Thalamus after Dopamine Depletion

The cerebral cortex, basal ganglia and motor thalamus form circuits important for purposeful movement. In Parkinsonism, basal ganglia neurons often exhibit dysrhythmic activity during, and with respect to, the slow (∼1 Hz) and beta-band (15-30 Hz) oscillations that emerge in cortex in a brain state-dependent manner. There remains, however, a pressing need to elucidate the extent to which motor thalamus activity becomes similarly dysrhythmic after dopamine depletion relevant to Parkinsonism. To address this, we recorded single-neuron and ensemble outputs in the basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) of motor thalamus in anesthetized male dopamine-intact rats and 6-OHDA-lesioned rats during two brain states, respectively defined by cortical slow-wave activity and activation. Two forms of thalamic input zone-selective dysrhythmia manifested after dopamine depletion: (1) BZ neurons, but not CZ neurons, exhibited abnormal phase-shifted firing with respect to cortical slow oscillations prevalent during slow-wave activity; and (2) BZ neurons, but not CZ neurons, inappropriately synchronized their firing and engaged with the exaggerated cortical beta oscillations arising in activated states. These dysrhythmias were not accompanied by the thalamic hypoactivity predicted by canonical firing rate-based models of circuit organization in Parkinsonism. Complementary recordings of neurons in substantia nigra pars reticulata suggested that their altered activity dynamics could underpin the BZ dysrhythmias. Finally, pharmacological perturbations demonstrated that ongoing activity in the motor thalamus bolsters exaggerated beta oscillations in motor cortex. We conclude that BZ neurons are selectively primed to mediate the detrimental influences of abnormal slow and beta-band rhythms on circuit information processing in Parkinsonism.SIGNIFICANCE STATEMENT Motor thalamus neurons mediate the influences of basal ganglia and cerebellum on the cerebral cortex to govern movement. Chronic depletion of dopamine from the basal ganglia causes some symptoms of Parkinson''s disease. Here, we elucidate how dopamine depletion alters the ways motor thalamus neurons engage with two distinct oscillations emerging in cortico-basal ganglia circuits in vivo. We discovered that, after dopamine depletion, neurons in the thalamic zone receiving basal ganglia inputs are particularly prone to becoming dysrhythmic, changing the phases and/or synchronization (but not rate) of their action potential firing. This bolsters cortical dysrhythmia. Our results provide important new insights into how aberrant rhythmicity in select parts of motor thalamus could detrimentally affect neural circuit dynamics and behavior in Parkinsonism.     

Neuronal activity in the basal ganglia and thalamus in patients with dystonia.

OBJECTIVE: To explore the role of abnormal neuronal activity in the basal ganglia and thalamus in the generation of dystonia. METHODS: Microelectrode recording was performed in the globus pallidus internus (GPi), ventral thalamic nuclear group ventral oral posterior/ventral intermediate, Vop/Vim) and subthalamic nucleus (STN) in patients with primary dystonia (n=11) or secondary dystonia (n=9) during surgery. Electromyogram (EMG) was simultaneously recorded in selected muscle groups. Single unit analysis and cross-correlations were carried out. RESULTS: Three hundred and sixty-seven neurons were obtained from 29 trajectories (GPi: 13; Vop/Vim: 12; STN: 4), 87% exhibited altered neuronal activity including grouped discharges in GPi (n=79) and STN (n=37), long-lasting neuronal activity (n=70) and rapid neuronal discharge (n=86) in Vop/Vim. There were neurons in Vop, GPi and STN firing at the same frequency as EMG during dystonia (mean: 0.39 Hz, range 0.12-0.84 Hz). Significant correlations between neuronal activity and EMG at the frequency of dystonia were obtained (GPi: r2=0.7 (n=31), Vop/Vim: r2=0.64 (n=18) and STN: r2=0.86 (n=17)). CONCLUSIONS: Consistent with previous findings of abnormalities observed in Vop/VIM and GPi in relation to dystonia, the present data further show that the altered activity in GPi, specifically in dorsal subregions of GPi, Vop/Vim and STN is likely to be directly involved in the production of dystonic movement. Dystonia-related neuronal activity observed in motor thalamus and basal ganglia nuclei of GPi and STN indicates a critical role of their interactions affecting both indirect and direct pathways in the development of either generalized or focal dystonia. SIGNIFICANCE: These data support a central role of the basal ganglia in producing dystonic movements.     

Motor cortical control of internal pallidal activity through glutamatergic and GABAergic inputs in awake monkeys

The internal segment of the globus pallidus (GPi) receives motor-related cortical signals mainly through the striatum, the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). The GPi sends its outputs outside the basal ganglia and plays a key role in motor control. Extracellular unit recordings were performed in awake monkeys to explore how glutamatergic STN inputs and GABAergic striatal and GPe inputs control spontaneous activity and how these inputs contribute to motor cortex stimulation-induced responses of GPi neurons. The typical responses of GPi neurons to cortical stimulation consisted of an early excitation, an inhibition and a late excitation. Local applications of the NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid and/or the AMPA/kainate receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide in the vicinity of recorded GPi neurons reduced the firing rate, and abolished or attenuated both early and late excitations following cortical stimulation. Local application of the GABA_A receptor antagonist gabazine increased the firing rate, induced oscillatory firings and diminished the cortically induced inhibition. Muscimol or gabazine injection into the STN or GPe also altered the firing rate, and attenuated the late excitation of GPi neurons. The gabazine injection into the STN occasionally induced dyskinesia with significantly decreased GPi activity. These data suggest that the early and late excitations are glutamatergic and induced by the cortico-STN-GPi and cortico-striato-GPe-STN-GPi pathways, respectively. The inhibition is GABAergic and induced by the cortico-striato-GPi pathway. In addition, these inputs are the main factors governing the spontaneous activity of GPi neurons.     

Effects of ramped-frequency thalamic deep brain stimulation on tremor and activity of modeled neurons

ObjectiveWe conducted intraoperative measurements of tremor to quantify the effects of temporally patterned ramped-frequency DBS trains on tremor.MethodsSeven patterns of stimulation were tested in nine subjects with thalamic DBS for essential tremor: stimulation ‘off’, three ramped-frequency stimulation (RFS) trains from 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz, and three constant frequency stimulation (CFS) trains at 72, 82, and 130 Hz. The same patterns were applied to a computational model of the thalamic neural network.ResultsTemporally patterned 130 → 60 Hz ramped-frequency trains suppressed tremor relative to stimulation ‘off,’ but 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz ramped-frequency trains were no more effective than constant frequency stimulation with the same mean interpulse interval (IPI). Computational modeling revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but long IPIs, concurrent with pauses in afferent cerebellar and cortical firing, allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions.ConclusionFrequency-ramped DBS produced equivalent tremor suppression as constant frequency thalamic DBS. Tremor-related thalamic burst activity may result from burst-driver input, rather than by an intrinsic rebound mechanism.SignificanceRamping stimulation frequency may exacerbate thalamic burst firing by introducing consecutive pauses of increasing duration to the stimulation pattern.     

Oscillatory activity in the globus pallidus internus: Comparison between Parkinson’s disease and dystonia

ObjectiveDeep brain stimulation in the globus pallidus internus (GPi) is used to alleviate the motor symptoms of both Parkinson’s disease (PD) and dystonia. We tested the hypothesis that PD and dystonia are characterized by different temporal patterns of synchronized oscillations in the GPi, and that the dopaminergic loss in PD makes the basal ganglia more susceptible to oscillatory activity.MethodsNeuronal firing and local field potentials (LFPs) were simultaneously recorded from the GPi in four PD patients and seven dystonia patients using two independently driven microelectrodes.ResultsIn the PD patients, beta (11–30 Hz) oscillations were observed in the LFPs and the firing activity of ～30% of the neurons was significantly coherent with the LFP. However, in the dystonia group, the peak frequency of LFP oscillations was lower (8–20 Hz) and there was a significantly smaller proportion of neurons (～10%) firing in coherence with the LFP (P < 0.001).ConclusionsThese findings suggest that synchronization of neuronal firing with LFP oscillations is a more prominent feature in PD than in dystonia.SignificanceThis study adds to the growing evidence that dopaminergic loss in PD may increase the sensitivity of the basal ganglia network to rhythmic oscillatory inputs.     

External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) are effective for the treatment of advanced Parkinson's disease (PD). We have shown previously that DBS of the external segment of the globus pallidus (GPe) is associated with improvements in parkinsonian motor signs; however, the mechanism of this effect is not known. In this study, we extend our findings on the effect of STN and GPi DBS on neuronal activity in the basal ganglia thalamic network to include GPe DBS using the 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) monkey model. Stimulation parameters that improved bradykinesia were associated with changes in the pattern and mean discharge rate of neuronal activity in the GPi, STN, and the pallidal [ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)] and cerebellar [ventralis lateralis posterior pars oralis (VPLo)] receiving areas of the motor thalamus. Population post-stimulation time histograms revealed a complex pattern of stimulation-related inhibition and excitation for the GPi and VA/VLo, with a more consistent pattern of inhibition in STN and excitation in VPLo. Mean discharge rate was reduced in the GPi and STN and increased in the VPLo. Effective GPe DBS also reduced bursting in the STN and GPi. These data support the hypothesis that therapeutic DBS activates output from the stimulated structure and changes the temporal pattern of neuronal activity throughout the basal ganglia thalamic network and provide further support for GPe as a potential therapeutic target for DBS in the treatment of PD.     

Subdyskinetic apomorphine responses in globus pallidus and subthalamus of parkinsonian patients: lack of clear evidence for the 'indirect pathway'.

OBJECTIVES: Previous studies suggested that the hypo-activity of the external pallidus (GPe) might drive the hyper-activity of subthalamic neurons, which underlies the cardinal symptoms of Parkinson's disease. We have challenged this view, based on the so-called 'indirect pathway', by recording apomorphine effects from both structures of parkinsonian patients, at rest and during passive movements. METHODS: We performed single-unit recordings from external pallidus (GPe), internal pallidus (GPi) and subthalamic nucleus (STN) during the stereotactic neurosurgery aimed to implant deep brain stimulating electrodes in GPi or STN. First, we verified the firing frequency of each structure in off-state conditions. Then, therapeutic, subdyskinetic concentrations of the dopaminergic agonist apomorphine was delivered to assess each nucleus response. RESULTS: The firing rate of STN averaged about 40 Hz; a large proportion (75%) of STN units exhibited marked responsiveness to passive movements. Apomorphine reduced the firing discharge of parkinsonian STN in all cells, although electrophysiological recovery was usually incomplete. Movement-related activity was also dramatically reduced. In contrast, apomorphine failed to modify the firing frequency of GPe, despite the amelioration of hypo-kinetic symptoms and the simultaneous inhibition of GPi firing discharge. CONCLUSIONS: We demonstrate that part of the models on basal ganglia circuitry needs to be revised. The re-balancing of STN hyper-activity, when patients benefit from dopaminergic therapy, is not due to an increased input from GPe, but, instead, due to changes in STN intrinsic firing properties and/or modulation of glutamatergic inputs.     

Targeting the caudal intralaminar nuclei for functional neurosurgery of movement disorders

The caudal intralaminar nuclei, in particular the Centrum-Medianum Parafascicularis (CM-Pf) nucleus complex, are involved in various functions, particularly in pain processing and in motor control, through their projections to the subthalamic nucleus and their afferents from the pallidum internus (GPi) (or entopeduncular nucleus in the rat). The nociceptive inputs received by the CM-Pf are modulated by the somato-sensory thalamus. The lateral habenula (HbL) receives noxious inputs and has an inhibitory influence on the nigral dopaminergic neurons. CM-Pf and the HbL share comparable response characteristics to noxious inputs and might play comparable, and perhaps complementary, roles in conveying the nociceptive information to the basal ganglia system, thereby modulating motor responses, such as freezing and dyskinesias. The interaction between CM-Pf, HbL, GPi, STN and SNC might provide a new template for high frequency stimulation strategies in the treatment of movement disorders.     

Anesthesia reduces discharge rates in the human pallidum without changing the discharge rate ratio between pallidal segments

Classical rate models of basal ganglia circuitry associate discharge rate of the globus pallidus external and internal segments (GPe, GPi respectively) solely with dopaminergic state and predict an inverse ratio between the discharge rates of the two pallidal segments. In contrast, the effects of other rate modulators such as general anesthesia (GA) on this ratio have been ignored. To respond to this need, we recorded the neuronal activity in the GPe and GPi in awake and anesthetized human patients with dystonia (57 and 53 trajectories respectively) and in awake patients with Parkinson's disease (PD, 16 trajectories) undergoing deep brain stimulation procedures. This triad enabled us to dissociate pallidal discharge ratio from general discharge modulation. An automatic offline spike detection and isolation quality system was used to select 1560 highly isolated units for analysis. The mean discharge rate in the GPi of awake PD patients was dramatically higher than in awake dystonia patients although the firing rate in the GPe was similar. Firing rates in dystonic patients under anesthesia were lower in both nuclei. Surprisingly, in all three groups, GPe firing rates were correlated with firing rates in the ipsilateral GPi. Thus, the firing rate ratio of ipsilateral GPi/GPe pairs was similar in awake and anesthetized patients with dystonia and significantly higher in PD. We suggest that pallidal activity is modulated by at least two independent processes: dopaminergic state which changes the GPi/GPe firing rate ratio, and anesthesia which modulates firing rates in both pallidal nuclei without changing the ratio between their firing rates.     

Effects of apomorphine on globus pallidus neurons in parkinsonian patients

Current hypotheses of basal ganglia dysfunction in Parkinson's disease (PD) propose that neuronal hypoactivity in the globus pallidus externus (GPe), and hyperactivity in the output nuclei and the external and internal portions of the globus pallidus internus (GPi, e and GPi, i, respectively), result in the cardinal symptoms of PD. To test this theory, the nonselective D₁- and D₂-dopamine receptor agonist apomorphine (30–100 μg/kg SC) was administered to 14 levodoparesponsive PD patients who were off medication (“of” state) while recording neurons in GP. For 15 neurons that were continuously monitored, apomorphine was found to increase the firing rate of 3 neurons in GPe, and decrease the rate of 12 in GPi. The mean firing rates of many different neurons were determined before (n = 285) and at various intervals after (n = 184) the injection of the drug. The mean rates before apomorphine were as follows: GPe, 45 Hz (SD 15, n = 85); GPi, e, 67 Hz (SD 14, n = 125); and GPi, i, 85 Hz (SD 19, n = 75). At 25 to 35 minutes after APO, the rate of GPe neurons had increased to 72 Hz (SD 18, n = 7), the rate of GPi, e neurons had decreased to 39 Hz (SD 15, n = 15), and in GPi, i the rate decreased to 34 Hz (SD 22, n = 18). Eighty minutes after apomorphine administration, the mean firing rates returned to preadministration values. This study supports current models of basal ganglia dysfunction in PD and suggests that the thereapeutic effect of apomorphine results from a normalization of the imbalance of neuronal activity in the direct and indirect pathways.     

Information processing from the motor cortices to the subthalamic nucleus and globus pallidus and their somatotopic organizations revealed electrophysiologically in monkeys

To understand how the information derived from different motor cortical areas representing different body parts is organized in the basal ganglia, we examined the neuronal responses in the subthalamic nucleus (STN), and the external (GPe) and internal (GPi) segments of the globus pallidus (input, relay and output nuclei, respectively) to stimulation of the orofacial, forelimb and hindlimb regions of the primary motor cortex (MI) and supplementary motor area (SMA) in macaque monkeys under the awake state. Most STN and GPe/GPi neurons responded exclusively to stimulation of either the MI or SMA, and one‐fourth to one‐third of neurons responded to both. STN neurons responding to the hindlimb, forelimb and orofacial regions of the MI were located along the medial–lateral axis in the posterolateral STN, while neurons responding to the orofacial region of the SMA were located more medially than the others in the anteromedial STN. GPe/GPi neurons responding to the hindlimb, forelimb and orofacial regions of the MI were found along the dorsal–ventral axis in the posterolateral GPe/GPi, and neurons responding to the corresponding regions of the SMA were similarly but less clearly distributed in more anteromedial regions. Moreover, neurons responding to the distal and proximal forelimb MI regions were found along the lateral–medial axis in the STN and the ventral–dorsal axis in the GPe/GPi. Most STN and GPe/GPi neurons showed kinaesthetic responses with similar somatotopic maps. These observations suggest that the somatotopically organized inputs from the MI and SMA are well preserved in the STN and GPe/GPi with partial convergence.     

Premotor Ramping of Thalamic Neuronal Activity Is Modulated by Nigral Inputs and Contributes to Control the Timing of Action Release

The ventromedial (VM)/ventro-anterior-lateral (VAL) motor thalamus is a key junction within the brain circuits sustaining normal and pathologic motor control functions and decision-making. In this area of thalamus, on one hand, the inhibitory nigro-thalamic pathway provides a main output from the basal ganglia, and, on the other hand, motor thalamo-cortical loops are involved in the maintenance of ramping preparatory activity before goal-directed movements. To better understand the nigral impact on thalamic activity, we recorded electrophysiological responses from VM/VAL neurons while male and female mice were performing a delayed right/left decision licking task. Analysis of correct (corr) and error trials revealed that thalamic ramping activity was stronger for premature licks (impulsive action) and weaker for trials with no licks [omission (omi)] compared with correct trials. Suppressing ramping activity through optogenetic activation of nigral terminals in the motor thalamus during the delay epoch of the task led to a reduced probability of impulsive action and an increased amount of omissions trials. We propose a parsimonious model explaining our data and conclude that a thalamic ramping mechanism contributes to the control of proper timing of action release and that inhibitory nigral inputs are sufficient to interrupt this mechanism and modulate the amount of motor impulsivity in this task.SIGNIFICANCE STATEMENT Coordinated neural activity in motor circuits is essential for correct movement preparation and execution, and even slight imbalances in neural processing can lead to failure in behavioral tasks or motor disorders. Here we focused on how failure to regulate the control of activity balance in the motor thalamus can be implicated in impulsive action release or omissions to act, through an activity ramping mechanism that is required for proper action release. Using optogenetic activation of inhibitory basal ganglia terminals in motor thalamus we show that basal ganglia input is well positioned to control this ramping activity and determine the timing of action initiation.     

The spontaneous firing patterns of forebrain neurons. IV. Effects of bilateral and unilateral frontal cortical ablations on firing of caudate, globus pallidus and thalamic neurons

To assess the effects of partial deafferentation of the neostriatum on spontaneous neuronal activity in the basal ganglia and related thalamic nuclei, ablations of frontal cortex were carried out in adult cats. Postoperative measures of interspike intervals of single neurons in the caudate nucleus, globus pallidus and ventral anterior-ventral lateral complex of the thalamus revealed a slowing of neuronal firing in these structures as compared with non-lesioned controls. The fact that deafferentation by cortical damage produces changes in neuronal firing in target neurons of the striatum (globus pallidus) and in thalamic neurons at least two synapses removed from the striatum is noteworthy. The possible extent to which these results might have been influenced by reduction of cortical inputs to or denervation of the thalamus is discussed.     

Parvalbumin‐producing striatal interneurons receive excitatory inputs onto proximal dendrites from the motor thalamus in male mice

In rodents, the dorsolateral striatum regulates voluntary movement by integrating excitatory inputs from the motor‐related cerebral cortex and thalamus to produce contingent inhibitory output to other basal ganglia nuclei. Striatal parvalbumin (PV)‐producing interneurons receiving this excitatory input then inhibit medium spiny neurons (MSNs) and modify their outputs. To understand basal ganglia function in motor control, it is important to reveal the precise synaptic organization of motor‐related cortical and thalamic inputs to striatal PV interneurons. To examine which domains of the PV neurons receive these excitatory inputs, we used male bacterial artificial chromosome transgenic mice expressing somatodendritic membrane–targeted green fluorescent protein in PV neurons. An anterograde tracing study with the adeno‐associated virus vector combined with immunodetection of pre‐ and postsynaptic markers visualized the distribution of the excitatory appositions on PV dendrites. Statistical analysis revealed that the density of thalamostriatal appositions along the dendrites was significantly higher on the proximal than distal dendrites. In contrast, there was no positional preference in the density of appositions from axons of the dorsofrontal cortex. Population observations of thalamostriatal and corticostriatal appositions by immunohistochemistry for pathway‐specific vesicular glutamate transporters confirmed that thalamic inputs preferentially, and cortical ones less preferentially, made apposition on proximal dendrites of PV neurons. This axodendritic organization suggests that PV neurons produce fast and reliable inhibition of MSNs in response to thalamic inputs and process excitatory inputs from motor cortices locally and plastically, possibly together with other GABAergic and dopaminergic dendritic inputs, to modulate MSN inhibition.     

Pallidal neuronal discharge in Huntington's disease: support for selective loss of striatal cells originating the indirect pathway

Chorea is the predominant motor manifestation in the early symptomatic phase of adult onset Huntington's disease (HD). Pathologically, this stage is marked by differential loss of striatal neurons contributing to the indirect pathway. This pattern of neuronal loss predicts decreased neuronal firing rates in GPi and increased firing rates in GPe, the opposite of the changes in firing rate known to occur in Parkinson's disease (PD). We present single-unit discharge characteristics (33 neurons) observed in an awake patient with HD (41 CAG repeats) undergoing microelectrode guided surgery for pallidal deep brain stimulation. Pallidal single-unit activity at "rest" and during voluntary movement was discriminated off line by principal component analysis and evaluated with respect to discharge rate, bursting, and oscillatory activity in the 0-200 Hz range. 24 GPi and 9 GPe units were studied, and compared with 132 GPi and 50 GPe units from 14 patients with PD. The mean (+/-SEM) spontaneous discharge rate for HD was 58+/-4 for GPi and 73+/-5 for GPe. This contrasted with discharge rates in PD of 95+/-2 for GPi and 57+/-3 for GPe. HD GPi units showed more bursting than PD GPi units but much less oscillatory activity in the 2-35 Hz frequency range at rest. These findings are consistent with selective early loss of striatal cells originating the indirect pathway.     

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.     

Multi-site stimulation of subthalamic nucleus diminishes thalamocortical relay errors in a biophysical network model

This paper presents results on a computational study of how multi-site stimulation of the subthalamic nucleus (STN), within the basal ganglia, can improve the fidelity of thalamocortical (TC) relay in a parkinsonian network model. In the absence of stimulation, the network model generates activity featuring synchronized bursting by clusters of neurons in the STN and internal segment of the globus pallidus (GPi), as occurs experimentally in parkinsonian states. This activity yields rhythmic inhibition from GPi to TC neurons, which compromises TC relay of excitatory inputs. We incorporate two types of multi-site STN stimulation into the network model. One stimulation paradigm features coordinated reset pulses that are on for different subintervals of each period at different sites. The other is based on a filtered version of the local field potential recorded from the STN population. Our computational results show that both types of stimulation significantly diminish TC relay errors; the former reduces the rhythmicity of the net GPi input to TC neurons and the latter reduces, but does not eliminate, STN activity. Both types of stimulation represent promising directions for possible therapeutic use with Parkinson’s disease patients.     

Gamma activity and reactivity in human thalamic local field potentials

Depth recordings in patients with Parkinson's disease on dopaminergic therapy have revealed a tendency for oscillatory activity in the basal ganglia that is sharply tuned to frequencies of ∼70 Hz and increases with voluntary movement. It is unclear whether this activity is essentially physiological and whether it might be involved in arousal processes. Here we demonstrate an oscillatory activity with similar spectral characteristics and motor reactivity in the human thalamus. Depth signals were recorded in 29 patients in whom the ventral intermediate or centromedian nucleus were surgically targeted for deep brain stimulation. Thirteen patients with four different pathologies showed sharply tuned activity centred at ∼70 Hz in spectra of thalamic local field potential (LFP) recordings. This activity was modulated by movement and, critically, varied over the sleep–wake cycle, being suppressed during slow wave sleep and re-emergent during rapid eye movement sleep, which physiologically bears strong similarities with the waking state. It was enhanced by startle-eliciting stimuli, also consistent with modulation by arousal state. The link between this pattern of thalamic activity and that of similar frequency in the basal ganglia was strengthened by the finding that fast thalamic oscillations were lost in untreated parkinsonian patients, paralleling the behaviour of this activity in the basal ganglia. Furthermore, there was sharply tuned coherence between thalamic and pallidal LFP activity at ∼70 Hz in eight out of the 11 patients in whom globus pallidus and thalamus were simultaneously implanted. Subcortical oscillatory activity at ∼70 Hz may be involved in movement and arousal.     

Does stimulation of the GPi control dyskinesia by activating inhibitory axons?

A 69-year-old woman with Parkinson's disease and levodopa-induced dyskinesias had a deep brain stimulation (DBS) electrode inserted into the right globus pallidus internus (GPi). During the operation, the GPi was mapped with dual microelectrode recordings. Stimulation through one microelectrode in GPi inhibited the firing of GPi neurons recorded with another microelectrode 600--1,000 microm distant. The inhibition could be obtained with pulse widths of 150 micros and intensities as low as 10 microA. Single stimuli inhibited GPi neurons for approximately 50 ms. Trains of 300 Hz stimuli inhibited GPi neuron firing almost completely. Postoperatively, stimulation through macroelectrode contacts located in the posterior ventral pallidum controlled the patient's dyskinesias. The effect could be obtained with pulse widths of 50 micros and frequencies as low as 70--80 Hz. We postulate stimulation of the ventral pallidum controls dyskinesias by activating large axons which inhibit GPi neurons.     

The anterior paraventricular thalamus modulates neuronal excitability in the suprachiasmatic nuclei of the rat

The suprachiasmatic nucleus (SCN) in mammals is the master clock which regulates circadian rhythms. Neural activity of SCN neurons is synchronized to external light through the retinohypothalamic tract (RHT). The paraventricular thalamic nucleus (PVT) is a neural structure that receives synaptic inputs from, and projects back to, the SCN. Lesioning the anterior PVT (aPVT) modifies the behavioral phase response curve induced by short pulses of bright light. In order to study the influence of the aPVT on SCN neural activity, we addressed whether the stimulation of the aPVT can modulate the electrical response of the SCN to either retinal or RHT stimulation. Using in vitro and in vivo recordings, we found a large population of SCN neurons responsive to the stimulation of either aPVT or RHT pathways. Furthermore, we found that simultaneous stimulation of the aPVT and the RHT increased neuronal responsiveness and spontaneous firing rate (SFR) in neurons with a low basal SFR (which also have more negative membrane potentials), such as quiescent and arrhythmic neurons, but no change was observed in neurons with rhythmic firing patterns and more depolarized membrane potentials. These results suggest that inputs from the aPVT could shift the membrane potential of an SCN neuron to values closer to its firing threshold and thus contribute to integration of the response of the circadian clock to light.