Movement related functions of oscillations in the basal ganglia-thalamocortical system in Parkinson’s disease

Movement related functions of oscillations in the basal

ganglia-thalamocortical system in Parkinson’s disease

Bachelor thesis 2.0 by Tijl van den Bos 5823293 5.302 words (without abstract and references)

Olympia Colizoli

The introduction of deep brain stimulation has given the opportunity to measure subcortical structures with good spatial and temporal resolution. To achieve the best therapeutic result the macroelectrodes used in deep brain stimulation are commonly placed in the subthalamic nuclei. The subthalamic nuclei are part of the basal ganglia-thalamocortical system which appears to be excessively synchronized in patients with Parkinson’s disease. Recorded local field potentials from the subthalamic nuclei show that oscillations in the beta band are antikinetic, as they are inversely related to voluntary movements. In contrast, oscillations in the gamma band are prokinetic, as they are positively related to voluntary movements. It seems likely that alpha band oscillations are also prokinetic, but future research is needed to support this. Knowledge about oscillations in the basal ganglia might be used to fine-tune the settings of deep brain stimulation, to regularize the abnormal oscillations in patients with PD and to ameliorate motor deficits and increase the quality of life.

Table of contents

Abstract 1

Introduction 3

Beta band oscillations in relation to motor movement in Parkinson’s disease 7

Complementary roles: beta is antikinetic and gamma is prokinetic 8

Are lower frequency oscillations increased or decreased during movement? 10

Discussion 12

References 14

Introduction

Parkinson’s Disease (PD), first described in 1817, is one of the most common movement disorders affecting 0.5-3% of the population over the age of 65 (Tanner and Goldman, 1996). Patients with PD can have slowness of movement (bradykinesia), difficulty initiating movement (akinesia), rigidity of the muscles, uncontrollable resting tremor, involuntary movement (dyskinesia), stooped posture, shuffling gait, but also sleep disturbance, poor facial expressions, tiny handwriting and monotonous speech (Toffano-Nioche, Beroule and Tassin, 1998; Albada et al., 2009). These symptoms can impede patients with PD in functioning in their daily lives. Turning while walking is often found to be difficult, as are tasks that require manual dexterity, like buttoning (Machin, 2000). Fulfilling basic needs are also often compromised as patients with PD have difficulty chewing food and using utensils (Andersson and Sidenvall, 2001). The reduced motor functions can make patients with PD experience helplessness and vulnerability, but are also a source of embarrassment (Hayes, 2000). This is reflected by reports that indicate that patients with PD are more isolated from social contacts, than their healthy peers (Singer, 1973). Social isolation could also be due to the many psychiatric symptoms that go along the motor deficits. These psychiatric symptoms include depression, anxiety, dementia and cognitive impairments in the domain of speed of mental processing and executive functioning (Ring and Serra-Mestres, 2014).

The primary cause of PD is thought to be a degeneration of dopamine neurons in the substantia nigra (SN) and to a lesser extent the ventral tegmental area (VTA) (Bernheimer et al., 1973; Ehringer and Hornykiewicz, 1960; Hirsch, Graybiel and Agid, 1988; Uhl, Hedreen an Price, 1985), which causes disinhibition of the subthalamic nuclei (STN) and globus pallidus internal (GPi). Research done to discover the etiology of PD supports the role of nigral cell death. Gene mutations (PARK1-8) (Golbe et al., 1990) and several susceptibility genes (Gasser, 2001) have been found which are associated with nigral degeneration, and the metabolism of dopamine and enzymes that protect against environmental toxins, respectively. However, twin and family studies show very conflicting results, so it remains unknown how big the contribution of these genes are to the cause of PD (Warner and Schapira, 2003). Environmental factors also appear to play a role in the onset of PD. The designer drug 1-methyl-4-phenyl-1,2,3,6-tetrahypdropyridine (MPTP) can induce parkinsonian symptoms in 7 to 14 days by causing nigral cell death (Vingerhoets et al., 1994). Likewise, exposure to pesticide and herbicide seems to make people more susceptible to PD (Betarbet et al., 2000).

In the healthy brain the SN and VTA provide dopaminergic input to the basal ganglia (BG), which in turn are involved in acquiring automatic behaviour to enhance the efficiency of higher order functions (Raunch and Savage, 1997). To achieve automatic behaviour, the BG modulate movement

(Mink, 1996), attention, working memory, implicit learning, memory and reward processing (Ring and Serra-Mestres, 2014). The BG consist of the following structures: the striatum, the SN, the STN, the GPi and the globus pallidus external (GPe). The BG are connected to the cortex via the thalamus in what is named the basal ganglia-thalamocortical system (BGTCS) (Albada, Gray and Robinson, 2009) depicted in Figure 1. The cortex projects with excitatory input onto the basal ganglia, mainly on the striatum. D1 striatal neurons have inhibitory projections on the GPi and the SN. D2 striatal neurons have inhibitory projections on the GPe. The GPi and SN both exert an inhibitory influence on thalamus. The thalamus in turn projects back on the cortex with excitatory neurons completing the direct loop. In another loop, the GPe has inhibitory projections on the STN which in turn has excitatory projections on the GPi and SN. The GPi and SN again project on the thalamus completing the indirect loop via the cortex. The hyperdirect loop goes from the cortex with excitatory projections directly on the STN and then follows the indirect loop. As shown in Figure 1, the STN also projects back on the GPe with excitatory actions creating the STN-GPe loop.

Figure 1. The basal ganglia-thalamocortical system. The basal ganglia include the striatum, the globus pallidus internal (GPi) and external (GPe), the substantia nigra (SN) and the subthalamic nuclei (STN). The STN and GPi together form the STN-GPi loop. The green lines are excitatory connections. The red lines are inhibitory connections. The arrow indicates the direction of the projection. The thickness of the line gives no indication of the strength of the connection.

The introduction of deep brain stimulation (DBS) in 1987 gave patients with Parkinson’s disease a good alternative to neurosurgical removal of certain brain areas as to ameliorate the resting tremor (Chen et al., 2012). DBS makes use of unilateral or bilateral placement of macroelectrodes in the brain. Each macroelectrode has four contact points to stimulate with, or record from. More often used as a stimulator, recording with the macroelectrodes is very advantageous for research since deeper structures can be measured than in electroencephalography (EEG) or magnetoencephalography (MEG). DBS electrodes in the brain of PD patients are most commonly placed in the STN and GPi due to their hyperactivity in PD (Rodriguez-Oroz and Jahanshahi, 2009). STN DBS is favoured over GPi DBS as a target since it significantly decreases the daily dose of dopaminergic medication needed and the PD patients show better motor functioning (Moro et al., 2010; Witt et al., 2008). In the healthy brain, the STN is involved in a large variety of functions: attention, executive functions, verbal learning and memory, verbal abstract reasoning, conflict resolution, and emotions (Balâz et al., 2011). In relation to motor functioning, the STN is thought to have an inhibitory effect; inhibiting movement (Rowe and Siebner, 2012).

After loss of striatal dopamine the STN-GPe loop is more sensitive to rhythmic inputs (Bevan et al., 2006). Also, the STN-GPe loop seems to be able to enhance rhythmic oscillations coming from the striatum (Baufreton et al., 2005), possibly reinforcing the already abnormal neuronal discharge created by the loss of striatal dopamine. Also, in-vitro studies have demonstrated that the STN-GPe loop is capable of pace making activity, in isolation from other synaptic input (Plenz and Kital, 1999). Taken together, this could mean that the STN-GPe loop generates oscillatory frequencies (Albada et al., 2009) and might be more prone to do so in PD. Consequently these abnormal oscillatory activities spread to the BG output nuclei, thalamus and cortex (Deuschl et al., 2000; Terman and Goldman, 2002). The involvement of the STN-GPe loop in rhythmic oscillations could be another reason why targeting the STN with DBS over other structures in the BG, has the best therapeutic effect.

The macroelectrodes used in DBS can measure local field potentials (LFP) when connected to an amplifier and converted into a digital signal, just like it is done with EEG. LFPs are created by the synchronised summation of postsynaptic changes measured in the extracellular space (Buzsaki, Anastassiou and Koch, 2012). In other words, the DBS electrodes measures neuronal input and output between neuronal populations ranging over 1 millimetre (Stein and Bar-Gad, 2013). The synchronized firing rate of the measured neurons can be expressed in frequency bands ranging from delta (0-3Hz), theta (4-7Hz), alpha (8-12 Hz), beta (13-30Hz) to gamma (>30Hz) (Rodriguez-Oroz et al., 2001). The defined ranges of these frequency bands can vary slightly between articles, but no more than one or two hertz.

The depletion of striatal dopamine in PD seems to be related to abnormal neuronal discharge synchrony in the basal ganglia. Animal studies have shown that the synchronous firing in the GPi/GPe or STN is very low in monkeys with PD in comparison with healthy monkeys (Heimer et al., 2006). In rats with PD, activities between the BG and the motor cortex are more found to be in the theta and gamma band frequency in comparison to healthy rats (Magill et al., 2006; Berke, 2009).

Since the introduction of DBS multiple studies have done similar research with humans. There seems to be strong support for abnormal beta band activity in the BG in patients with PD (Quiroga-Varela et al., 2013; Alegre and Valencia, 2013; Rivlin-Etzion et al., 2006). However, there is no consensus on the role of this abnormal beta activity in the BG. Multiple theories have been proposed: maintenance of the current behavioural state (Engel and Fries, 2010), involvement in movement initiation and termination (Alegre and Valencia, 2013), and a gating role to facilitate processing and initiation of movement (Klostermann et al., 2007; Kühn et al., 2004). In addition, there seems to be no correlation between beta band activity and specific motor symptoms such as bradykinesia, akinesia and rigidity (Moran et al., 2008). Thus abnormal beta band oscillations are present in the BG in patients with PD, however it is unclear how this is related to PD.

Other recent studies have found gamma band oscillations in the BG in PD patients, but just like the beta band oscillations, the function of gamma band oscillations is unclear. As gamma band oscillations are related to a state of arousal (Kempf et al., 2009) and are correlated to the speed and scale of voluntary movements (Brücke et al., 2012) it has been suggested that gamma band oscillations might determine the vigour or effort for a response (Jenksinson, Kühn and Brown, 2013). Others have related gamma oscillations to increased resting tremor in PD patients (Weinberger et al., 2009) and to improvements in motor symptoms upon treatment of dopamine medication (Khün et al., 2006). When dyskinesia becomes apparent in PD patients there also seems to be a negative correlation between gamma and beta band activity (Alonso-French et al., 2006).

Varying results have also been reported for the lower frequency bands. Alpha and theta bands are related to parkinsonian rest and action tremor (Brown et al., 2004; Cassidy et al., 2002), dystonia and levodopa induced dyskinesia (Brown and Williams, 2005). Taken together with beta band oscillations (8-30 Hz) alpha band oscillations have also found to be suppressed during voluntary movement (Brown and Williams, 2005). From these studies it seems likely that lower frequencies like alpha and theta are negatively related to motor control, however the function of the lower frequency bands in the BG remain very unspecific.

In the current review, the role of beta, gamma, theta and alpha band oscillations will be further discussed. I propose that beta band oscillations are antikinetic, because it has been shown

that beta band oscillations in the BG increased when no voluntary movement is made and were inversely correlated with motor control. As a complement to the antikinetic role of beta oscillations, I propose that gamma band oscillations are prokinetic in the BG, since they were enhanced during voluntary movement and positively related to motor control. Finally, theta and alpha band oscillations are proposed to be prokinetic, however, this remains inconclusive. It should be noted that all the measures in the research discussed below have been done using the macroelectrodes placed in the PD patients for the use of DBS. If other instruments are used, this will be indicated.

Beta band oscillations in relation to motor movement in Parkinson’s disease

Different theories have been proposed in regard to beta band oscillations in the STN in PD. In this review, evidence for an antikinetic role will be discussed. A study where patients with PD had to sit on a chair without making any voluntary movements, supports the antikinetic role of beta band oscillations (Little et al., 2013). Results show that the patients had an increase in beta band synchronization, in comparison to when they did make voluntary movements. This increase in beta band synchronization was suppressed when dopamine medication was administered. Supporting the idea that striatal dopamine depletion and increased beta band oscillations are closely related. The increased beta band synchronization was expressed as coherency, co-modulation and phase locking between the left and right STN. Phase locking in particular is an indication of synchronous neuronal firing (Little et al., 2013), implying that beta band oscillations are strengthened when PD patients showed no voluntary movements.

In addition, when PD patients had to respond in a movement task beta band desynchronization occurred in the STN, compared to when the patients had to remain still (Oswal, et al., 2012). Thus, when a movement is needed, beta band oscillations in the STN desynchronize. The desynchronized state was greater when the patients were on dopamine medication compared to when they were off medication. This evidence is complementary to the study of Little et al. (2013) which stated that no movement is related to beta band synchronization in the STN. Desynchronization also occurred in the STN in patients with PD when they were tapping their fingers at a slow, medium or high rate (Joundi et al., 2013). In between taps, a relative rebound in synchronization in the beta band frequency was noticed, but only for the slow and medium tap rate. Although the patients were on medication only, it still is in line with the previous studies supporting the inverse relationship between movement and beta band oscillations in the STN. In addition, the level of beta band desynchronization was the same for all the finger tapping rates, indicating that the beta band oscillations are related to moving or not moving instead of the movement mechanisms that are applied (Joundi et al., 2013).

A study in which stimulation was applied in the STN in patients with PD showed that the performance during a finger tapping task was made worse when DBS was set at 5-10 (theta and alpha) and 20-25 Hz (beta) (Fogelson et al., 2005). Although it is uncertain if stimulating the STN in a certain frequency triggers the STN to produce the same frequency, it has been suggested that stimulating the STN results in local neuronal synchronization measured in the GPi (Brown et al., 2004). Nevertheless, the frequency responsible for decreased tapping performance lies again in the beta band. This study also hints at a causal relationship between movement and oscillations in the beta band, where the oscillations are the cause for decreased motor performance.

The beta band oscillations found in the STN in PD patients were also found in the ipsilateral sensorimotor and premotor cortex in the same patients (Hirschman et al., 2011). Coherence between the beta band frequencies was found using MEG and DBS to measure LFPs in the surface of the whole brain and the STN, respectively. In addition to beta band oscillations, alpha band oscillations were also found in the STN. The alpha band oscillations in the STN showed coherence with the same frequency in the ipsilateral temporal lobe. The PD patients were not to move and although no movement task was applied to compare the findings the patients were off medication, which could imply that the found coherence in oscillations could be abnormal. That the found oscillations might be abnormal, is in account of evidence that shows that striatal dopamine depletion is closely related to increased beta band oscillations in the STN (Little et al., 2013).

The coherency between the motor cortex and the STN is in line with the BGTCS supporting the idea that the BG, thalamus and cortex are abnormally synchronized because of the STN-GPe loop (Albada et al., 2009). Together with the findings that desynchronization in the beta band in the STN are related to voluntary movements and synchronization in the beta band is related to no movement or deterioration of movement, it is likely that beta band oscillations serve as an antikinetic and inhibit movement. Alonso-French et al., (2006) found that Beta band oscillations were negatively correlated to gamma band oscillations in the STN, in regard to movement. This negative correlation suggests that gamma band oscillations in the STN are prokinetic and complement the antikinetic effect of beta band oscillations. Support for the prokinetic role of gamma band oscillations is found in multiple studies and will be discussed next.

Complementary roles: beta is antikinetic and gamma is prokinetic

The antikinetic function of beta band oscillations in the STN seems to be convincing. The following studies will demonstrate that gamma band oscillations complement beta band oscillations, as they appear to be positively related to movement in the STN. A study where patients with PD had to grab and release a force dynamometer demonstrated these complementary roles (Tan et al.,

2013a). A force dynamometer is a handle which can be squeezed to measure the distribution of force in ones hands. When force decrement was higher, but contraction should have been sustained a decrease in gamma band oscillations (55-375 HZ) and an increase in beta band oscillations (13-23 Hz) was observed in the STN. This evidence supports the theory that beta and gamma band oscillations might serve as an antikinetic and a prokinetic mediator, respectively. Furthermore, increased theta and alpha (5-12 Hz) band oscillations predicted better performance, reduced force decrement, shortened release time and faster force offset (Tan et al., 2013a). Results on theta and alpha band oscillations will be discussed in the section about these lower frequencies.

More support for the antikinetic and prokinetic role of beta and gamma band oscillations in the STN, respectively, was found by three studies using arm movement or grasping tasks (Joundi et al., 2012a; Tan et al., 2013b; Alegre et al., 2010). In all three studies, beta band oscillations were suppressed during movement and gamma band oscillations were enhanced during movement. In addition, the beta band oscillations were a predictor for low effort to move and gamma band oscillations were a predictor for high effort to move (Tan et al., 2013b). This could support a wider role for the kinetic modulation of beta and gamma oscillations in the STN. Instead of being directly related to the movement dynamics like muscle contractions, beta and gamma oscillations could be more related to the effort to be assigned to a response that is then organised elsewhere (Schadmehr and Krakauer, 2008). In two of the three studies (Tan et al., 2013b; Alegre et al., 2010) theta and alpha bands oscillations were also enhanced during movement.

The prokinetic and antikinetic role of gamma and beta band oscillations was also shown in the motor cortex, in healthy subjects while performing a go/no-go task (Joundi et al., 2012b). During the task the participants were stimulated using transcranial alternating current stimulation (TACS) on the hand area of the motor cortex. TACS can entrain oscillatory activities in the cortex in a non-invasive manner (Pogosyan et al., 2009) at the frequency of the stimulation (Zaehle, Rach and Herrmann, 2010). TACS provides an opportunity to study the effects of specific frequencies on the cortex. In go trials, the force development and force peak was reduced and increased with 20 Hz and 70 Hz stimulation, respectively, in comparison to no stimulation. In no-go trials, 20 Hz stimulation resulted in a decrease in force development, in contrast to no stimulation. Thus, the beta and gamma band oscillations in the STN also seem to be present in the motor cortex, in the same manner.

Evidence that the complementary functions of beta and gamma band oscillations are also present in the motor cortex, is supported by the study of Shimato et al. (2013). Shimamoto et al. (2013) found that the oscillations in the STN seem to be excessively synchronized to the oscillations in the primary motor cortex. Neuronal discharges in the STN where measured using single unit

recordings with microelectrodes in the STN and cross-correlated to LFPs in the primary motor cortex, which were measured with subdural electrocorticography (ECoG). To measure LFPs using ECoG, contact electrodes have to be put on the cortex by means of surgery. With the electrodes under the skull, the spatial and temporal resolution is excellent (Shimamoto et al., 2013). Shimamoto et al. (2013) found that the oscillations in the STN were phase-amplitude coupled to that of the gamma oscillations in the primary motor cortex. In other words, the neuronal discharge in the STN was driven by gamma band oscillations in the primary motor cortex. In turn, the gamma oscillations in the primary motor cortex were modulated by lower frequency oscillations (4-30 Hz). These results were PD specific, as they were not found in patients with primary craniocervical dystonia.

Thus, support for the antikinetic role of beta band oscillations and the prokinetic role of gamma band oscillations in the STN seems to be convincing. Most likely, theta, alpha and beta band oscillations in the motor cortex mediate the power of gamma band oscillations, which in turn drives the STN via the hyperdirect pathway (Shimamoto et al., 2013). As stated earlier, the STN can be more sensitive to rhythmic input after striatal dopamine depletion (Bevan et al., 2006) and is capable of enhancing rhythmic oscillations (Baufreton et al., 2005), possibly keeping the excessive synchronization with the motor cortex intact. Besides mediating gamma power, theta and alpha band oscillations in the STN also seemed to be positively related to grasping performance in patients with PD (Tan et al., 2013a; Tan et al., 2013b; Alegre et al., 2010). In the next section these lower frequencies will be further discussed to specify their function in the BG.

Are lower frequency oscillations increased or decreased during movement?

Earlier studies show that theta and alpha band oscillations are correlated to tremor (Brown et al., 2004; Cassidy et al., 2002), dystonia and dyskinesia (Brown and Williams, 2005). More recent research hints towards a prokinetic role of theta and alpha band oscillations in the STN. However, the role for the lower frequency bands remains inconclusive since contradictory results have been found, as will be indicated with the next studies. First it was observed that patients with PD had increased alpha band synchronization in the STN during fast boxing like movements of the arm (Singh et al., 2011). Singh et al. (2011) argued that the increased alpha activity was task specific because they found the same alpha band oscillations in patients with dystonia. In accordance with this study, more recent findings show that during fast grasping movements patients with PD show increased theta, alpha and gamma band oscillations in the STN (Anzak et al., 2012). Thus, lower frequencies seem to be increased during (fast) movements, which implies that they are prokinetic. This is in line with the previously discussed research, stating that increased theta and alpha band power predicts better grasping performance (Tan et al., 2013a) and that alpha band oscillations were enhanced during

movement (Tan et al., 2013b; Alegre et al., 2010), supporting a prokinetic role for alpha band oscillations in the STN.

On the other hand, while performing a finger-moving task, patients with PD appeared to have reduced alpha band oscillations in the STN, starting two seconds before movement onset (Oswal, Brown and Litvak, 2013). In addition, alpha band coherence between the STN and temporal lobe was also decreased during movement. Measurements on the temporal lobe were done with MEG while recording from the macroelectrodes in the STN placed for DBS. MEG measures the magnetic fields of postsynaptic dendrites and so can measure LFPs in the cortical surface with relatively good spatial resolution (Oswal et al, 2013). Results from Oswal et al. (2013) suggest that the role of alpha band oscillations are not prokinetic, but antikinetic since they are reduced during movement.

The evidence for desynchronized alpha band oscillations between the STN and the temporal lobe, during movement, complement the results from Hirschman et al. (2011). Hirschman et al. (2011) found that, during rest, the alpha band oscillations were synchronized between the STN and the temporal lobe. Thus alpha seems to be active between the STN and the temporal lobe. In contrast to beta and gamma band oscillations, which seems to be active between the STN and motor cortex, as depicted in Figure 2. According to Hirschman et al. (2011), the alpha band coherence could reflect a coupling between the sensory region of the basal ganglia and the temporal cortex, which may play a role in attentional processing. Others (Palva and Palva, 2007) have also related alpha activities to attentional mechanisms. As stated earlier the STN are involved in attentional processes (Balâz et al., 2011), so it should not be surprising to find frequencies that are related to attentional mechanisms, when recording from the STN. As a concluding remark, it has been found that involuntary spatial attention processes were more active in patients with PD, than in healthy controls (Briand et al., 2001). More research should point out if the found alpha band oscillations between the STN and the temporal lobe are related to these involuntary spatial attentional processes specifically.

In short, research shows contradictory results on the role of theta and alpha band oscillations, but the majority support the role for a prokinetic modulator. How this relates to tremors, dystonia and dyskinesia remains unclear. However, evidence shows that the lower oscillations are active between the STN and the temporal lobe. In contrast to the higher frequencies, which are active between the STN and the motor cortex.

Figure 2. A simplified view of the oscillatory connections between the subthalamic nucleus (STN) and the motor cortex and the STN and the temporal lobe.

Discussion

Parkinson’s disease is a very common illness that has a very broad spectrum of motor symptoms like tremors, bradykinesia, akinesia and dyskinesia. In addition, around half the patients with PD also experience psychiatric symptoms, like depressions or dementia (Ring and Serra-Mestres, 2014). The symptoms can make the daily life of a patient very problematic, considering fundamental tasks like walking (Machin, 2000) and eating (Andersson and Sidenvall, 2001) are made difficult. Since the introduction of DBS patients have an alternative treatment to ameliorate the tremors, that patients with PD often experience (Chen et al., 2012). Besides the therapeutic effect of DBS, the placed macroelectrodes can also be used to record LFPs. This is very convenient for research, since deep structures can be measure that are out of reach for EEG and MEG. In the current review, frequencies of neuronal discharge (oscillations) of the BG are related to movement in patients with PD. Beta band oscillations and gamma band oscillations appeared to complement each other. Beta band oscillations are related to movement decrement and are suppressed during movement, thus, supporting an antikinetic role. Gamma band oscillations on the other hand are related to voluntary movements, therefore, supporting a prokinetic role.

Converging evidence on lower frequencies like theta and alpha band oscillations in the STN is less clear. However, since the majority of the results relate theta and alpha band oscillations to voluntary movement, there is a trend towards a more prokinetic role for these frequencies. These results seem to be in contrast to theta and alpha band oscillations being related to tremor (Brown et

al., 2004; Cassidy et al., 2002), dystonia and dyskinesia (Brown and Williams, 2005), because these symptoms are defined as a state in which involuntary movements are made. However, most patients with PD that undergo DBS require DBS to ameliorate tremors or dystonia (Chen et al., 2012). Form the research discussed that reported theta and alpha band oscillations only one (Anzak et al., 2012) reported the specific symptoms (dyskinesia) of the patients. So it might be the case that the patients tested in the discussed research have tremors and/ or dystonia, and when they make a voluntary movement, this movement is related to increased theta and alpha band oscillations. Still, this is very speculative and future research should test the specific relation of movement to the lower frequency bands in the BG in patients with PD.

The antikinetic role of beta band oscillations is in line with the theory that beta band oscillations are involved in movement initiation and termination (Alegre and Valencia, 2013). Also Klostermann et al. (2004) theorized that beta band oscillations have a gating role to facilitate processing and initiation of movement. The gating role of beta band oscillations was supported by Shimamoto et al. (2013), who found that beta band oscillations together with theta and alpha band oscillations mediate the power of gamma band oscillations in the motor cortex. The modulated gamma band oscillations project on the STN via the hyperdirect pathway where rhythmic oscillations can be strengthened by the STN-GPe loop and via the indirect pathway go back to the cortex, closing the loop.

Another interesting finding was that theta and alpha band oscillations were more active between the STN and the temporal lobe, than between the STN and the motor cortex. According to Hirschman et al. (2011) this could mean that alpha band oscillations are more related to attentional mechanisms in relation to movement. As was stated earlier, patients with PD have more active involuntary visual attention processes, than healthy people (Briand et al., 2001). So the increased alpha band oscillations between the STN and the temporal lobe (Hirschman et al., 2001) could be these more activated attention processes. If these more activated involuntary visual attention processes are a product of PD, or a learned mechanism to cope with the disease, remains unclear.

A few limitations should be noted. First, only one study (Tan et al., 2013) reported using a control group consisting of healthy subjects. The lack of control groups in the discussed research is because DBS is a very invasive procedure that healthy people most likely do not need. So it is difficult to test if the found neuronal oscillations are abnormal or that they also occur in healthy people. Second, only two authors reported using more than 20 subjects (Little et al., 2013; Shimamoto et al., 2013). Most of the discussed articles stated very small subject groups were recruited, consisting of around ten subjects. Giving another reason to generalize the found results with caution. Even so, DBS

gives an opportunity to measure LFPs deep in the brain, with very good temporal and spatial resolution, that is not matched by other electrophysiological measures (Chen et al., 2012). Making it a very useful instrument to measure brain activity.

In conclusion, patients with PD show increased beta and gamma band oscillations in the STN when making not voluntary movements and making voluntary movements, respectively. PD is caused by a depletion of striatal dopamine (Bernheimer et al., 1973) which might cause the STN-GPe loop to generate and strengthen neuronal oscillations. Evidence that the STN-GPe loop reacts differently on input when the BG is depleted of dopamine (Bevan et al., 2006), indicates that the found beta and gamma band oscillations might be abnormal. The lower frequency bands in PD are less clear in their functional relation to the disease, but the majority of the research on PD points towards a prokinetic role for the lower frequency bands in the BG. Future research should specify how these frequencies relate to Parkinsonian symptoms like dystonia and tremors and how they are related to attentional mechanisms. An option would be to recruit PD patients with DBS who only experience tremors and patients with DBS who only experience dystonia, as motor deficits. These two groups should then be compared, when executing a movement task. To also incorporate attention in the study, one could ask the patients to direct their attention elsewhere when they are performing a movement task.

Although DBS is not a cure for PD, it improves the quality of life by ameliorating motor deficits (Deuschl et al., 2006; Weaver et al., 2009; Schüpbach et al., 2007) and giving patients with PD the ability to function in their everyday life. As is reported by patients with PD, maintaining independence is one of the most important issues in dealing with the disease (Hayes, 2002). DBS is the right treatment to give back the independence that patients need. The settings that are used in DBS vary greatly among patients and finding the right setting may take over a year (Okun, 2012). Since DBS has thought to regularize neural firing patterns across the BGTCS (McIntyre and Hahn, 2010) knowledge about which oscillations in the BG are dysfunctional might allow us to better tune the DBS treatment to deal with the symptoms of PD faster.

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