Functional neuroimaging and repetitive transcranial magnetic stimulation in Parkinson's disease

Functional neuroimaging provides insights into the pathogenesis of motor symptoms in Parkinson's disease (PD) and improves our understanding of both established neuromodulatory therapies such as deep brain stimulation (DBS) and potential ones such as repetitive transcranial magnetic stimulation (rTMS). Functional imaging studies can reveal the consequences of the dopaminergic lesion in PD among a widespread network of subcortical-cortical regions. Characteristic patterns of normal cortical brain activation for motor tasks are systematically altered in PD. Recent work has emphasized the task dependence of these changes and their gradual evolution over the course of the disease. Clinically relevant PD treatment with medications or DBS tends to normalize these patterns. In this context, rTMS is discussed as a potential noninvasive alternative for neuromodulation of cortical function. Although rTMS is not a current treatment, we review recent rTMS studies in PD that suggest its promise, illustrate how functional imaging can guide application of rTMS, and suggest that subcortical dopamine release could be an rTMS mechanism of action. The combination of rTMS and functional neuroimaging broadens our knowledge of functional cortical networks in PD, which can eventually provide physicians with pathophysiologic information about different PD treatment options and rationales for neuromodulatory interventions.     

High-frequency rTMS improves time perception in Parkinson disease

Patients with Parkinson disease (PD) are impaired in time processing. The authors investigated the effects of high-frequency (5 Hz) repetitive transcranial magnetic stimulation (rTMS) in patients with PD performing a time reproduction task. The authors found significant improvement in time processing induced by rTMS when trains were applied over the right dorsolateral prefrontal cortex (DLPFC) but not over the supplementary motor area, suggesting that the circuit involving the basal ganglia and the DLPFC might constitute the neural network subserving time perception.     

Repetitive transcranial magnetic stimulation to improve mood and motor function in Parkinson's disease

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that can produce lasting changes in excitability and activity in cortical regions underneath the stimulation coil (local effect), but also within functionally connected cortical or subcortical regions (remote effects). Since the clinical presentation of Parkinson's disease (PD) is related to abnormal neuronal activity within the basal ganglia and cortical regions, including the primary motor cortex, the premotor cortex and the prefrontal cortex, several studies have used rTMS to improve brain function in PD. Here, we review the studies that have investigated the possible therapeutic effects of rTMS on mood and motor function in PD patients. We highlight some methodological inconsistencies and problems, including the difficulty to define the most effective protocol for rTMS or to establish an appropriate placebo condition. We finally propose future directions of research that may help to improve the therapeutic efficacy of rTMS in PD.     

Modulatory effects of 5Hz rTMS over the primary somatosensory cortex in focal dystonia—An fMRI‐TMS study

Dystonia is associated with impaired somatosensory ability. The electrophysiological method of repetitive transcranial magnetic stimulation (rTMS) can be used for noninvasive stimulation of the human cortex and can alter cortical excitability and associated behavior. Among others, rTMS can alter/improve somatosensory discrimation abilities, as shown in healthy controls. We applied 5Hz‐rTMS over the left primary somatosensory cortex (S1) in 5 patients with right‐sided writer's dystonia and 5 controls. We studied rTMS effects on tactile discrimination accuracy and concomitant rTMS‐induced changes in hemodynamic activity measured by functional magnetic resonance imaging (fMRI). Before rTMS, patients performed worse on the discrimination task than controls even though fMRI showed greater task‐related activation bilaterally in the basal ganglia (BG). In controls, rTMS led to improved discrimination; fMRI revealed this was associated with increased activity of the stimulated S1, bilateral premotor cortex and BG. In dystonia patients, rTMS had no effect on discrimination; fMRI showed similar cortical effects to controls except for no effects in BG. Improved discrimination after rTMS in controls is linked to enhanced activation of S1 and BG. Failure of rTMS to increase BG activation in dystonia may be associated with the lack of effect on sensory discrimination in this group and may reflect impaired processing in BG‐S1 connections. Alternatively, the increased BG activation seen in the baseline state without rTMS may reflect a compensatory strategy that saturates a BG contribution to this task. © 2010 Movement Disorder Society     

Baseline functional connectivity may predict placebo responses to accelerated rTMS treatment in major depression

Although in theory sham repetitive transcranial magnetic stimulation (rTMS) has no inherent therapeutic value, nonetheless, such placebo stimulations may have relevant therapeutic effects in clinically depressed patients. On the other hand, antidepressant responses to sham rTMS are quite heterogeneous across individuals and its neural underpinnings have not been explored yet. The current brain imaging study aims to detect baseline neural fingerprints resulting in clinically beneficial placebo rTMS treatment responses. We collected resting‐state functional magnetic resonance imaging data prior to a registered randomized clinical trial of accelerated placebo stimulation protocol in patients documented with treatment‐resistant depression ( http://clinicaltrials.gov/show/NCT01832805 ). In addition to global brain connectivity and rostral anterior cingulate cortex (rACC) seed‐based functional connectivity (FC), elastic‐net regression and cross‐validation procedures were used to identify baseline intrinsic brain connectivity biomarkers for sham‐rTMS responses. Placebo responses to accelerated sham rTMS were correlated with baseline global brain connectivity in the rACC/ventral medial prefrontal cortex (vmPFC). Concerning the rACC seed‐based FC analysis, the placebo response was associated positively with the precuneus/posterior cingulate (PCun/PCC) cortex and negatively with the middle frontal gyrus. Our findings provide first brain imaging evidence for placebo responses to sham stimulation being predictable from rACC rsFC profiles, especially in brain areas implicated in (re)appraisal and self‐focus processes.     

Disturbances of self-other distinction after stimulation of the extrastriate body area in the human brain

In a recent experiment with functional magnetic-resonance imaging, we found that brain activity in the extrastriate body area (EBA) distinguished between observed self- and other-generated movements, being significantly higher during observation of someone else's movement. Here, we investigated further the role of EBA in self-other distinctions using low-frequency repetitive transcranial magnetic stimulation (rTMS). As compared with rTMS applied over a control site, rTMS applied over the EBA increased reaction times, without affecting accuracy, for the detection of other-generated movements. Performance on a control motion-direction detection task was unaffected. These findings provide additional evidence for the role of the EBA in processing information necessary for identifying ourselves as agents of self-generated movements.     

Deep brain stimulation of globus pallidus internus for dystonia

Neuromodulation is the functional modification of neural structures through the use of electrical stimulation. Its most clinically applicable use is deep brain stimulation (DBS) of basal ganglia structures in Parkinson's disease (PD) and essential tremor (ET). More recently, it has been used as a means of treating dystonic movement disorders. The main target of DBS for dystonia is the posteroventral globus pallidus internus (GPi), although the thalamus has been used as an alternate target in a minority of cases. In comparison to the effects seen in PD, the improvement in dystonic postures appear to differ in several ways--delay of clinical benefit, higher voltage requirements, and varied stimulator settings. In this review, the authors discuss the clinical characteristics, pathophysiology, microelectrode recording (MER) signatures, optimal surgical targets, programming parameters and outcomes in dystonia.     

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

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

Controlling pallidal oscillations in real-time in Parkinson's disease using evoked interference deep brain stimulation (eiDBS): Proof of concept in the human

Approaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 13–35 Hz (“beta band”) oscillatory dynamics in the manifestation of Parkinson's disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulses with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequency-specific (16–22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.     

Effects of low-frequency stimulation of the subthalamic nucleus on movement in Parkinson's disease

Excessive synchronization of basal ganglia neural activity at low frequencies is considered a hallmark of Parkinson's disease (PD). However, few studies have unambiguously linked this activity to movement impairment through direct stimulation of basal ganglia targets at low frequency. Furthermore, these studies have varied in their methodology and findings, so it remains unclear whether stimulation at any or all frequencies < or = 20 Hz impairs movement and if so, whether effects are identical across this broad frequency band. To address these issues, 18 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both subthalamic nuclei were stimulated bilaterally at 5, 10 and 20 Hz after overnight withdrawal of their medication and the effects of the DBS on a finger tapping task were compared to performance without DBS (0 Hz). Tapping rate decreased at 5 and 20 Hz compared to 0 Hz (by 11.8+/-4.9%, p=0.022 and 7.4+/-2.6%, p=0.009, respectively) on those sides with relatively preserved baseline task performance. Moreover, the coefficient of variation of tap intervals increased at 5 and 10 Hz compared to 0 Hz (by 70.4+/-35.8%, p=0.038 and 81.5+/-48.2%, p=0.043, respectively). These data suggest that the susceptibility of basal ganglia networks to the effects of excessive synchronization may be elevated across a broad low-frequency band in parkinsonian patients, although the nature of the consequent motor impairment may depend on the precise frequencies at which synchronization occurs.     

Disturbances of self–other distinction after stimulation of the extrastriate body area in the human brain

Abstract

In a recent experiment with functional magnetic-resonance imaging, we found that brain activity in the extrastriate body area (EBA) distinguished between observed self- and other-generated movements, being significantly higher during observation of someone else's movement. Here, we investigated further the role of EBA in self–other distinctions using low-frequency repetitive transcranial magnetic stimulation (rTMS). As compared with rTMS applied over a control site, rTMS applied over the EBA increased reaction times, without affecting accuracy, for the detection of other-generated movements. Performance on a control motion-direction detection task was unaffected. These findings provide additional evidence for the role of the EBA in processing information necessary for identifying ourselves as agents of self-generated movements.     

Exploring the after-effects of theta burst magnetic stimulation on the human motor cortex: a functional imaging study

Theta burst stimulation (TBS) is a protocol of subthreshold repetitive transcranial magnetic stimulation (rTMS) inducing changes in cortical excitability. From functional imaging studies with conventional subthreshold rTMS protocols, it remains unclear what type of modulation occurs (direction and dependency to neural activity) and whether putative effects are bound to unspecific changes in cerebral perfusion or require a functional challenge. In a within-subjects (n = 17) repeated measurement design including real TBS and a control session without stimulation, we examined neural activation in a choice-reaction task after application of intermittent TBS, a protocol, which enhances cortical excitability over the left motor cortex (M1). Brain activity was monitored by blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging interleaved with measuring regional cerebral blood flow (rCBF) at rest using MR-based perfusion imaging. On a separate day, TMS-induced compound muscle action potentials (cMAPs) amplitude of the right hand was measured after excitatory TBS. Compared to control, a significant decrease in BOLD signal due to right hand motor activity during the choice-reaction task was observed mainly in the stimulated M1 and motor-related remote areas after stimulation. This decrease might represent a facilitating effect, because cMAPs amplitude increased upon TBS compared to control. No changes in rCBF at rest were observed. The data demonstrate that subthreshold intermittent TBS targets both the stimulated cortical area as well as remote areas. The facilitation changing the efficacy of neural signal transmission seems to be reflected by a BOLD signal decrease, whereas the network at rest does not appear to be affected.     

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease

ObjectivesDeep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.Materials and MethodsWe measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.ResultsA short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).ConclusionsOur results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for the study is NCT04658641.     

Functional connectivity of the anterior cingulate cortex predicts treatment outcome for rTMS in treatment-resistant depression at 3-month follow-up

Background and objectiveRepetitive transcranial magnetic stimulation (rTMS) is a first-line treatment for treatment-resistant depression (TRD). The mechanisms of action of rTMS are not fully understood, and no biomarkers are available to assist in clinical practice to predict response to rTMS. This study aimed to demonstrate that after-rTMS clinical improvement is associated with functional connectivity (FC) changes of the subgenual cingulate cortex (sgACC) and rostral anterior cingulate (rACC), and FC of sgACC and rACC might serve as potential predictors for treatment response.MethodsResting-state functional magnetic resonance imaging (rs-fMRI) data were collected within 1 week before rTMS initiation in 50 TRD patients to predict subsequent response to rTMS on the left dorsolateral prefrontal cortex (DLPFC). Follow-up rs-fMRI was obtained 12 weeks after completion of rTMS and neural correlates of rTMS in sgACC- and rACC-related FC patterns were compared to before rTMS data and with rs-fMRI from healthy participants.ResultsTreatment response was associated with lower FC of sgACC to right DLPFC and higher FC of rACC to left lateral parietal cortex (IPL) measured at baseline. Using sgACC-DLPFC and rACC-IPL connectivity as features, responder-nonresponder classification accuracies of 84% and 76% (end-of-treatment), 88% and 81% (3-month follow-up), respectively were achieved. Longitudinal rs-fMRI data analyses revealed that the hyperconnectivity between sgACC and visual cortex was normalized to a level which was comparable to that of healthy participants.ConclusionsBrain activity patterns in depression are predictive of treatment response to rTMS, and longitudinal change of brain activity in relevant brain circuits after rTMS is associated with treatment response in depression. Target engagement paradigms may offer opportunities to increase the efficacy of rTMS in TRD by optimal selection of patients for treatment.Trial registrationClinicalTrials.gov Identifiers: NCT01887782 and NCT02800226.     

1 hz rTMS over the right prefrontal cortex reduces vigilant attention to unmasked but not to masked fearful faces.

BACKGROUND: Recent repetitive transcranial magnetic stimulation (rTMS) research in healthy subjects suggests that the emotions anger and anxiety are lateralized in the prefrontal cortex. Low-frequency rTMS over the right prefrontal cortex (PFC) shifts the anterior asymmetry in brain activation to the left hemisphere and reduces anxiety. The same rTMS technique results in enhanced anger-related emotional processing, observed as elevations in attention for angry faces. The current study used low-frequency rTMS over the right PFC and indexed selective attention to fearful faces, hypothesizing a reduction in attention for fearful faces, i.e., a reversal of the latter effect. METHODS: In a placebo-controlled design, 1 Hz rTMS at 130% of the individual motor threshold (MT) was applied continuously over the right PFC of eight healthy subjects for 20 minutes. Effects on motivated attention were investigated by means of an emotional Stroop task, indexing selective attention to masked and unmasked fearful faces. RESULTS: Vigilant attention for masked and unmasked fearful faces was observed after placebo stimulation. As hypothesized, rTMS reduced the vigilant emotional response to the fearful face, but only in the unmasked task. CONCLUSIONS: These data provide further support for the lateralization of the emotions anger and anxiety in the prefrontal cortex. In addition, the absence of an effect for masked fearful faces suggests that changes in emotional processing after a single session of rTMS predominantly involve the cortical affective pathways.     

High‐frequency rTMS over the supplementary motor area for treatment of Parkinson's disease

Dysfunction of the basal ganglia‐thalamocortical motor circuit is a fundamental model to account for motor symptoms in Parkinson's disease (PD). Using high‐frequency repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA), we investigated whether modulation of SMA excitability engenders therapeutic effects on motor symptoms in PD. In this double‐blind placebo‐controlled study, 99 patients were enrolled and assigned randomly to SMA‐stimulation and sham‐stimulation groups. For SMA stimulation, 20 trains of 50 transcranial magnetic stimuli at 5 Hz were delivered at an intensity of 110% active motor threshold for leg muscles in one session. The sham stimulation was 20 trains of electric stimuli given through electrodes fixed on the head to mimic the cutaneous sensation during rTMS. Each session of intervention was carried out once a week for the first 8 weeks. The SMA stimulation, in contrast to the sham stimulation, engendered significant improvements in total scores and motor scores of the Unified Parkinson's Disease Rating Scale. Mean improvements in motor scores were 4.5 points in the SMA‐stimulation group and ?0.1 points in the sham‐stimulation group. Results indicate that 5 Hz rTMS over SMA modestly improves motor symptoms in PD patients; SMA is a potential stimulation site for PD treatment. © 2008 Movement Disorder Society     

Amodal semantic representations depend on both anterior temporal lobes: Evidence from repetitive transcranial magnetic stimulation

The key question of how the brain codes the meaning of words and pictures is the focus of vigorous debate. Is there a “semantic hub” in the temporal poles where these different inputs converge to form amodal conceptual representations? Alternatively, are there distinct neural circuits that underpin our comprehension of pictures and words? Understanding words might be primarily left-lateralised, linked to other language areas, while semantic representation of pictures may be more bilateral. To elucidate this debate, we used offline, low-frequency, repetitive transcranial magnetic stimulation (rTMS) to disrupt neural processing temporarily in the left or right temporal poles. During the induced refractory period, participants made judgements of semantic association for verbal and pictorial stimuli. The efficiency of semantic processing was reduced by rTMS, yet a perceptual task of comparable difficulty was unaffected. rTMS applied to the left or right temporal poles disrupted semantic processing for words and pictures to the same degree, while rTMS delivered at a control site had no impact. The results confirm that both temporal poles form a critical substrate within the neural network that supports conceptual knowledge, regardless of modality.     

Effects of deep brain stimulation on prehensile movements in PD patients are less pronounced when external timing cues are provided

It has been repeatedly demonstrated that the movements of patients with Parkinson's disease (PD) are less impaired when external timing cues are provided. This suggests that the basal ganglia, which are impaired in PD, are less involved in the control of externally timed movements. In the present study, we tested this hypothesis by contrasting the effect of deep brain stimulation (DBS) in the basal ganglia (more precisely, the internal globus pallidum) on internally versus externally timed movements. Our first movement task was a standard prehensile task involving a reach-to-grasp movement. In the externally-timed condition, the target object was moving rapidly away from the subject; in the internally-timed condition, the target object was stationary. We found, that for most aspects of the prehensile movement the effect of DBS was less pronounced in the externally than in the internally timed condition. A similar reduction of the DBS effects in the externally-timed condition was also found for a second movement task, which required an isolated grasping movement. We conclude that the basal ganglia are significantly less involved in the control of externally timed movements.     

Resting state functional connectivity of the subthalamic nucleus in Parkinson's disease assessed using arterial spin‐labeled perfusion fMRI

Neurophysiological changes within the cortico‐basal ganglia‐thalamocortical circuits appear to be a characteristic of Parkinson's disease (PD) pathophysiology. The subthalamic nucleus (STN) is one of the basal ganglia components showing pathological neural activity patterns in PD. In this study, perfusion imaging data, acquired noninvasively using arterial spin‐labeled (ASL) perfusion MRI, were used to assess the resting state functional connectivity (FC) of the STN in 24 early‐to‐moderate PD patients and 34 age‐matched healthy controls, to determine whether altered FC in the very low frequency range of the perfusion time signal occurs as a result of the disease. Our results showed that the healthy STN was functionally connected with other nuclei of the basal ganglia and the thalamus, as well as with discrete cortical areas including the insular cortex and the hippocampus. In PD patients, connectivity of the STN was increased with two cortical areas involved in motor and cognitive processes. These findings suggest that hyperconnectivity of the STN could underlie some of the motor and cognitive deficits often present even at early stages of the disease. The FC measures provided good discrimination between controls and patients, suggesting that ASL‐derived FC metrics could be a putative PD biomarker. Hum Brain Mapp 36:1937–1950, 2015. © 2015 Wiley Periodicals, Inc .     

PreSMA stimulation changes task‐free functional connectivity in the fronto‐basal‐ganglia that correlates with response inhibition efficiency

Previous work using transcranial magnetic stimulation (TMS) demonstrated that the right presupplementary motor area (preSMA), a node in the fronto‐basal‐ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single‐pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop‐signal task. The results showed that preSMA‐TMS increased activation in the right inferior‐frontal cortex (rIFC) and basal ganglia and modulated their task‐free functional connectivity. Both the TMS‐induced changes in the basal‐ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the white‐matter microstructure along the preSMA–rIFC pathway. These results suggest that the task‐free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition. Hum Brain Mapp 37:3236–3249, 2016. © 2016 Wiley Periodicals, Inc.