Portable Neuroimaging Guided Non-invasive Brain Stimulation of Cortico-cerebello-thalamo-cortical Loop in Substance Use Disorder

Background: Maladaptive neuroplasticity related learned response in substance use disorder (SUD) can be ameliorated using non-invasive brain stimulation (NIBS); however, inter-individual variability needs to be addressed for clinical translation. Objective: Our first objective was to develop a hypothesis for NIBS for learned response in SUD based on competing neurobehavioral decision systems model. Next objective was to conduct computational simulation of NIBS of cortico-cerebello-thalamo-cortical (CCTC) loop in cannabis use disorder (CUD) related dysfunctional “cue-reactivity” – a closely related construct of “craving” that is a core symptom. Our third objective was to test the feasibility of our neuroimaging guided rational NIBS approach in healthy humans. Methods: “Cue-reactivity” can be measured using behavioral paradigms and portable neuroimaging, including functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG), metrics of sensorimotor gating. Therefore, we conducted computational simulation of NIBS, including transcranial direct current stimulation(tDCS) and transcranial alternating current stimulation(tACS) of the cerebellar cortex and deep cerebellar nuclei(DCN), of the CCTC loop for its postulated effects on fNIRS and EEG metrics. We also developed a rational neuroimaging guided NIBS approach for cerebellar lobule (VII) and prefrontal cortex based on healthy human study. Results: Simulation study of cerebellar tDCS induced gamma oscillations in the cerebral cortex while tTIS induced gamma-to-beta frequency shift. Experimental fNIRS study found that 2mA cerebellar tDCS evoked similar oxyhemoglobin(HbO) response in-the-range of 5x10-6M across cerebellum and PFC brain regions (=0.01); however, infra-slow (0.01–0.10 Hz) prefrontal cortex HbO driven(phase-amplitude-coupling, PAC) 4Hz, ±2mA (max.) cerebellar tACS evoked HbO in-the-range of 10-7M that was statistically different (=0.01) across those brain regions. Conclusion: Our healthy human study showed the feasibility of fNIRS of cerebellum and PFC as well as fNIRS-driven ctACS at 4Hz that may facilitate cerebellar cognitive function via the frontoparietal network. Future work needs to combine fNIRS with EEG for multi-modal imaging.

Split-Belt Training but Not Cerebellar Anodal tDCS Improves Stability Control and Reduces Risk of Fall in Patients with Multiple Sclerosis

The objective of this study was to examine the therapeutic potential of multiple sessions of training on a split-belt treadmill (SBT) combined with cerebellar anodal transcranial direct current stimulation (tDCS) on gait and balance in People with Multiple Sclerosis (PwMS). Twenty-two PwMS received six sessions of anodal (PwMSreal, n = 12) or sham (PwMSsham, n = 10) tDCS to the cerebellum prior to performing the locomotor adaptation task on the SBT. To evaluate the effect of the intervention, functional gait assessment (FGA) scores and distance walked in 2 min (2MWT) were measured at the baseline (T0), day 6 (T5), and at the 4-week follow up (T6). Locomotor performance and changes of motor outcomes were similar in PwMSreal and PwMSsham independently from tDCS mode applied to the cerebellum (anodal vs. sham, on FGA, p = 0.23; and 2MWT, p = 0.49). When the data were pooled across the groups to investigate the effects of multiple sessions of SBT training alone, significant improvement of gait and balance was found on T5 and T6, respectively, relative to baseline (FGA, p < 0.001 for both time points). The FGA change at T6 was significantly higher than at T5 (p = 0.01) underlining a long-lasting improvement. An improvement of the distance walked during the 2MWT was also observed on T5 and T6 relative to T0 (p = 0.002). Multiple sessions of SBT training resulted in a lasting improvement of gait stability and endurance, thus potentially reducing the risk of fall as measured by FGA and 2MWT. Application of cerebellar tDCS during SBT walking had no additional effect on locomotor outcomes.

Transcranial direct current stimulation of cerebellum alters spiking precision in cerebellar cortex: A modeling study of cellular responses

Transcranial direct current stimulation (tDCS) of the cerebellum has rapidly raised interest but the effects of tDCS on cerebellar neurons remain unclear. Assessing the cellular response to tDCS is challenging because of the uneven, highly stratified cytoarchitecture of the cerebellum, within which cellular morphologies, physiological properties, and function vary largely across several types of neurons. In this study, we combine MRI-based segmentation of the cerebellum and a finite element model of the tDCS-induced electric field (EF) inside the cerebellum to determine the field imposed on the cerebellar neurons throughout the region. We then pair the EF with multicompartment models of the Purkinje cell (PC), deep cerebellar neuron (DCN), and granule cell (GrC) and quantify the acute response of these neurons under various orientations, physiological conditions, and sequences of presynaptic stimuli. We show that cerebellar tDCS significantly modulates the postsynaptic spiking precision of the PC, which is expressed as a change in the spike count and timing in response to presynaptic stimuli. tDCS has modest effects, instead, on the PC tonic firing at rest and on the postsynaptic activity of DCN and GrC. In Purkinje cells, anodal tDCS shortens the repolarization phase following complex spikes (-14.7 ± 6.5% of baseline value, mean ± S.D.; max: -22.7%) and promotes burstiness with longer bursts compared to resting conditions. Cathodal tDCS, instead, promotes irregular spiking by enhancing somatic excitability and significantly prolongs the repolarization after complex spikes compared to baseline (+37.0 ± 28.9%, mean ± S.D.; max: +84.3%). tDCS-induced changes to the repolarization phase and firing pattern exceed 10% of the baseline values in Purkinje cells covering up to 20% of the cerebellar cortex, with the effects being distributed along the EF direction and concentrated in the area under the electrode over the cerebellum. Altogether, the acute effects of tDCS on cerebellum mainly focus on Purkinje cells and modulate the precision of the response to synaptic stimuli, thus having the largest impact when the cerebellar cortex is active. Since the spatiotemporal precision of the PC spiking is critical to learning and coordination, our results suggest cerebellar tDCS as a viable therapeutic option for disorders involving cerebellar hyperactivity such as ataxia.

Effects of Cerebellar Transcranial Direct Current Stimulation on Upper Limb Motor Function After Stroke: Study Protocol for the Pilot of a Randomized Controlled Trial

Background: Transcranial direct current stimulation (tDCS) is a technique that can noninvasively modulate neural states in a targeted brain region. As cerebellar activity levels are associated with upper limb motor improvement after stroke, the cerebellum is a plausible target of tDCS. However, the effect of tDCS remains unclear. Here, we designed a pilot study to assess: 1) the feasibility of a study that aims to examine the effects of cerebellar tDCS combined with an intensive rehabilitation approach based on the concept of constraint-induced movement therapy (CIMT), and 2) the preliminary outcome of the combined approach on upper limb motor function in patients with stroke in the chronic stage.Methods: This pilot study has a double-blind randomized controlled design. Twenty-four chronic stroke patients with mild to moderate levels of upper limb motor impairment will be randomly assigned to an active or sham tDCS group. The participants will receive 20 min of active or sham tDCS to the contralesional cerebellum at the commencement of 4 hours of daily intensive training, repeatedly for 5 days per week for 2 weeks. The primary outcome is upper limb motor function which will be evaluated using the Action Research Arm Test. Secondary outcomes comprise scores of the Fugl-Meyer Assessment for the upper extremity and the Motor Activity Log. Additionally, neurophysiological and neuroanatomical assessments of the cerebellum will be performed using transcranial magnetic stimulation and magnetic resonance imaging. These assessments will be conducted before, at the middle, and after the 2-week intervention, and finally 1 month after the intervention. Any adverse events that occur during the study will be recorded.Discussion: Cerebellar tDCS combined with intensive upper limb training may increase the gains of motor improvement when compared to the sham condition. The present study should provide valuable evidence regarding the feasibility of the design and the efficacy of cerebellar tDCS for upper limb motor function in patients with stroke before a future large trial is conducted.Trial registration: This study has been registered at the Japan Registry of Clinical Trials (jRCTs042200078; https://jrct.niph.go.jp/en-latest-detail/jRCTs042200078). Registered 17 December 2020

Effects of Anodal Cerebellar Transcranial Direct Current Stimulation on Movements in Patients with Cerebellar Ataxias: A Systematic Review

Cerebellar transcranial direct current stimulation (cerebellar tDCS) is a promising therapy for cerebellar ataxias and has attracted increasing attention from researchers and clinicians. A timely systematic review focusing on randomized sham-controlled trials and repeated measures studies is warranted. This study was to systematically review existing evidence regarding effects of anodal cerebellar tDCS on movements in patients with cerebellar ataxias. The searched databases included Web of Science, MEDLINE, PsycINFO, CINAHL, EMBASE, Cochrane Library, and EBSCOhost. Methodological quality of the selected studies was assessed using the Physiotherapy Evidence Database scale. Five studies with 86 patients were identified. Among these, four studies showed positive effects of anodal cerebellar tDCS. Specifically, anodal cerebellar tDCS decreased disease severity and improved finger dexterity and quality of life in patients, but showed incongruent effects on gait control and balance, which may be due to heterogeneity of research participants and choices of measures. The protocols of anodal cerebellar tDCS that improved movements in patients commonly placed the anode over the whole cerebellum and provided ten 2-mA 20-min stimulation sessions. The results may show preliminary evidence that anodal cerebellar tDCS is beneficial to reducing disease severity and improving finger dexterity and quality of life in patients, which lays the groundwork for future studies further examining responses in the cerebello-thalamo-cortical pathway. An increase in sample size, the use of homogeneous patient groups, exploration of the optimal stimulation protocol, and investigation of detailed neural mechanisms are clearly needed in future studies.

The Effect of Transcranial Direct Current Stimulation and Core Stability Training on the Balance and Disability of Patients With Multiple Sclerosis

Purpose: Physicians report balance disorders and fatigue as the symptoms of Multiple Sclerosis (MS) disease. The present study compares the effect of transcranial Direct Current Stimulation (tDCS) and core stability training on the balance and disability of patients with MS. Methods: This is a pre-test, post-test experiment study. The statistical population included all patients with MS who reffered to Rofaydeh Rehabilitation Hospital in Tehran City, Iran, in the winter of 2019. A total of 30 male and female patients aged 27-70 years were selected through available and purposive sampling methods and then randomly divided into experimental and control groups (each group 15 persons). The initial measurements of the participants’ kinetic variables of postural control were carried out by the posturography device, and afterward, Kurtzke Expanded Disability Status Scale (EDSS) was employed to measure disability. The participants’ training included core stability training for 8 weeks (30-40 min, 3 sessions per week) with 20 min online cerebellar transcranial direct current stimulation, 2 sessions per week (The first and third sessions). Then, the research variables were measured again. Results: The results demonstrated the significant influence of cerebellar tDCS on the variables of postural control equilibrium in the second sensory condition (P<0.001), third sensory condition (P<0.001), fourth sensory condition (P<0.001), fifth sensory condition (P=0.034), and combine equilibrium (P<0.001). Besides, the cerebellar current stimulation enhanced the sensory performance of the experimental group in using the vestibular system input data (P<0.001) and vision (P<0.001), but it had no significant effect on the ability to use somatosensory input (P=0.203) and vision preference (P=0.343). This research also revealed that the cerebellar current stimulation decreased EDSS in MS patients (P=0.026). Conclusion: The cerebellar tDCS has a beneficial effect on balance, EDSS, and modified fatigue impact scale in MS patients. The study findings also indicate that the cerebellum, vestibular system, and visual system are related, and they have an impact on balance, and cerebellar stimulation can facilitate learning motor skills.

Anodal Transcranial Direct Current Stimulation over the Cerebellum Enhances Sadness Recognition in Parkinson’s Disease Patients: a Pilot Study

Emotional processing impairments, resulting in a difficulty to decode emotions from faces especially for negative emotions, are characteristic non-motor features of Parkinson’s disease (PD). There is limited evidence about the specific contribution of the cerebellum to the recognition of emotional contents in facial expressions even though patients with cerebellar dysfunction often lose this ability. In this study, we aimed to evaluate whether the recognition of facial expressions can be modulated by cerebellar transcranial direct current stimulation (tDCS) in PD patients. Nine PD patients were enrolled and received anodal and sham tDCS (2 mA, 20 min), for 5 consecutive days, in two separate cycles at intervals of at least 1 month. The facial emotion recognition task was administered at baseline (T0) and after cerebellar tDCS on day 5 (T1). Our preliminary study showed that anodal cerebellar tDCS significantly enhanced emotional recognition in response to sad facial expressions by about 16%, but left recognition of anger, happiness, and neutral facial expressions unchanged. Despite the small sample size, our preliminary results show that anodal tDCS applied for five consecutive days over the cerebellum modulates the way PD patients recognize specific facial expressions, thus suggesting that the cerebellum plays a crucial role in recognition of negative emotions and corroborating previous knowledge on the link between social cognition and the cerebellum.