Parkinson’s disease is a condition affecting the human brain that becomes worse over time. The most common symptoms are tremors, muscle spasms and movements that are much slower than normal; all of which decrease an individual’s quality of life. Although there is currently no cure, the brain structures involved in Parkinson’s disease are known. These are collectively termed the basal ganglia, and are often targeted to treat the symptoms of Parkinson’s disease. For example, electrically stimulating the subthalamic nucleus (STN), one part of the basal ganglia, reduces muscle tremors and stiffness.

Pain is another common symptom in Parkinson’s disease. Patients often report strange burning or stabbing sensations with no obvious physical cause. They are also likely to be more sensitive to painful stimuli and have a lower pain threshold than normal. This suggested that the brain circuits that allow us to perceive and process pain could be somehow involved in Parkinson’s disease. Indeed, stimulating the STN is known to relieve pain in Parkinson’s disease, as well as the muscle symptoms, but exactly how the STN might link up with the brain’s ‘pain network’ remains poorly understood. Pautrat et al. therefore set out to explore the connection between pain networks and the STN, and determine its potential role in Parkinson’s disease.

First, the electrical activity of nerve cells in the STN of rats was measured, which revealed that these cells do respond to mildly painful sensations. Experiments using dyes to label cells in both the STN and brain structures known to transmit painful signals showed that the STN was indeed directly linked to the brain’s pain network. Moreover, rats with a STN that did not work properly also responded abnormally to painful stimuli, confirming that the STN did indeed influence their perception of pain. Finally, Pautrat et al. repeated their measurements of electrical activity in the STN, this time using rats that lacked the same group of nerve cells affected in the basal ganglia of patients with Parkinson’s disease. Such rats are commonly used to model the disease in laboratory experiments. In these rats, the STN cells responded very strongly to painful stimuli, suggesting that problems with the STN could be causing some of the pain symptoms in Parkinson’s disease.

This work reveals a new role for the STN in controlling responses to pain, both in health and disease. Pautrat et al. hope that their results will inspire research into more effective treatments of nerve pain in both Parkinson’s disease and other neurodegenerative conditions.

Pain is highly prevalent in Parkinson’s disease (PD) and includes primary symptoms assumed to originate from a dysfunction of the central nervous system. Patients describe bizarre and unexplained painful sensations such as burning, stabbing, aching, itching or tingling sensations, predominating on the more affected side (Schestatsky et al., 2007). These symptoms are not directly related to the pain caused by the motor symptoms (Ha and Jankovic, 2012). Sensitivity to noxious stimulation is also increased in patients with PD, with or without pain symptoms (Berardelli et al., 2012; Brefel-Courbon et al., 2013; Tinazzi et al., 2008), and their nociceptive threshold is altered (Chudler and Dong, 1995; Conte et al., 2013; Djaldetti et al., 2004). Although it is well known that PD affects the basal ganglia, there is to date no clear description of a link between the basal ganglia and the cerebral network involved in pain. Interestingly, deep brain stimulation of the subthalamic nucleus (STN-DBS) in PD, a valuable and effective therapeutic technique for motor symptoms (Krack et al., 2003; Limousin et al., 1998), has also been shown to reduce pain (Cury et al., 2014; Hanagasi et al., 2011; Kim et al., 2008; Klingelhoefer et al., 2014). By contrast, the effects of dopamine replacement therapy on the pain symptoms in PD are controversial, with some investigations reporting an improvement, no effect or an aggravation of pain symptoms or nociceptive thresholds (Conte et al., 2013; Dellapina et al., 2011). These variable results of dopamine replacement therapy indicate a role for other systems in the pain symptoms observed in PD. Importantly in the present context, it has been demonstrated that pain relief following STN-DBS is superior to that following dopaminergic treatment, further positioning STN as a crucial structure in pain symptoms in PD and their relief (Sürücü et al., 2013).

The mechanism by which STN-DBS improves pain in PD patients remains unclear, which raises a fundamental question about the link between the subthalamic nucleus (STN) and pain. Preliminary evidence suggests that noxious stimulation can modulate background activity in the STN, at least in the Parkinsonian brain (Belasen et al., 2016; Heise et al., 2008). As a consequence, the STN could be linked to a nociceptive network involved in the perception of noxious stimuli, although this has yet to be explored fully. Despite the classical description of a sensory territory in the STN (Alexander et al., 1986) and the functional impact that STN sensory responses could have on the basal ganglia (Baunez et al., 2011), there is a paucity of information in the literature regarding the type of sensory stimuli that activate this structure and the afferent sensory source(s) (Coizet et al., 2009; Hammond et al., 1978; Matsumura et al., 1992). Two major subcortical central targets for ascending nociceptive information from the spinal cord are potential relays for nociceptive information to the STN: the superior colliculus (SC) and the parabrachial nucleus (PBN) (Hylden et al., 1989; Craig, 1995; Klop et al., 2005; McHaffie et al., 1989).

We have shown that the SC, a highly conserved but evolutionarily ancient subcortical multi-sensory structure, directly projects to the STN and is the primary, if not exclusive, source of visual input into the STN (Coizet et al., 2009; Tokuno et al., 1994). This projection shows that subcortical hyper-direct pathways exist between brainstem sensorimotor structures and the STN which predate, from an evolutionary perspective, those from the cortex — thus reinforcing the position of the STN as a critical input structure processing short latency visual signals in the basal ganglia (Baunez et al., 2011). The substantia nigra pars compacta (SNc) is also on the input side of the basal ganglia and we have shown that SNc receives nociceptive-related afferents from the PBN (Coizet et al., 2010), raising the possibility that the STN may also receive such inputs.

It is interesting to note that the STN is well known to project heavily to basal ganglia output structures such as the substantia nigra pars reticulata (SNr) (Alexander et al., 1986; Gurney et al., 2001), which in turn projects to the SC and PBN (Schneider, 1986; Deniau and Chevalier, 1992), linking the STN, SNr and SC/PBN anatomically. With the STN in a position to modulate a nociceptive network involving the SC/PBN, the elevated activity in the STN in Parkinsonism (Bergman et al., 1994; Albin et al., 1995) could underlie some of the unexplained pain symptoms in this disease, with STN-DBS acting (at least in part) locally to achieve its analgesic effects. Nociceptive processing in the STN would also be consistent with the nucleus’s role as part of the brain’s interrupt circuitry (Jahanshahi et al., 2015), terminating behaviors that achieve negative outcomes, of which pain is a clear example.

Therefore, the main objective of the present work was to characterize the link between STN and nociception, answering the following questions:

• Does the STN process nociceptive information? We explored the possibility that noxious stimulation could induce nociceptive responses in the rat STN with in vivo electrophysiology.

• Is the STN linked to a nociceptive network? We tested the potential role of the SC and PBN in the transmission of nociceptive information to the STN, both physiologically and, in the case of the PBN, anatomically.

• Can manipulation of the integrity of the STN change nociceptive responses measured behaviorally? We tested STN-lesioned and sham-operated rats using a hotplate test.

• Finally, to examine the hypothesis that STN dysfunction could underlie some of the pain symptoms observed in PD, we evaluated whether STN nociceptive responses were abnormal in a rat model of PD.

We present convergent evidence that the STN is functionally linked to a nociceptive network and that STN nociceptive responses are affected in Parkinsonism. The objectives above are summarized in Figure 1.

Figure 1

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The present study demonstrates for the first time that a large majority of STN neurons exhibit various mono- or multi-phasic responses to noxious stimulation, consistent with the hypothesis that one of the functions of the STN is to interrupt behavior when appropriate (Jahanshahi et al., 2015); in this case, to select a more appropriate action to try to relieve the noxious sensation. STN nociceptive responses mainly had a short latency (~20–40 ms) and could be recorded all over the structure. We have shown that most of the responsive cells are nociceptive-specific, as only few of them also respond to non-noxious somatosensory stimulation. In addition, we found that we could differentiate three types of STN neurons, which showed an increase, a decrease or no change, respectively, in their baseline firing rate upon introduction of the noxious stimulation. The spontaneous firing rate of STN ‘down’ cells was significantly higher than that of the two other groups, suggesting the possibility of a separate group of cells. Furthermore, we have shown that STN responses to nociceptive stimuli were abnormal in a rat model of PD, suggesting that the nociceptive responses recorded in STN depend on the integrity of the nigrostriatal DA system.

When determining the afferent source of nociception-related influence on STN activity, we have revealed a crucial role for two brainstem structures, the PBN and the SC, by demonstrating the effects of their inactivation on nociceptive responses in the STN and also by highlighting the existence of an anatomical direct pathway from the PBN to the STN. This parabrachio-subthalamic projection represents a second example of a subcortical hyperdirect pathway to the STN from a sensori-motor structure, in addition to the tecto-subthalamic pathway described previously (Coizet et al., 2009; Tokuno et al., 1994). Finally, we have shown that these anatomico-electrophysiological findings translate into a functional role for the STN in mediating nociception, in that nociceptive behavioral responses were affected by lesions of the STN. However, a note of caution is required since we used only male rats, and thus care should be taken in extrapolating our results to females.

Using noxious electrical stimulation of the hindpaw allowed us to record precisely the timing of responses in our structures of interest with controlled parameters of stimulation. It is interesting to note that the majority of STN nociceptive responses had short latencies (76/79) and were monophasic (40/79), a pattern of responses that is similar in proportion to the pattern of STN responses following visual stimulation (Coizet et al., 2009) but dissimilar to the pattern of STN responses following stimulation of the frontal (Magill et al., 2004), sensorimotor (Fujimoto and Kita, 1993) or motor cortex (Kolomiets et al., 2001). The latter — in the majority of cases — are multi-phasic, with two excitatory phases (equivalent to the present biphasic +/+) often separated by an inhibition (equivalent to the present triphasic +/–/+). It has been hypothesized previously (Magill et al., 2004; Kitai and Deniau, 1981) that the short latency excitation following cortical stimulation appears to be driven by a hyperdirect pathway to the STN,whereas the later phases of the response arise from polysynaptic interactions, which are manifested more slowly. The inhibition following the first excitation has been hypothesized to involve the reciprocally connected STN–globus pallidus (GP) network (Fujimoto and Kita, 1993). STN excitation may activate GP GABAergic neurons, which in return inhibit the STN. Overall, our data suggest that when the rat is subjected to noxious stimulation, the main pathway to the STN that is activated is a fast hyperdirect pathway, originating in part in the PBN. The fact that we only have a few cells showing an inhibitory second phase (10 biphasic and 5 triphasic, 15/79) indicates that STN nociceptive cells are rarely closely connected to the GP and lack GP-STN feedforward control.

Functionally antagonistic STN neuronal subpopulations have been found in the STN. Specific GO and STOP cells have been described in PD patients performing a stop signal paradigm, during motor execution or response inhibition, respectively (Benis et al., 2016). Sub-populations of STN cells have also been shown to code exclusively for reward magnitude (4% vs 32% sucrose [Lardeux et al., 2009]), error-related activity (‘Oops neurons’ [Lardeux et al., 2009]), reward value (cocaine or sucrose [Lardeux et al., 2013]) and for positive and aversive reinforcers (Breysse et al., 2015).

A major finding of our work is that we were able to differentiate a subpopulation of STN neurons that had a higher spontaneous firing rate on the basis of the effect of noxious stimuli on general tonic activity. This finding is important as glutamatergic tone from the STN is likely to have a strong impact on the tonic level of activity in the basal ganglia network, especially in the output structures (as we hypothesized that nociceptive-responding STN cells may not be densely connected to GP). The results from previous computational studies (Gurney et al., 2001) suggest that tonic control by the STN may adjust the general level of activity of the inhibitory GABAergic neurons of the basal ganglia output structures, which are known to project to the SC and PBN (Schneider, 1986; Deniau and Chevalier, 1992). This tonic STN control is hypothesized to be used by the basal ganglia to optimize selection of the most appropriate action. The identification of separate subpopulations of cells in the STN according to their spontaneous firing rate, and the orientation of the change of their firing rate following the occurrence of noxious stimulation,suggests that the tonic excitatory effects of the STN may not be uniform, although further work is required to elucidate the connectivity of the STN subpopulations. This mechanism is important in the context of PD in which STN activity is pathologically increased (Bergman et al., 1994; Albin et al., 1995), probably disrupting this control. This possibility is further supported by our results showing enhanced phasic nociceptive responses in a PD rat model, with an increase in the latency to make nocifensive responses in the hotplate test following lesions of the STN. As well as interfering with action selection, disrupted STN control in PD would probably have an impact on the SC and PBN and their role in sensory signal processing.

In addition to demonstrating that STN neurons process nociceptive information, we also assessed whether two subcortical sensori-motor structures from the brain stem transmit nociceptive signals to the STN. Despite SC nociceptive responses having shorter latencies than those of STN neurons to the same stimulus, chemical suppression and lesions of SC had relatively minor effects on the responses of STN to noxious footshock. Lesions of the SC with acid ibotenic reduced the number of cells that do not respond to noxious stimulation, suggesting that the SC gates the pool of responding cells in the STN. Our previous work has demonstrated that the SC is a critical relay for short-latency visual input into DA neurons (Dommett et al., 2005) but not for short-latency nociceptive input (Coizet et al., 2006) transmitted by the PBN (Coizet et al., 2010). The current results suggest the same organization when considering visual and nociceptive input into the STN. The SC is a crucial structure to transmit visual information while the PBN strongly contributes to the relay of nociceptive signals. PBN lesions significantly reduced the number of STN cells responding to noxious stimuli, sparing a group of cells with short latency short duration responses (Figure 7C), which are possibly activated by nociceptive information relayed by the thalamus (Dostrovsky, 2000a). This nociceptive network linked to the STN is the probable substrate underlying the successful analgesic effects of STN deep-brain stimulation. Kim et al. (2012) hypothesized that STN-DBS improves secondary pain symptoms in PD because this stimulation decreases the abnormally increased muscle tone in patients and may alleviate the primary nociception processing in the central nervous system. DBS effects are complex and despite the success of DBS in treating a variety of psychiatric and neurological disorders, the mechanisms underpinning its therapeutic efficacy remain unclear (McIntyre et al., 2004; Ashkan et al., 2017). DBS is hypothesized to induce a ‘functional lesion’ of the STN (Follett, 2000), via depolarization blockade and synaptic inhibition (Beurrier et al., 2001; Dostrovsky et al., 2000b), which would lead to a suppression of the activity of STN neurons. We hypothesize that these mechanisms would reduce the pathologically increased firing rate in the STN in PD (and thus the pain symptoms), as well as nociceptive responses.

Our current work using anterograde tract-tracing neuroanatomy coupled with 3D reconstruction indicates that a small ascending bundle leaves the PBN and then splits into three massive projections traveling toward the SC, the thalamus and the SNc/STN. Some fibers from this last ascending pathway continue rostrally to terminate in the amygdala and the cortex. Comparison of the size of the bundle leaving the PBN and the size of the bundles traveling to their targets indicate that the number of labelled fibers clearly increase, suggesting that PBN axons have collaterals. This PBN-STN projection is possibly interconnected with other PBN efferents, such as the PBN–amygdala projection, which partly travels through the STN and has cells of origin that are of a similar type to those of the PBN cells projecting to STN (Sarhan et al., 2005). With a DBS effect on axons and fibers (Chiken and Nambu, 2014), the characterization of this projection and network are important in the context of the effects of STN-DBS on pain symptoms. Overall, STN-DBS would not only impact STN and PBN nociceptive processing but would also modulate PBN-amygdala fibers and possibly other PBN efferents via the collaterals. The effect of STN-DBS would therefore impact many aspects of pain such as, for example, pain-related emotional reactions when activating the PBN-amygdaloid connection or neuroendocrine homeostatic regulation in response to pain by activating the PBN-hypothalamic pathway (Gauriau and Bernard, 2002). Further experiments are now needed to fully characterize the effect of STN-DBS on nociceptive processing in our rat models and how aspects of that network are modulated to achieve a DBS-related analgesic effect.

Pain is a multifaceted experience that can be understood in terms of somatosensory, affective and cognitive dimensions. DBS therapies that are focused on a single facet of pain, originally targeting somatosensory networks or more recently targeting affective regions (Schneider, 1986). The STN is a small structure with functional territories such as the limbic, cognitive and sensory, in close proximity to each other. This would allow the potential modulation of different modalities of pain and, in the future, the best placements of DBS electrodes within those territories would have to be tested to maximize the analgesic effect. Finally, numerous non-motor symptoms can worsen or improve depending on the electrical stimulation parameters, as well as the location of the electrode (Kim et al., 2015). The best parameters of stimulation for nociception would need to take into account the effect of those parameters on other symptoms of PD.

Finally, non-neuropathic pain, recently recognized as a frequent and disabling symptom in PD, is a complaint affecting many patients who have numerous neurodegenerative disease such as Alzheimer’s disease and other dementias, motor neuron disease, Huntington’s disease, spinocerebellar ataxia and spinal muscular atrophy (de Tommaso et al., 2016). Our findings on the involvement of the STN in nociceptive processing and its link to a nociceptive network open a new direction for research to explore a possible role of this structure in other pain syndromes, especially extra-pyramidal ones like Huntington’s disease, which is characterized by a dysfunction of the basal ganglia. It also opens up the possibility of developing therapeutic strategies using DBS. A variety of brain sites have been identified for chronic stimulation procedures to attenuate pain (Davis et al., 1998). These targets include the thalamus, the periventricular gray nucleus, the cingulate cortex and the motor cortex (Gorecki et al., 1989; Davis et al., 1998). With the involvement of the STN in a nociceptive network as demonstrated in our work, the STN-DBS technique can thus be considered in the future as a new target for the treatment of pain not only in pharmaco-resistant patients suffering from previously described neurodegenerative disease, but also, for example, in those with chronic pain disease or pharmaco-resistant patients with certain forms of migraine that have been shown to activate the STN (Schwedt et al., 2014).

All data generated or analysed during this study are included in the manuscript and supporting files. Matlab scripts used to analyse the data are freely available on the ImaGIN platform website (https://f-tract.eu/software/imagin/ ; copy of the source code archived at https://github.com/elifesciences-publications/ImaGIN2_source_code).

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Author details

1. Arnaud Pautrat

   1. Inserm, Grenoble, France
   2. Grenoble Institute of Neurosciences, Université Grenoble Alpes, Grenoble, France

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

2. Marta Rolland

   1. Inserm, Grenoble, France
   2. Grenoble Institute of Neurosciences, Université Grenoble Alpes, Grenoble, France

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

3. Margaux Barthelemy

   1. Inserm, Grenoble, France
   2. Grenoble Institute of Neurosciences, Université Grenoble Alpes, Grenoble, France

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Christelle Baunez

   Institut de Neurosciences de la Timone, Aix-Marseille Université, Marseille, France

   Contribution

   Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4368-652X

5. Valérie Sinniger

   1. Grenoble Institute of Neurosciences, Université Grenoble Alpes, Grenoble, France
   2. Service d’Hépato-Gastroentérologie, CHU Grenoble Alpes, Grenoble, France

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

6. Brigitte Piallat

   1. Inserm, Grenoble, France
   2. Grenoble Institute of Neurosciences, Université Grenoble Alpes, Grenoble, France

   Contribution

   Software, Formal analysis, Methodology

   Competing interests

   No competing interests declared

7. Marc Savasta

   1. Inserm, Grenoble, France
   2. Grenoble Institute of Neurosciences, Université Grenoble Alpes, Grenoble, France

   Contribution

   Funding acquisition, Writing—review and editing

   Competing interests

   No competing interests declared

8. Paul G Overton

   Department of Psychology, University of Sheffield, Sheffield, United Kingdom

   Contribution

   Conceptualization, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

9. Olivier David

   1. Inserm, Grenoble, France
   2. Grenoble Institute of Neurosciences, Université Grenoble Alpes, Grenoble, France

   Contribution

   Formal analysis, Funding acquisition, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

10. Veronique Coizet

    1. Inserm, Grenoble, France
    2. Grenoble Institute of Neurosciences, Université Grenoble Alpes, Grenoble, France

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Validation, Methodology, Writing—original draft, Project administration, Writing—review and editing

    For correspondence

    veronique.coizet@univ-grenoble-alpes.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5192-6610

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