Cerebellar Modulation of Sensorimotor Associative Plasticity Is Impaired in Cervical Dystonia

Background

In recent years, cervical dystonia (CD) has been recognized as a network disorder that involves not only the basal ganglia but other brain regions, such as the primary motor and somatosensory cortex, brainstem, and cerebellum. So far, the role of the cerebellum in the pathophysiology of dystonia is only poorly understood.

Objective

The objective of this study was to investigate the role of the cerebellum on sensorimotor associative plasticity in patients with CD.

Methods

Sixteen patients with CD and 13 healthy subjects received cerebellar transcranial direct current stimulation (ctDCS) followed by a paired associative stimulation (PAS) protocol based on transcranial magnetic stimulation that induces sensorimotor associative plasticity. Across three sessions the participants received excitatory anodal, inhibitory cathodal, and sham ctDCS in a double-blind crossover design. Before and after the intervention, motor cortical excitability and motor symptom severity were assessed.

Results

PAS induced an increase in motor cortical excitability in both healthy control subjects and patients with CD. In healthy subjects this effect was attenuated by both anodal and cathodal ctDCS with a stronger effect of cathodal stimulation. In patients with CD, anodal stimulation suppressed the PAS effect, whereas cathodal stimulation had no influence on PAS. Motor symptom severity was unchanged after the intervention.

Conclusions

Cerebellar modulation with cathodal ctDCS had no effect on sensorimotor associative plasticity in patients with CD, in contrast with the net inhibitory effect in healthy subjects. This is further evidence that the cerebello-thalamo-cortical network plays a role in the pathophysiology of dystonia. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

A Systematic Review of the Safety and Tolerability of Theta Burst Stimulation in Children and Adolescents

ObjectivesTheta burst stimulation (TBS) is often used in clinical practice and research protocols for adults with neuropsychiatric disorders. There are substantial knowledge gaps related to the application of TBS in children and adolescents. This systematic review examined the safety and tolerability of TBS in children and adolescents.Materials and MethodsA systematic review of human TBS studies in children and adolescents was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following inclusion criteria were applied: 1) articles in English language only; 2) studies that included child and adolescent participants (up to 21 years of age); 3) studies that administered intermittent TBS or continuous TBS or both to participants; 4) studies that had an outcome measure; and 5) availability of full text material. The primary outcome measures were tolerability and safety. When feasible, the clinical effects were reviewed.ResultsTwenty relevant articles met the criteria for inclusion. The reported adverse events were mild and similar to what is noted in adult studies. The most common symptom was headache. One case report described a seizure induced by TBS. Collectively, the studies were heterogeneous but the methodologic quality of randomized trials was high.ConclusionsTBS interventions in children may have similar safety, tolerability, and feasibility as compared to adults. However, long-term, follow-up studies of TBS are lacking. Future dose-ranging studies with systematic assessment of adverse events will be important in the translation of findings with TBS from adults to youth.     

Theta Burst Stimulation Modulates Cerebellar-Cortical Connectivity in Patients with Progressive Supranuclear Palsy

BackgroundProgressive Supranuclear Palsy (PSP) is an atypical degenerative Parkinsonism characterized by postural instability, supranuclear gaze palsy and frontal deficits. Recent imaging studies revealed that the volume of cerebellar peduncles and midbrain were reduced in PSP. Transcranial magnetic stimulation (TMS) studies demonstrated a cerebellar involvement in PSP showing an impairment of functional connectivity between the cerebellar hemisphere (Cb) and the contralateral primary motor cortex (M1) (cerebellar brain inhibition-CBI).ObjectiveTo investigate the plasticity of the cerebello-thalamo-cortical circuits in ten PSP patients after two-week course of cerebellar intermittent theta burst stimulation (iTBS), a form of repetitive TMS.MethodsBefore and after the iTBS sessions we measured functional connectivity between Cb and contralateral M1 (CBI), short intracortical inhibition (SICI) and intracortical facilitation (ICF) and short latency afferent inhibition (SLAI) in contralateral M1. We also performed resting state functional magnetic resonance (rs-fMRI) and we administered clinical rating scale (PSP-RS).ResultsAt baseline PSP patients had decreased efficiency of CBI, SICI and SLAI in comparison to PD patients and healthy subjects. Cerebellar iTBS increased the deficient functional cerebellar-motor connectivity as assessed by CBI. No effect was seen for SICI/ICF and SLAI circuits. Following iTBS there was an increased signal in the head of the caudate nucleus bilaterally as shown by rs-fMRI. Moreover, PSP-RS showed an improvement of dysarthria in all patients.ConclusionsiTBS enhanced functional connectivity between the cerebellar hemisphere, the caudate nucleus and the cortex, that was paralleled by some clinical improvement. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.     

Pallidal Deep Brain Stimulation in Primary Cervical Dystonia with Phasic Type : Clinical Outcome and Postoperative Course

Objective

The purpose of this study was to analyze in detail the relationship between outcome and time course of effect in medically refractory primary cervical dystonia (CD) with phasic type that was treated by bilateral globus pallidus internus (Gpi) deep brain stimulation (DBS).

Methods

Six patients underwent bilateral implantation of DBS into the Gpi under the guide of microelectrode recording and were followed for 18.7 ± 11.1 months. The mean duration of the CD was 5.8 ± 3.4 years. The mean age at time of surgery was 54.2 ± 10.2 years. Patients were evaluated with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and relief scale using patient self-reporting.

Results

The TWSTRS total scores improved by 64.5%, 65.5%, 75.8%, and 76.0% at 3, 6, 12 months, and at the last available follow-up after surgery, respectively. Statistically significant improvements in the TWSTRS scores were observed 3 months after surgery (p = 0.028) with gradual improvement up to 12 months after surgery, thereafter, the improvement was sustained. However, there was no statistically significant difference between the scores at 3 and 12 months. Subjective improvement reported averaged 81.7 ± 6.8% at last follow-up. Mild dysarthria, the most frequent adverse event, occurred in 3 patients.

Conclusions

Our results show that the bilateral Gpi-DBS can offer a significant therapeutic effect from 3 months postoperatively in patients with primary CD with phasic type, without significant side effects.     

Long Disease Duration Interferes With Therapeutic Effect of Globus Pallidus Internus Pallidal Stimulation in Primary Cervical Dystonia

Objectives: We retrospectively investigated the correlation between disease duration and the therapeutic effect of globus pallidus internus (GPi) stimulation in patients with primary cervical dystonia (CD). Materials and Methods: Eight patients with CD unresponsive to medical treatments underwent bilateral GPi deep brain stimulation (DBS). They were followed for 63.5 ± 38.2 months (mean ± standard deviation) and were assessed before and at 1, 12, 24, and 36 months after surgery and at their final visit to our outpatient clinic using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Univariate analysis was performed to identify factors that affected their postoperative TWSTRS score. Results: At last follow‐up, disease severity and the degree of disability and pain on the TWSTRS were significantly improved by 70.2%, 76.1%, and 87.1%, respectively (p < 0.05, Wilcoxon signed‐rank test). Neither age nor preoperative CD severity was predictive of postoperative improvement; however, the disease duration affected their reduction rate of TWSTRS severity score at each time point investigated (p < 0.05). Conclusions: Bilateral GPi‐DBS is an effective long‐term therapy in patients with CD. The delivery of GPi stimulation in the earlier course of CD may yield greater postoperative improvement.     

Modulatory Effects of Theta Burst Stimulation on Cerebellar Nonsomatic Functions

Clinical and functional imaging studies suggest that the cerebellar vermis is involved in the regulation of a range of nonsomatic functions including cardiovascular control, thirst, feeding behavior, and primal emotions. Cerebello-hypothalamic circuits have been postulated to be a potential neuroanatomical substrate underlying this modulation. We tested this putative relationship between the cerebellar vermis and nonsomatic functions by stimulating the cerebellum noninvasively via neuronavigated transcranial magnetic stimulation. In this randomized, counter-balanced, within-subject study, intermittent theta burst stimulation (TBS) was applied on three different days to the vermis and the right and left cerebellar hemispheres of 12 right-handed normal subjects with the aim of modulating activity in the targeted cerebellar structure. TBS-associated changes were investigated via cardiovascular monitoring, a series of emotionally arousing picture stimuli, subjective analog scales for primal emotions, and the Profile of Mood States test. All 36 sessions of cerebellar stimulation were tolerated well without serious adverse events. Cardiovascular monitoring pointed to a mild but significant decrease in heart rate subsequent to vermal stimulation; no changes were detected in systolic or diastolic blood pressure measurements. Subjective ratings detected a significant increase in Thirst and a trend toward increased Appetite following vermal stimulation. These observations are consistent with existing neurophysiological and neuroimaging data indicating a role for the cerebellum in the regulation of visceral responses. In conjunction with the modulatory function of the cerebellum, our results suggest a role for the vermis in somatovisceral integration likely through cerebello-hypothalamic pathways. Further research is warranted to elucidate the potential mechanisms underlying the cerebellar modulation of nonsomatic functions.     

Theta Burst Stimulation Is Not Inferior to High-Frequency Repetitive Transcranial Magnetic Stimulation in Reducing Symptoms of Posttraumatic Stress Disorder in Veterans With Depression: A Retrospective Case Series

ObjectivesTwo commonly used forms of repetitive transcranial magnetic stimulation (rTMS) were recently shown to be equivalent for the treatment of depression: high-frequency stimulation (10 Hz), a protocol that lasts between 19 and 38 minutes, and intermittent theta burst stimulation (iTBS), a protocol that can be delivered in just three minutes. However, it is unclear whether iTBS treatment offers the same benefits as those of standard 10-Hz rTMS for comorbid symptoms such as those seen in posttraumatic stress disorder (PTSD).Materials and MethodsIn this retrospective case series, we analyzed treatment outcomes in veterans from the Veterans Affairs San Diego Healthcare System who received 10-Hz (n = 47) or iTBS (n = 51)-rTMS treatments for treatment-resistant depression between February 2018 and June 2022. We compared outcomes between these two stimulation protocols in symptoms of depression (using changes in the Patient Health Questionnaire-9 [PHQ-9]) and PTSD (using changes in the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, or Patient Checklist [PCL]-5).ResultsThere was an imbalance of sex between groups (p < 0.05). After controlling for sex, we found no significant difference by stimulation protocol for depression (PHQ-9, F [1,94] = 0.16, p = 0.69, eta-squared = 0.002), confirming the original study previously noted. We also showed no difference by stimulation protocol of changes in PTSD symptoms (PCL-5, F [1,94] = 3.46, p = 0.067, eta-squared = 0.036). The iTBS group showed a decrease from 41.9 ± 4.4 to 25.1 ± 4.9 (a difference of 16.8 points) on the PCL-5 scale whereas the 10-Hz group showed a decrease from 43.6 ± 2.9 to 35.2 ± 3.2 on this scale (a difference of 8.4 points). Follow-up analyses restricting the sample in various ways did not meaningfully change these results (no follow-up analyses showed that there was a significant difference between stimulation protocols).ConclusionsAlthough limited by small sample size, nonblind, and pseudorandomized assignment, our data suggest that iTBS is similar to 10-Hz stimulation in inducing reductions in PTSD symptoms and depression in military veterans.     

Long‐Term Follow‐Up Study of Chronic Deep Brain Stimulation of the Subthalamic Nucleus for Cervical Dystonia

Objectives. Medically refractory cervical dystonia has recently been treated using deep brain stimulation (DBS), targeting the subthalamic nucleus (STN). There has been limited literature regarding short‐term outcomes and no literature regarding long‐term outcomes for refractory cervical dystonia following DBS of the STN. Materials and Methods. Two patients with medically refractory cervical dystonia underwent STN DBS. Patients were rated using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) preoperatively and immediately postoperatively as well as just prior to turning on the stimulators and subsequently at 24–48 hours, six months, one, two, and three years after stimulation. Microrecordings were used to identify the STN and substantia nigra reticulata (SNr). Results. Significant immediate and sustained long‐term improvements were seen in motor, disability, pain, and total TWSTRS scores. In one patient, only unilateral stimulation was required. The STN and SNr were easily identified as having activity similar to off‐state Parkinson's patients. Conclusions. DBS therapy for cervical dystonia utilizing the STN as the surgical target may be novel and may be an alternative target to the globus pallidus internus as supported by this first long‐term outcome report. Further studies need to be performed to confirm these conclusions.     

Inter- and Intra-individual Variability Following Intermittent Theta Burst Stimulation: Implications for Rehabilitation and Recovery

BackgroundThe continued refinement of non-invasive brain stimulation (NBS) techniques is indicative of promising clinical and rehabilitative interventions that are able to modulate cortical excitability. Intermittent theta burst stimulation (iTBS) is one such technique that can increase cortical excitability, purportedly via LTP-like mechanisms. While iTBS may have the capacity to promote recovery after neurological injury, and to combat cognitive and motor decline, recent reports observed highly variable effects across individuals, questioning the efficacy of iTBS as a clinical tool.ObjectiveThe aim of this study was to examine intra-individual reliability and inter-individual variability in responses to iTBS.MethodsThirty healthy participants completed two experimental sessions of the iTBS protocol 1–3 weeks apart. Motor evoked potentials in response to single pulse TMS were used to assess corticospinal excitability prior to, and up to 36 min following, iTBS.ResultsAt the group level, iTBS evoked statistically significant increases in motor cortical excitability across both sessions (P < 0.001), with 22 out of 30 participants exhibiting increases in excitability in both sessions. A strong intraclass correlation demonstrated that both the direction, and magnitude of the plastic changes were reliable at the individual level.ConclusionsOverall, our results suggest that iTBS is capable of inducing relatively robust and consistent effects within and between young individuals. As such, the capacity for iTBS to be exploited in clinical and rehabilitative interventions should continue to be explored.     

Neuromodulation in Dystonia: Current Aspects of Deep Brain Stimulation

Among the surgical treatment options for patients with medically refractory dystonia chronic deep brain stimulation (DBS) of different targets in the basal ganglia circuitry has become one of the most important tools. The globus pallidus internus nowadays is the target of choice, while there is only limited experience with other targets. At this time, patients with primary (genetic or sporadic) generalized and segmental dystonia, and patients with (complex) cervical dystonia are thought to be the best candidates for pallidal DBS. Advantages of DBS are its reversibility, its adjustability, and the continuous access to modify the target in the basal ganglia. The present review gives an account on the development of surgical neuromodulation therapy for dystonia, surgical approaches, hardware‐related problems, DBS programming and patient management, and clinical outcome. Studies conducted according to the practices of evidence‐based medicine confirm the results of early pilot studies. The wide majority of patients achieve beneficial lasting outcome at a relatively low rate of manageable side‐effects. Along with improvement of the movement disorder, studies report on amelioration of quality‐of‐life surrogates. We also provide an overview on DBS surgery in less common dystonic syndromes, such as craniofacial dystonia, status dystonicus, task‐specific dystonia, paroxysmal dystonia, camptocormia, and secondary dystonias, including choreoathetosis, hemidystonia, tardive dystonia, and pantothenate kinase‐associated neurodegeneration. Furthermore, we discuss the implications of intra‐operative microelectrode recordings and pallidal field potentials for the pathophysiology of dystonia and the particular possible mechanisms of DBS in dystonia. Finally, future perspectives are outlined.     

Inter-individual Variability in Response to Non-invasive Brain Stimulation Paradigms

BackgroundNon-invasive Brain Stimulation (NIBS) paradigms are unique in their ability to safely modulate cortical plasticity for experimental or therapeutic applications. However, increasingly, there is concern regarding inter-individual variability in the efficacy and reliability of these paradigms.HypothesisInter-individual variability in response to NIBS paradigms would be better explained if a multimodal distribution was assumed.MethodsIn three different sessions for each subject (n = 56), we studied the Paired Associative Stimulation (PAS₂₅), Anodal transcranial DC stimulation (AtDCS) and intermittent theta burst stimulation (iTBS) protocols. We applied cluster analysis to detect distinct patterns of response between individuals. Furthermore, we tested whether baseline TMS measures (such as short intracortical inhibition (SICI), resting motor threshold (RMT)) or factors such as time of day could predict each individual's response pattern.ResultsAll three paradigms show similar efficacy over the first hour post stimulation – there is no significant effect on excitatory or inhibitory circuits for the whole sample, and AtDCS fares no better than iTBS or PAS₂₅. Cluster analysis reveals a bimodal response pattern – but only 39%, 45% and 43% of subjects responded as expected to PAS₂₅, AtDCS, and iTBS respectively. Pre-stimulation SICI accounted for 10% of the variability in response to PAS₂₅, but no other baseline measures were predictive of response. Finally, we report implications for sample size calculation and the remarkable effect of sample enrichment.ConclusionThe implications of the high rate of ‘dose-failure’ for experimental and therapeutic applications of NIBS lead us to conclude that addressing inter-individual variability is a key area of concern for the field.     

Brain-Derived Neurotrophic Factor Gene Polymorphism Predicts Response to Continuous Theta Burst Stimulation in Chronic Stroke Patients

ObjectivesThe efficacy of repetitive transcranial magnetic stimulation (rTMS) in clinically relevant neuroplasticity research depends on the degree to which stimulation induces robust, reliable effects. The high degree of interindividual and intraindividual variability observed in response to rTMS protocols, such as continuous theta burst stimulation (cTBS), therefore represents an obstacle to its utilization as treatment for neurological disorders. Brain-derived neurotrophic factor (BDNF) is a protein involved in human synaptic and neural plasticity, and a common polymorphism in the BDNF gene (Val66Met) may influence the capacity for neuroplastic changes that underlie the effects of cTBS and other rTMS protocols. While evidence from healthy individuals suggests that Val66Met polymorphism carriers may show diminished or facilitative effects of rTMS compared to their homozygous Val66Val counterparts, this has yet to be demonstrated in the patient populations where neuromodulatory therapies are most relevant.Materials and MethodsWe examined the effects of BDNF Val66Met polymorphism on cTBS aftereffects in stroke patients. We compared approximately 30 log-transformed motor-evoked potentials (LnMEPs) obtained per time point: at baseline and at 0, 10, 20, and 30 min after cTBS-600, from 18 patients with chronic stroke using single TMS pulses. We used linear mixed-effects regression with trial-level data nested by subject for higher statistical power.ResultsWe found a significant interaction between BDNF genotype and pre-/post-cTBS LnMEPs. Val66Val carriers showed decrease in cortical excitability, whereas Val66Met carriers exhibited a modest increase in cortical excitability for 20 min poststimulation, followed by inhibition 30 min after cTBS-600.ConclusionsOur findings strongly suggest that BDNF genotype differentially affects neuroplastic responses to TMS in individuals with chronic stroke. This provides novel insight into potential sources of variability in cTBS response in patients, which has important implications for optimizing the utility of this neuromodulation approach. Incorporating BDNF polymorphism genetic screening to stratify patients prior to use of cTBS as a neuromodulatory technique in therapy or research may optimize response rates.