Noninvasive cerebellar stimulation and behavioral interventions: A crucial synergy for post-stroke motor rehabilitation

Abstract

BACKGROUND:

Improvement of functional movements after supratentorial stroke occurs through spontaneous biological recovery and training-induced reorganization of remnant neural networks. The cerebellum, through its connectivity with the cortex, brainstem and spinal cord, is actively engaged in both recovery and reorganization processes within the cognitive and sensorimotor systems. Noninvasive cerebellar stimulation (NiCBS) offers a safe, clinically feasible and potentially effective way to modulate the excitability of spared neural networks and promote movement recovery after supratentorial stroke. NiCBS modulates cerebellar connectivity to the cerebral cortex and brainstem, as well as influences the sensorimotor and frontoparietal networks.

OBJECTIVE:

Our objective was twofold: (a) to conduct a scoping review of studies that employed NiCBS to influence motor recovery and learning in individuals with stroke, and (b) to present a theory-driven framework to inform the use of NiCBS to target distinct stroke-related deficits.

METHODS:

A scoping review of current research up to August 2023 was conducted to determine the effect size of NiCBS effect on movement recovery of upper extremity function, balance, walking and motor learning in humans with stroke.

RESULTS:

Calculated effect sizes were moderate to high, offering promise for improving upper extremity, balance and walking outcomes after stroke. We present a conceptual framework that capitalizes on cognitive-motor specialization of the cerebellum to formulate a synergy between NiCBS and behavioral interventions to target specific movement deficits.

CONCLUSION:

NiCBS enhances recovery of upper extremity impairments, balance and walking after stroke. Physiologically-informed synergies between NiCBS and behavioral interventions have the potential to enhance recovery. Finally, we propose future directions in neurophysiological, behavioral, and clinical research to move NiCBS through the translational pipeline and augment motor recovery after stroke.

Keywords

Stroke cerebellum brain movement neurological rehabilitation brain stimulation

1 Introduction

Stroke is one of the leading causes of disability worldwide. Just alone within the United States, nearly 800,000 people suffer a stroke each year and are left with long-standing disability. Post-stroke motor, sensory and cognitive deficits impair functional activities such as upper extremity function, balance and walking, thus forcing stroke survivors to discontinue over 60% of their daily activities. The physical disability and consequent caregiver burden also generates negative psychological and social outcomes and reduces their quality of life.

The ability to regain the capacity for functional movements (i.e., movement recovery) such as walking and upper extremity function are important patient goals for post-stroke rehabilitation. Movement recovery relies on an interaction of spontaneous biological recovery and behavior-driven reorganization/plasticity in the remnant neural networks. Noninvasive Neuromodulation using transcranial magnetic (TMS), direct current (tDCS) or random noise stimulation (tRNS) can influence both recovery and reorganization to improve functional outcomes (Ahmed et al., 2023; Plow et al., 2016). To date, numerous studies have employed noninvasive brain stimulation to the ipsilesional motor cortex and have yielded variable results (Di Pino et al., 2014). This variability arises from the heterogeneity of lesion location and size, small sample sizes and an attempt to stimulate a damaged corticospinal system with limited residual capacity (Sankarasubramanian et al., 2017). An alternate strategy is to modulate undamaged neural substrates and pathways that play a key role in motor recovery (Di Pino et al., 2014; Kantak et al., 2012). Accordingly, contralesional primary motor and premotor stimulation has been investigated with varying levels of success (Sankarasubramanian et al., 2017). Following a supratentorial stroke, cerebellum is a key node within the anatomically intact neural network that has the potential to impact cognitive and sensorimotor mechanisms of recovery and reorganization (Wathen et al., 2018). Recently, invasive deep brain stimulation of cerebellar dentate nucleus has shown promise in improving motor recovery in animal models and early human studies (Baker et al., 2023). Noninvasive brain stimulation methods are more accessible clinically and have allowed modulation of cerebellar excitability to influence motor performance and learning in awake humans. Noninvasive cerebellar stimulation (NiCBS) therefore opens an exciting and clinically feasible possibility to augment and/or accelerate movement recovery by targeting motor, sensory and cognitive mechanisms.

The overall thesis of this paper is to examine the theory and application of NiCBS as an innovative adjuvant to behavioral approaches for enhancing movement recovery after supratentorial stroke. In the first part of this paper, we discuss the potential role of cerebellum in motor, sensory and cognitive recovery following supratentorial stroke. We review current evidence and effect sizes for NiCBS in improving movement outcomes after supratentorial stroke. We then present a theoretical, mechanisms-driven framework to assist the design of hypothesis-driven interventions combining NiCBS and behavioral training (e.g., practice) to promote recovery. Finally, we identify directions of future research that will advance NiCBS as an adjuvant to behavioral approaches in a way that preferentially harnesses the plasticity in distinct cerebellar pathways to improve specific outcomes. While there have been previous calls to align behavioral interventions with ongoing neuroplastic changes during stroke recovery (Zeiler & Krakauer, 2013), we propose that a synergistic interaction between cerebellar neuromodulation and behavioral interventions may help improve specific motor outcomes, thus taking us a step closer to precision medicine.

1.1 The complexity of movement recovery and the role of cerebellum following supratentorial stroke

The behavioral phenotype of supratentorial stroke is complex and includes impairments in the motor, sensory and cognitive systems that often interact with each other during functional actions (Sathian et al., 2011). Within the motor system, multiple deficits such as impaired force production and coordination, abnormal tone, abnormal movement synergies (impaired individuation), poor motor planning and execution contribute to impaired task performance. Post-stroke sensory impairments are common and range from impaired ability to sense touch/proprioception to perceptual deficits (e.g., neglect). Finally, cognitive processes such as executive-function, working-memory and ability to dual-task are often impaired in patients with supratentorial stroke, dependent on lesion location. These motor, cognitive and sensory impairments interact to collectively amplify deficits in activity performance, recovery and participation.

Recovery of functional movements after stroke relies on restoration and reorganization within the motor, sensory and cognitive systems. In the context of this review, we define movement recovery as the capacity to complete a functional task successfully in a manner that is consistently accurate and efficient. This movement recovery after stroke is implemented by both restoring the function in the intact neural structures that were initially inactivated after the episode of stroke (e.g., diaschisis) and reorganization in the remnant neural networks that allow for efficient task performance (Fig. 1). While much attention has been focused on cortical reorganization, emerging evidence suggests that restorative and reorganizational processes after supratentorial stroke occur in cortical, subcortical, and spinal networks. Cerebellum, through its connectivity with cerebral cortex, brainstem and spinal networks, is exceptionally poised to contribute to both restoration and reorganization within the sensorimotor and cognitive systems.

Fig. 1

Movement recovery occurs through recovery from diaschisis and reorganization in sensory, motor and cognitive systems. Cerebellum is engaged in both these processes.

Early after supratentorial stroke (∼2–3 days), there is a period of reduced activity in intact neural networks with greatest reduction observed in the perilesional cortex and structures functionally connected to the lesioned brain areas (Rehme et al., 2011; Seitz et al., 1999). For example, there is a reduction in blood flow and metabolism in the contralateral cerebellum putatively due to a functional disconnection of the corticopontocerebellar pathway, a phenomenon described as crossed cerebellar diaschisis (CCD) (Infeld et al., 1995). The extent of early CCD is associated with early motor dysfunction and functional performance in early subacute stage (Takasawa et al., 2002). In a recent study, the volume of lobules IV, VI and VIII-B, all of which share reciprocal connections with frontorparietal and motor circuits, predicted functional independence on a Modified Rankin Scale in supratenotorial stroke survivors (Sadeghihassanabadi et al., 2022). Over the subacute phase (7days- 6months in humans (Bernhardt et al., 2017)), improvements in motor recovery are accompanied by resolution of CCD, although in some cases, diaschisis persists through the chronic phase. Persisting CCD in the chronic phase is thought to be mediated by transsynaptic degeneration of corticocerebellar and cerebellocortical pathways rather than secondary to the decreased perfusion. In chronic stage, the degree of CCD is associated with the severity of neurologic and behavioral deficits (Chang et al., 2017; De Reuck et al., 1997; Serrati et al., 1994). Collectively, these data suggest that cerebellum plays a key role in spontaneous recovery, and that the resolution of CCD is a potent mechanistic target to promote restorative plasticity for recovery.

Concurrently with mechanisms of recovery from diaschisis, reorganization of the remaining neural networks evolves as early as ten days post-stroke and continues into the chronic phases (Grefkes & Ward, 2014). The engagement of the cerebellum in network reorganization is evidenced by functional imaging studies of patients with supratentorial stroke. The cerebellum shows increased activity during goal-directed movements suggesting its engagement in residual motor performance. Longitudinal studies demonstrate increased resting state connectivity between ipsilesional motor cortex and contralesional cerebellum as motor recovery progresses (Park et al., 2011; Tombari et al., 2004; Wang et al., 2010). Finally, experience dependent changes in neural networks with behavioral interventions such as task practice also engage the cerebellum (Puh et al., 2007; Tombari et al., 2004; Várkuti et al., 2013; Ward et al., 2003). Johansen-Berg and colleagues reported a significant correlation between increased fMRI signal change in the cerebellum and improved motor function (Johansen-Berg et al., 2002). Thus, mounting evidence points to cerebellar engagement in reorganization of remnant neural networks to promote movement recovery after stroke. While functional activation of cerebellum associated with motor recovery provides correlational evidence, fundamental research in animal models provides stronger support for the critical role of cerebellum in movement recovery after stroke. In particular, deep brain stimulation and epidural stimulation of the cerebellum after stroke in animal models modulate cortical dynamics and improve motor outcomes (Abbasi et al., 2021; Cooperrider et al., 2014). A detailed review of fundamental research in animal models is beyond the scope of this paper; and can be found elsewhere (Cooperrider et al., 2020).

Given the evidence for cerebellar engagement in spontaneous recovery and reorganization, modulating cerebellar excitability may have therapeutic value. In the subsequent section, we review and summarize the current state of literature focused on noninvasive neuromodulation of cerebellum and its effects on motor performance and recovery after supratentorial stroke.

1.2 Noninvasive cerebellar stimulation to improve motor outcomes in individuals with unilateral stroke: A scoping review

The growing evidence for the role of cerebellum in motor recovery is strongly supported by recent studies that have applied deep cerebellar stimulation as adjunct to behavioral interventions. A recent non-randomized phase I trial demonstrated that invasive deep brain stimulation to the cerebellar dentate nucleus combined with physical rehabilitation led to clinically significant (median 7 point) change in Fugl-Meyer score in a sample of 12 individuals with stroke who had moderate-to-severe impairment (Baker et al., 2023). These promising results provide further evidence to support the role of cerebellum in post-stroke recovery. Because noninvasive stimulation techniques are more clinically accessible and potentially have lower risks than invasive deep brain stimulation, there have been an increasing number of proof-of-concept studies of NiCBS as an adjunct to behavioral interventions such as motor practice, physical and occupational therapy over the past few years. Here, we present a scoping review to synthesize the current evidence and determine the strength of the effect and parameters of NiCBS used to improve movement recovery in humans with stroke.

2 Methods

For this paper, we reviewed studies that (a) included individuals over 18 years of age with supratentorial stroke (ischemic or hemorrhagic) regardless of sex, duration and severity of initial impairment, (b) used non-invasive cerebellar stimulation (rTMS, tDCS, TBS or cerebellum-motor cortex PAS), and (c) included motor performance or clinical measures of motor recovery as outcome measures. We excluded studies (a) with individuals with infratentorial stroke (e.g., cerebellar infarction) or other neurological deficits (e.g., Parkinson’s disease/multiple sclerosis), (b) that applied invasive stimulation (e.g.,DBS), (c) that did not include motor function, and (d) animal studies. Four scientific databases were systematically searched: MEDLINE (Medical Literature Analyses and Retrieval System Online; through the PubMed interface), EMBASE (Expert medical Database), Cochrane Central Register of Controlled Trials (CENTRAL), DORIS (Database of Research in Stroke) and PEDro (Physiotherapy Evidence Database). The following keywords were used: stroke, cerebellum, non-invasive brain stimulation, transcranial magnetic stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, theta burst stimulation, motor learning, motor recovery. The search was restricted to peer-reviewed studies in the English language. Retrieved titles and abstracts of the studies were independently assessed by two authors. The flowchart for selection of studies is illustrated in Fig. 2. After reading full-text articles, the authors selected studies according to the inclusion criteria. Any disagreements between the two authors were resolved through discussion and consensus. All quasi-experimental as well as randomized controlled trials (RCTs) published until August 2023 were included in this scoping review. We qualitatively evaluated the included studies (RCTs, single-arm and within-group studies) with the PEDro Scale.

Fig. 2

Steps in selection of studies using NiCBS in stroke survivors.

3 Results and discussion

Study characteristics: Eighteen studies were chosen from the literature that met the search criteria. The included studies were published until 2023 with 56% of the studies published over the past 3 years. Among the studies, 33% were carried out in China, 22% in Italy, 17% in India, and 6% in France, New Zealand, Pakistan, the United States, and Switzerland. The total sample of 18 articles included RCTs (n = 12) studies with a crossover design (n = 4), case-control studies (n = 1), and case studies (n = 1). The mean participant sample size for case studies was 4 and for RCTs were 41 (range: 11–90).

Quality of studies : Evaluation of each study based on the PEDro criteria is summarized in Supplementary Table 1. The mean score for the included studies was 88.3% suggesting that the studies were evaluated as high or very high quality.

Study domains: The included studies were reviewed and categorized into five distinct domains of function: upper extremity function (Chen et al., 2021; Gong et al., 2023; Rosso et al., 2022; Wessel et al., 2023), posture and balance (Liao et al., 2021; Qurat-ul-ain et al., 2022; Ranjan et al., 2021; Rezaee et al., 2020; Xia et al., 2022; Zandvliet et al., 2018), walking (Koch et al., 2019; Kumari et al., 2020; Picelli et al., 2018, 2019; Solanki et al., 2020; Xie et al., 2021), a combined upper and lower extremity function (Li et al., 2021), and laboratory-based motor task learning (Bonnì et al., 2020). Effect sizes were measured by calculating Cohen’s d, and were considered small at 0.2, moderate at 0.5, and large at 0.8 or higher.

Types of NiCBS used: Multiple different noninvasive neuromodulation techniques have been used to stimulate the cerebellum and induce plasticity to influence motor performance. Repetitive TMS when applied at slow rates (0.2–1 Hz) transiently decreases the excitability of the underlying neural structures; in contrast, rTMS applied at faster rates (5 Hz or higher) transiently increases the excitability of the underlying neural pathways (Hallett, 2007). Theta-burst stimulation is a form of patterned repetitive TMS where stimuli are applied in bursts of three, delivered at a frequency of 50 Hz and an interburst interval of 200 ms (5 Hz). TBS applied continuously for 40 seconds decreases excitability while intermittent TBS applied as 20 2 s periods (10 bursts) applied at a rate of 0.1 Hz increases excitability (Huang et al., 2005). Transcranial direct current stimulation involves application of a weak electric current, traditionally via two electrodes (anode and cathode) secured over the scalp. Cathodal stimulation temporarily suppresses the excitability of the underlying brain region while anodal stimulation temporarily enhances the excitability of the underlying brain region (Reis et al., 2008). Paired associative stimulation involves repetitive application of 120 conditioning-test stimuli pairs delivered at a frequency of 0.25 Hz. The conditioning stimulus is applied over the cerebellum preceding a focal test stimulus applied over contralateral motor cortex with an interstimulus interval of 2ms (Lu et al., 2012).

Report of ES across studies: Figure 3 summarizes the effect sizes calculated from the data of studies from each domain of function. Table 1 provides details of the methods and findings of each study.

Fig. 3

Effect sizes of cerebellar noninvasive brain stimulation and behavioral interventions on upper extremity function, balance and walking outcomes in stroke survivors.

Table 1

Study characteristics

Domain of function	Type of study	Sample size	Cerebellar stimulation	Behavioral intervention	Main outcome(s)	Results	Change scores
Upper Extremity Function
Chen et al., 2021	RCT	32	iTBS over ipsilesional lateral cerebellum, 70 mm Fig. 8 coil oriented tangentially to the scalp with the handle pointing superiorly, 600 pulses over 200 s delivered at 80% AMT, location: 1 cm inferior and 3 cm lateral to inion, prior to PT intervention, 10 sessions over 2 weeks	Physical Therapy	Modified Ashworth scale (MAS), the Modified Tardieu scale (MTS), Shear Wave Velocity (SWV), and Barthel Index (BI)	Compared to sham, iTBS group showed reduced MAS scores for affected elbow flexors (P = 0.004) and wrist flexors (P = 0.002), MTS scores in the elbow flexors (P < 0.001) and wrist flexors (P < 0.001) and SWV values of upper limb (biceps brachii: P = 0.015; flexor carpi radialis: P < 0.001). Patients of both groups showed significant improvement the BI compared with baseline (P < 0.001)	MTS Wrist flexor (51.93), SWV Biceps brachii (0.92), SWV Flexor carpi radialis (0.87), BI (9.06)
Rosso et al., 2022	Pilot RCT	28	CER_M1 PAS: Placed laterally (3 cm right or left from the inion) contralesional cerebellum, 110-mm double-cone coil, 120 pairs of stimuli at 0.2 Hz. Daily totalling 5 sessions followed by 45 min of physical training. TMS: Placed over the ipsilesional M1, 70 mm Fig. 8 coil; MEP from FDI recorded at 140% rMT; intensity for conditioning stimulus was 90% rMT and 140% for test stimulus	N/a	Baseline Jebsen-Taylor hand function test ratio of affected and unaffected hands (JTTr) &Baseline Grip strength ratio of affected and unaffected hands (GSr)	JTTr: Showed a group x time interaction. Significant improvement in the active vs. sham group at D30 (P = 0.01). GSr: No effect of treatment. No time by group interaction in the JTT or GS performances of unaffected hand.	JTTr: D0 to D30 (0.61)
Gong et al., 2023	RCT	72	tDCS: Anode-right CB 3 cm lateral to inion; Cathode- contralateral shoulder. Intesnity of 2 mA for a duration of 20 min. In Sham group: a 0.5 mA ramp up of 30 s, followed by a ramp down of 30 s, 19 min of 0 mA current ending with a 0.5 mA ramp up of 30 s, and a ramp down of 30 s.	Physical Therapy	Fugl-Meyer Upper Extremity (FM-UE)	The FMA-UE score in the tDCS group was significantly higher than that in the control group (P = 0.013). Compared with the baseline, the mean FMA-UE score was also significantly higher in the tDCS group than that in the control group (difference between the two groups was 6.2 points, P = 0.043)	FM-UE: 4.9 points (between groups), 18.9 points (tDCS group), 12.7 points (control group)
Wessel et al., 2023	RCT	11	tDCS; Sequential multifocal stimulation (M1-CBM1-CB) &Monofocal control condition (M1-sham-M1-sham); M1 Stimulation: Anode- 1 mA applied for a duration of 20 min to the M1 hotspot contralesional to the affected hand; Electrode- supraorbital region ipsilateral to the affected hand. CB Stimulation: Anode-2 mA applied for a duration of 20 min located 3 cm lateral of the inion over the CB ipsilateral over the affected hand; Electrode- over the ipsilateral buccinator muscle	N/a	Motor Learning task: Movement trajectory of correctly performed trials	Active vs. Sham CB-tDCS: Significant effect of stimulation (p = .004), session (p = .006), and a significant session×stimulation interaction (p = .022). The effect of stimulation was significant for session D1S2 (p = .002), but not for D2S2 (p = .979)	Not given
Posture and Balance
Liao et al., 2021	RCT	30	iTBS over contralesional lateral cerebellum, 70 mm Fig. 8 coil, 600 pulses over 200 s delivered at 80% AMT, location: 1 cm inferior and 3 cm lateral to inion, prior to PT intervention, 10 sessions over 2 weeks	Physiotherapy	Berg Balance Scale (BBS)	Compared to sham, iTBS with PT intervention significantly improved BBS at T2 (P = 0.003) and increased TIS scores at T2 (P = 0.023). No sigificant difference on FMA-LE and BI.	BBS: T0-T1 (3.42) T0-T2 (4.25)
Xia et al., 2022	Pilot RCT	31	iTBS over the cerebellum hemisphere contralesional lateral cerebellum &M1 ipsilesional to the affected side; 70 mm Fig. 8 coil; 600 pulses (3 pulses at 50 Hz repeated at 5 Hz). Completed inbetween intervention; 1 session	N/a	Balance Function Total Score	In the CB-SMA group, 12 out of the 14 parameters improved significantly in the EC condition after the intervention: COPs, COPa, ML- COPa, S-COPda, and L-COPdv (P < 0.01); ML-COPd, AP-COPd, ML-COPs, L-COPda, S-COPdv, COParea, and score (P < 0.05).	Composite Score (8.9)
Posture and Balance
Koch et al., 2018	RCT	34	iTBS over contralesional lateral cerebellum, 70 mm Fig. 8 coil; 1200 pulses (2X600 pulse blocks) at 80% AMT, prior to PT intervention for 3 weeks; 10 sessions	Physical therapy and Physiotherapy	Berg Balance Scale and Step Width	Compared to sham (mean change: 6 points), iTBS (mean change: 13 points) signifiantly improved BBS score (P = .03). No differences on FMA and BI scores between the 2 groups. Stepwidth, measured during the step of unaffected limb, was significantly reduced in the CRB-iTBS group (P < .01). No significance differences in steps performed with the affected limb, step length, or stance percentage duration were found.	BBS T0-T1 (8.9) BBS T0-T2 (13) Gait Analysis T0-T1 (2.5) Gait Analysis T0-T2 (Not given) Steps performed with affected limb T0-T1 (1.8) Steps performed with affected limb T0-T2 (Not given)
Domain of function	Type of study	Sample size	Cerebellar stimulation	Behavioral intervention	Main outcome(s)	Results	Change scores
Rezaee et al., 2020	Pilot Crossover	10	tDCS-cathodal stimulation over cerebellum, 3.14 cm² disc electrodes; 2 mA bilaterally, 15 min; two montages- one targeting the dentate nucleus and the other targeting the LE representation of cerebellum; Stimulated inbetween task completion	N/a	Center of Pressure (CoP) target reach performance	Significant difference in the FRT success rate (P < 0.001) in the montage that targetted cerebellar dentate than the cerebellar LE representation.	Not given
Zandvliet et al., 2018	Case-Control	25	tDCS-Anodal stimulation applied over contralesional, ipsilesional cerebellum or sham; anode stim at 1–3 cm lateral of the inion; 3.14 cm² disc electrodes; 1.5 mA bilaterally, 20 min; applied during the center of pressure (CoP) tracking task	N/a	Center of Pressure (CoP) composite score: CoP amplitude and standard deviation, Velocity and standard deviation, and Range	Significant reduction in the CoP composite score in stroke group during contralesional cerebellar anodal stimulation during the challenging tandem position (p = 0.03). A significant decrease in ACoP (p = 0.02), varCoP (p = 0.01), range ratio (p = 0.01), and VCoP ratio (p = 0.02), but not varVCoP ratio. No effect of ipsilesional cerebellar stimulation or sham stimulation. Control group: No effect of stimulation or sham	Not given
Ranjan et al., 2021	Crossover	12	tDCS-cathodal stimulation over cerebellum, 3.14 cm² disc electrodes; 2 mA bilaterally, 15 min; targeting the dentate nucleus and the other targeting the LE representation of cerebellum in a cross-over design during weight-shifting training	N/a	Normalized Effectiveness Index (NEI), Length Ratio (LR), Center of Pressure (CoP) path length &sway	Improved NEI with both dentate (p < 0.05) and cerebellar lower extremity (p < 0.05) tDCS.	Not given
Qurat-ul-ain et al., 2022	RCT	66	tDCS with an intensity of 2 mA was applied for a duration of 20 min inbetween task completion. CbSG: Active anodal electrode was placed over the cerebellum, 1–2 cm below inion occipital protuberance, &cathodal electrode placed on right buccinator muscle. MSG: Anode positioned over the lesioned M1 &cathode placed over the contra-lateral supraorbital area. SSG: Same as MSG	Virtual Reality based LL functional training	Berg balance scale (BBS), timed up and go test (TUG), BESTest Balance Evaluation–Systems Test (BESTest), risk of fall (JHFRAT), and Mini mental state examination (MMSE)	Significant differences with p-value in BBS, (cerebellar vs. sham p≤0.001, cerebral vs. sham p = 0.011), TUG (cerebellar vs. sham p = 0.001, cerebral vs. sham p = 0.041), Bestest (cerebellar vs. sham p = 0.007, cerebral vs. sham p = 0.003), JHFRAT (cerebellar vs. sham p = 0.037). No significant differences between groups with MoCA but MMSE improved with M1 stimulation (M1 vs. cerebellar p = 0.036, M1 vs. sham p = 0.011). 6MWT and 25FWT showed non-significant results for both between group and within group analysis.	BBS-CbSG (6.28) BBS-MSG (9.09) TUG-CbSG (5.03) TUG-MSG (3.28) BESTest-CbSG (15.09) BESTest-MSG (18.09) MMSE-CbSG (2.74) MMSE-MSG (4.45) JHFRAT-CbSG (2.37) JHFRAT-MSG (0.01)
Upper and Lower Extermity Function
Li et al., 2021	RCT	90	Low Frequency rTMS (LF-rTMS): Placed over contralesional M1, circular treatment coil, 200 repititions (1000 total pulses, treatment time: 20 min), Delivered at 80% rMT to treatment group 1x/day for 6 days/week for 4 weeks followed by rehabilition. cTBS: 50 Hz cTBS was applied to right cerebellar hemisphere (3 cm lateral to the midline and 1 cm below the inion), applied at 80% AMT for 1200 pulses and a total treatment time of 80 s; Coil oriented tangentially to scalp	Rehabilitation and acupuncture therapy	Modified Ashworth Scale, FM, Barthel Index	MAS score was decreased (all groups P < 0.05), and FM (all groups P < 0.05) and MBI scores (all groups P < 0.05) were increased in the three groups after therapyy. After therapy, LF-rTMS + cTBS group showed lower MAS score (P < 0.01), higher FM (P < 0.01) and MBI scores (P < 0.01) than the LF-rTMS group and cTBS group	Not given
Walking
Xie et al., 2021	RCT	36	iTBS: over contralesional cerebellum (3 cm lateral and 1cmbelow inion), 70 mm Fig. 8 coil, bursts of three pulses at 50 Hz applied at a rate of 5 Hz, with 20 trains of 10 bursts delivered at 8-s intervals, achieving 600 pulses in total. prior to PT intervention for 10 sessions	Physical therapy	Fugl-Meyer Lower Extremity (FM-LE) and Ten-Meter Walk Test (TMWT)	Compared to sham, iTBS improved 10MWT performance for comfortable walking time (P = 0.0080) with between-group comparisons revealing significant differences at T1 (P = 0.0072) and T2 (P = 0.0133). No significant differences in the FM-LE, TUG, and FAC.	FM-LE T0-T1 (2) FM-LE T0-T2 (2.73) Comfortable Walking Time T0-T1 (3.08) Comfortable Walking Time T0-T2 (4.33) Max. Walking Time T0-T1 (1.71) Max. Walking Time T0-T2 (2.36)
Solanki et al., 2021	Crossover	10	tDCS-cathodal stimulation over cerebellum, 3.14 cm² disc electrodes; 2 mA bilaterally, 15 min; two montages- one targeting the dentate nucleus and the other targeting the LE representation of cerebellum; Stimulated inbetween task completion	N/a	Step Time Affected Leg and Stance Time Unaffected Leg	Significant difference in the effects between the two ctDCS montages where statistically signifcant effect was found for ’Step Time Affected Leg’ (p = 0.0257) and ’% Stance Time Unaffected Leg’ (p = 0.0376). No significant differences between the two montages for 10MWT, TUG and BBS were found.	Not given
Kumari et al., 2020	Case Study	4	tDCS-Anodal stimulation applied over contralesional cerebellum, anode at 1–3 cm lateral of the inion (contra-lesional stimulation); 2 mA, 10 min; applied during task practice	N/a	Step length symmetry during both over-ground and treadmill walking	Change in mean treadmill step length symmetry and over-ground step length symmetry from pre- to follow up was unchanged for 2 participants who received sham and one who received anodal tDCS. Treadmill step length symmetry &over-ground step length symmetry moved closer to the perfect symmetry value of 0.5 for one participant who received sham stimulation.	Case Study
Domain of function	Type of study	Sample size	Cerebellar stimulation	Behavioral intervention	Main outcome(s)	Results	Change scores
Picelli et al., 2018	RCT	20	tDCS (contralesional cerebellar hemisphere): cathode placed over CB hemisphere and anode placed over buccinator muscle on the same side. 2 mA and applied for 20 min during robot assisted gait therapy (RAGT); tDCS: over the damaged cerebral hemisphere: anode placed over lesioned M1 on the leg representation area &cathode placed above the orbit on the other side; 2 mA intensity for 20 min during RAGT; tsDCS: Cathode placed over the spinous process of the tenth thoracic vertebra. Anode placed above shoulder of the unaffected hemibody. Set at 2.5 mA and applied for 20 min during RAGT.	Robot-Assisted Gait Training	6 Minute Walk Test, Motricity Index leg sub-score (MI), and Cadence	The significant differences in the 6-minute walk test noted between groups at the first post-treatment evaluation (p = 0.041) were not maintained at either the 2-week (P = 0.650) or the 4-week (P = 0.545) follow-up evaluations.	6MWT-tcDCS + tsDCS T0-T1 (42.9) 6MWT-tcDCS + tsDCS T0-T2 (36) 6MWT-tcDCS + tsDCS T0-T3 (37.4) 6MWT-tDCS + tsDCS T0-T1 (22.5) 6MWT-tDCS + tsDCS T0-T2 (30.6) 6MWT-tDCS + tsDCS T0-T3 (15.05) Cadence-tcDCS + tsDCS T0-T1 (10.6) Cadence-tcDCS + tsDCS T0-T2 (4.6) Cadence-tcDCS + tsDCS T0-T3 (3.4) Cadence-tDCS + tsDCS T0-T1 (7.38) Cadence-tDCS + tsDCS T0-T2 (6.2) Cadence-tDCS + tsDCS T0-T3 (4.11)
Picelli et al., 2019	RCT	40	tcDCS: cathode placed over cerebellar hemisphere (side dependent on group) and anode placed over buccinator muscle on the same side. 2 mA and applied for 20 minutes during robot assisted gait therapy (RAGT) tsDCS: Cathode was placed over the spinous process of the tenth thoracic vertebra. Anode was placed above the shoulder of the unaffected hemibody. Set at 2.5 mA and applied for 20 minutes during RAGT.	Robot-Assisted Gait Training	6 Minute Walk Test	No significant differences in 6MWT, FAC, MI, MAS, cadence, or ratio between single and double support duration between the two groups was found at T1, T2, and T3.	6MWT-tcDCS + tsDCS T1-T2 (87.58) 6MWT-tcDCS + tsDCS T1-T3 (85.21) 6MWT tcDCS + tsDCS T1-T2 (5.21) 6MWT tcDCS + tsDCS T1-T3 (12.06)
Laboratory-Based Motor Task Learning
Bonnì et al., 2020	Pilot Crossover	8	iTBS over contralesional cerebellum, 2 s train of TBS repeated 20 times, every 10 s for a total of 190 s. Total of 600 pulses delivered at 80% of AMT: 1 cm inferior and 3 cm lateral to inion, prior to task practice	N/a	Error Reduction Learning and Re-adaptation	Compared to the sham stimulation, iTBS condition showed significantly higher rate of error reduction learning (P = 0.03) and re-adaptation (P = 0.04). No differences found for the de-adaptation phase (P = 0.63).	Baseline to Re-adaptation Phase (0.19)

The effect of NiCBS on upper extremity function: Of the eighteen studies reviewed, four examined the effects of NiCBS on upper extremity impairment and function. Two studies included stroke survivors in the early subacute phase with moderate to severe deficits, while two included participants in the chronic phase with mild to moderate deficits. Across all the studies, there was a greater representation of men over women (110 M, 33 F).

Each study utilized different NiCBS protocol and two combined stimulation with physical therapy. All studies were designed as RCTs. Outcome measures differed across studies from impairments such as spasticity scores (e.g.,Modified Tardieu Scale) and activity performance (e.g.,Jebsen-Taylor Hand Function Test) to global function (e.g.,Barthel Index).

One study (Chen et al., 2021) used iTBS over the ipsilesional cerebellum, another used PAS over contralesional cerebellum and ipsilesional M1 (Rosso et al., 2022), while the other two (Gong et al., 2023; Wessel et al., 2023) used tDCS 3 cm lateral to the inion, over the cerebellum (ipsilateral to the affected hand, and in the latter over the right cerebellum). Analyses of effect-size for upper extremity impairment and function utilizing iTBS and PAS indicated a large effect size (d = 2.13–2.9) on measures of muscle tone and stiffness (MTS, shear wave velocity) of wrist and elbow flexors. Effect sizes across measures of UE activity performance varied. Two studies found a relatively small effect (JTTr, d = 0.10, movement trajectory, d = 0.02), while a third found moderate to large effects (FM-UE Time 1, d = –0.75, FM-UE Time 2, d = 1.23). The effect on global function- Barthel Index (BI) was moderate (d = 0.47). These analyses indicate that NiCBS likely has a greater effect on impairment with relatively moderate effect on activity performance and participation.

The effect of NiCBS on posture and balance: Seven of the eighteen studies examined the effects of NiCBS on posture and balance outcomes. Four of seven studies included stroke survivors in the chronic phase (i.e., >6 months after stroke) with a mean duration of 37.54 months. Two studies included individuals who were in the early subacute phase to chronic phase, while one study did not specify the duration post-stroke. While each study included different clinical scale to determine baseline impairment/function (e.g., Fugl-Meyer- lower extremity, Berg Balance Scale, Johns Hopkins Falls Risk assessment scale, and NIH Stroke scale), it can be gauged that included participants had mild impairments in lower extremity function or balance. Most participants in these studies were men (158 M, 40 F).

The studies investigating the effects of cerebellar NIBS on posture and balance employed either iTBS or tDCS, and of the seven, three studies combined stimulation with practice/therapy. Four of these studies were RCTs, two were crossover studies, and one was a case-control study.

Of the seven studies, three studies applied iTBS over the contralesional cerebellum and four studies applied tDCS over the cerebellum to study the effects on balance and postural control. Analyses of effect size for posture and balance outcomes indicated a moderate to large effect size (d = 0.92–4.78) on measures of balance using the Berg Balance Score (BBS), BESTest (Koch et al., 2019; Liao et al., 2021; Qurat-ul-ain et al., 2022). Objective measures of CoP movements showed moderate (d = 0.73–0.75 (Ranjan et al., 2021)) to large (d = 1.59 (Xia et al., 2022)) size of NiCBS effects.

The effect of NiCBS on walking: Seven studies examined NiCBS effects on measures of walking. Five of these studies were RCTs, one as a crossover study, and one as a case-study. One study included participants in the early subacute phase (mean duration 2.57 months post-stroke), while the rest included participants in the chronic phase. All patients were ambulatory at baseline and had mild-to-moderate impairments (e.g., NIHSS: between 0–16). Cumulatively, studies included 74 males and 36 females. Stimulation techniques included iTBS, tDCS, and tcDCS with taDCS with all but two combining therapies with stimulation.

Of the seven studies, two applied iTBS over the contralesional cerebellum, one applied anodal stimulation to target dentate nuclei and the lower-limb representations (leg lobules VII-IX); two applied anodes 1–3 cm lateral to the inion, and the final two placed a cathode over the cerebellar hemisphere and an anode over the buccinator muscle of the same side. Analyses of effect size for walking outcomes indicated small effect size (d = 0.43–0.46) on measures of the 6 Minute Walk Test (6MWT), Motricity Index (MI) at a two-week follow up, Step width of the unaffected side, and Cadence (Koch et al., 2019; Picelli et al., 2018). Moderate effect sizes (d = 0.51–0.72) were found on measures such as MI immediately following treatment and at a 4-week follow up, and the Timed up and go test (TUG) scores (Picelli et al., 2018; Qurat-ul-ain et al., 2022).

The effect of NiCBS on upper and lower extremity function: One (Li et al., 2021) study, designed as an RCT examined the combined effects of low-frequency rTMS (LF-rTMS) over the ipsilesional M1 and continuous TBS (cTBS) over the contralesional CB on upper and lower extremity function. Fifty-seven male and 33 female stroke survivors in later subacute to chronic phase with moderate impairments were included in the study. Stimulation was paired with rehabilitation and acupuncture therapy. Outcome measures included the Modified Ashworth Scale (MAS), Fugl-Meyer (FM), and Barthel Index. Despite reported significant findings, effect sizes could not be calculated due to data unavailability.

The effect of NiCBS on laboratory-based motor task learning: One study (Bonnì et al., 2020) examined the effects of iTBS over contralesional cerebellum on motor adaptation in 6 male and 2 female stroke survivors with mild impairment (mean NIHSS: 4.38) using a cross-over design. Outcome measures included error reduction learning, re-adaptation, and de-adaptation. They reported a large effect size (d = 3.34–3.48) on measures of error reduction learning and re-adaptation. Effect size on de-adaptation was small (d = 0.047), though the findings were non-significant.

Stimulation alone or with therapy: Of the eighteen studies reviewed, half combined a form of therapy with stimulation. Interventions included physical therapy alone (Chen et al., 2021; Gong et al., 2023; Koch et al., 2019; Liao et al., 2021; Xie et al., 2021), rehabilitation and acupuncture therapy (Li et al., 2017), robot-assisted gait training (Picelli et al., 2018, 2019), and virtual reality-based LE functional training (Qurat-ul-ain et al., 2022). Stimulation techniques varied among the studies which included a form of therapy.

3.1 Limitations of the current review

The scoping review presented thus far provides preliminary evidence that NiCBS may be an effective adjunct to support movement recovery in individuals with stroke. While encouraging, multiple limitations of this scoping review call for critical considerations prior to clinical application. First, most included proof-of-concept studies have small sample sizes; thus, raising the risk of effect size inflation. Given the limited focality of noninvasive stimulation methods and the complexity of functional cerebellar organization, it is unclear which specific structures are stimulated and consequently, which mechanisms are implementing the observed effects. For example, the physiological effects of NiCBS on motor cortical excitability and plasticity after stroke are currently unclear. It is therefore crucial that larger sample studies in individuals with known brain lesions are conducted with concomitant neurophysiological measurements of changes in cerebellar-brain connectivity and cortical plasticity. Women were largely underrepresented in these studies, as is the case in many stroke NIBS trials. Finally, inadequate description of stimulation parameters and accompanying behavioral interventions preclude clear recommendations for integrating NiCBS with behavioral/clinical interventions.

The effectiveness of NiCBS can be further enhanced through an informed approach that combines it with well-defined targeted behavioral interventions. Distinct behavioral interventions rely on distinct mechanisms to implement their beneficial effect on treatment targets. A conceptual framework that considers cerebellar connections with cerebral cortex and brainstem networks may provide a theoretical basis for combining NiCBS and distinct behavioral interventions to target specified mechanisms for movement recovery.

3.2 Theory-driven mechanistic framework for noninvasive Neuromodulation of the cerebellum

A theory-driven framework that considers cerebellar specialization and connectivity to influence specific treatment targets underlying movement recovery is needed to inform the choice of NiCBS parameters, concurrently administered behavioral interventions and outcomes in neurorehabilitation research. Figure 4 outlines cerebellar functional regions and emergent cerebello-cortical and cerebellar-brainstem pathways that support mechanisms to improve specific treatment targets during post-stroke recovery. Below, we elaborate on each cerebellar region, and discuss the effects of cerebellar neuromodulation on physiological and/behavioral processes.

Fig. 4

Cerebellum has motor (green) and cognitive (pink) regions. Reciprocal cortico-cerebellar networks to and from motor and cognitive parts of the cerebellum putatively underlying sensorimotor and cognitive processes. Each of these networks form mechanisms for distinct treatment targets. Sensorimotor cerebellum connected to the motor-premotor cortex and brainstem nuclei has the potential to influence tone, agonist-antagonist control and coordination of joints crucial for individuation. Cognitive cerebellum, reciprocally connected to the prefrontal and parietal cortices, may influence cognitive processes such as attention, adaptation and learning.

Sensorimotor cerebellum: pathways to the brain-stem and motor, premotor areas: In the context of motor behavior, Lobules I-VI and VIII (Guell & Schmahmann, 2020), described as the sensorimotor cerebellum, are reciprocally connected with motor, premotor, supplementary motor area, somatosensory cortex, brainstem and spinal nuclei (Guell & Schmahmann, 2020; Judd et al., 2021). These connections are crucial for sensory-motor integration and motor control such as maintenance of tone, agonist-antagonist control, coordination between different body segments for smooth goal-directed actions. Difficulty in individuation (i.e., abnormal movement synergies) after supratentorial stroke are thought to arise from an imbalance between the ipsilesional corticospinal system and contralesional brainstem pathways such as the reticulospinal and vestibulospinal tracts (Li et al., 2019). The cerebellum, through its reciprocal connections with the motor, premotor cortex as well as the brainstem nuclei may provide a potential pathway to help improve tone and individuation in individuals with supratentorial stroke. NiCBS may modulate purkinjee cell excitability and influence control through two pathways (Fig. 5): one, modulate the dentato-thalamo-cortical pathway thus influencing the contralateral motor cortex, and two, influence the interposed and fastigial nucleus to affect the reticulospinal, vestibulospinal and rubrospinal tracts, thus influencing the spinal motor neurons. Chothia and colleagues found that anodal tDCS over ipsilateral cerebellum reduced the facilitation of the spinal motor neurons via the reticulo-propriospinal system (Chothia et al., 2016). In accordance with the physiological effects, iTBS over cerebellum coupled with physical-therapy significantly reduced spasticity in patients with subacute stroke compared with physical therapy alone (Chen et al., 2021).

Fig. 5

Cerebellar stimulation influences (a) dentato-thalamo-cortical pathway (red) to influence motor cortex and (b) cerebellar-brainstem pathways (blue arrows) to the red nucleus and reticular formation and modulate the rubrospinal and reticulospinal pathways.

A key motor deficit after stroke is the inability to coordinate multiple joints for functional actions such as reaching. Such impaired intersegmental coordination during multi-joint movement arises from deficits in feedforward control that requires planning for the effects of interactive torques (passive torques on a joint due to a movement at an adjacent joint) (Beer et al., 2000). Cerebellum plays a key role in feedforward specification of agonist-antagonist timing as well as coordination between different body segments prior to execution. NiCBS of the sensorimotor cerebellum, via its modulation of motor and premotor cortices, may help improve the ability to modulate muscle activity across multiple joints in anticipation of the mechanical interaction torques generated by one’s own movement and by external forces. NiCBS in neurotypical individuals alters cerebellar brain inhibition to the contralateral motor cortex, as well as influences contralateral corticospinal excitability and intracortical inhibition (Behrangrad et al., 2019; Koch et al., 2008). Whether these physiological effects can be harnessed to improve agonist-antagonist control as well as inter-joint coordination of the paretic arm is open for investigation.

Cognitive cerebellum and pathways to the prefrontal and parietal cortices: Cognitive cerebellum (Crus I and II) through its reciprocal connections with frontal and parietal networks is engaged in supporting a wide array of cognitive functions. While cognition is often considered separate from motor processes, cognitive processes such as attention, praxis, ability to dual task and memory play a key role in motor performance. Further, (re)learning of motor skills engages crucial cognitive processes such as error-driven adaptation, strategy formation and reinforcement. After stroke, cognitive cerebellum is engaged in movement recovery. Askim and colleagues demonstrated recruitment of ipsilesional remnant prefrontal and parietal cortices concomitantly with contralesional lateral cerebellum; thus, providing a preliminary support for the idea that cognitive cerebellum and its connectivity with frontal-parietal networks may implement movement recovery (Askim et al., 2009). Cerebellum is specialized for learning mechanisms that rely on sensory prediction errors between the predicted and actual effect of motor commands (Bastian, 2011). NiCBS applied over the cerebellum improved error-based adaptation in neurotypical individuals (Galea et al., 2011).

Complex networks are instrumental in driving cognitive-motor learning mechanisms. Through the dentato-thalamo-cortical projections, NiCBS of the contralesional cerebellum alters resting state connectivity in frontal-parietal networks that support remediation of cognitive processes and boost their engagement in recovery. As proposed by Wessel and Hummel, cerebellar stimulation may also influence the cognitive network, and thus be a more effective node to engage a wider network supporting cognitive-motor learning and recovery (Wessel & Hummel, 2018). The influence of cerebellar stimulation on motor skill acquisition may be mediated through multiple interacting mechanisms (Fig. 6). First, NiCBS may directly enhance cerebellar-motor cortical plasticity crucial for specific processes involved in motor learning (Kishore et al., 2014; Koch et al., 2008; Rastogi et al., 2017). Further, NiCBS may prime the motor cortex rendering it more plastic for subsequent peripheral input or behavioral training (Kishore et al., 2021). Second, cerebellar stimulation in conjunction with motor practice may augment the engagement of frontal and parietal areas during motor learning (Casula et al., 2016; Zheng et al., 2023). Third, cerebellar stimulation may also modulate the connectivity between different cortical/subcortical networks (Halko et al., 2014; Rastogi et al., 2017) that implement practice-induced learning improvements. Recent work demonstrating network-wide changes in the perilesional motor, sensory, preSMA, dorsal and ventral premotor areas following deep brain stimulation and behavioral training offers support to these mechanisms (Baker et al., 2023).

Fig. 6

Cerebellar NIBS influences and likely facilitates plasticity within and across multiple contralateral cortical regions: (a) directly via the dentato-thalamo-cortical tract to motor cortex- engaging motor processes (red arrows); (b) directly via the dentato-thalamo-cortical tracts to frontoparietal areas (green arrows)- engaging cognitive processes; (c) indirectly prime connectivity and plasticity between different cortical areas (blue arrows).

NICBS and behavioral intervention synergy: Cerebellum and its connectivity shows somatotopy for sensorimotor and cognitive specialization that potentially impact distinct treatment targets for movement recovery. Through its connections with the sensorimotor, premotor cortices and brainstem nuclei, the sensorimotor cerebellum is instrumental in recovery of predominant motor impairments such as tone, abnormal movement synergies and inter-joint coordination. The cognitive part of the cerebellum is more engaged in cognitive-motor processes such as motor adaptation and skill learning. Although these two parts interact, the relative engagement of each specialized region is distinct depending on the motor or cognitive requirements of the task.

Such distinct somatotopy, we suggest, has strong implications for NiCBS use in stroke recovery. Depending on the domain of the treatment target- motor vs. cognitive, it is ideal to tailor the stimulation to specific regions of the cerebellum. Invasive cerebellar stimulation has progressed to provide greater spatial resolution for stimulation; however, more efforts are needed to improve the spatial resolution of NiCBS. A combination of computational modeling and high-definition noninvasive paradigms such as tDCS or distinct coil models for TMS may be needed to improve the spatial resolution of NiCBS. Second, and a broader implication is that behavioral intervention aligned to the treatment target may yield better effects than nonspecific/undefined interventions. For intervention effects to be augmented, NiCBS should prime specific mechanisms/pathways driving the intervention effect for the intended treatment target. For example, if the goal is to improve interjoint coordination (treatment target), then both behavioral and NiCBS interventions must synergistically influence known mechanisms underlying interjoint coordination. While a detailed discussion of mechanisms-driven behavioral interventions for specific treatment targets is beyond the scope of this perspective, we provide a potential pairing of NiCBS and behavioral interventions to improve specific treatment targets in Table 2. These behavioral-NiCBS intervention synergies are conceptually driven, and further research is needed to demonstrate effectiveness of such synergies.

Table 2

Mapping of functional region of the cerebellum, its connectivity with treatment target and behavioral interventions to improve specific outcomes (i.e., measure of the treatment target)

Functional region of the cerebellum	Cerebellar lobules	Connectivity	Treatment target	Behavioral intervention	Outcome measures
Sensorimotor cerebellum	IV, VI, VIII	Brainstem, propriospinal pathways, motor cortex	Tone, Individuation, Suppression of abnormal synergies	Progressive abduction loading during goal-directed reaching practice, Bilateral priming	Tone- MAS Synergies- Fugl-Meyer Scale
	Motor cortex, premotor cortex	Coordination of interactive torques, agonist-antagonist control, Action selection	Goal-directed practice of multi-joint movements, Enriched environments to improve decision-making and action selection	Kinematic measures of inter-joint coordination and action selection
Cognitive cerebellum	Frontal cortex	Attention, dual-task, strategy learning, modify behavioral strategies	Task-specific practice with the use of explicit strategies	Improvement in task performance (e.g., gait speed; gait symmetry; Wolf Motor Function Test)
	Frontal and parietal cortex	Error-based learning including visuo-motor adaptation	Task-specific practice with error augmentation
	Basal ganglia	Reinforcement learning	Task-specific practice- exploring task space + reward and effort manipulations

Thus far, the proposed theoretical framework provides multiple mechanisms through which NiCBS may target sensorimotor and cognitive processes critical to recovery of motor control and learning. Future research will require neurophysiological, behavioral, and clinical studies that fill in crucial gaps needed to refine NiCBS-behavioral intervention combination to target specific impairments, augment motor learning and improve movement recovery.

3.3 Future directions

Current research in NiCBS is at a relatively incipient stage and would benefit from a staged research approach along the translational pipeline driven by a mechanistic framework such as one presented here. Below we outline future research areas in NiCBS to determine key mechanisms, identify and treat appropriate treatment targets, shed light on individual differences, and guide development of synergistic behavioral and neurophysiologic approaches to improve clinical outcomes in individuals with stroke.

Effects of NiCBS on motor physiology and motor learning mechanisms: Given the reliance of movement recovery on the physiology of restoration and relearning, determining the effects of distinct NiCBS protocols on motor physiology at the cortical and brainstem levels will be crucial to improve specific outcomes. Relearning after stroke relies on multiple learning mechanisms such as error-based, reinforcement and use-dependent mechanisms (Leech et al., 2022). While cerebellum is predominantly implicated in error-based adaptation, there is emerging evidence that cerebellum is also involved in mechanisms that drive reinforcement, use-dependent and strategic learning (Wessel et al., 2023). Systematic research is needed to identify the precise role of cerebellum in these different motor learning mechanisms and their interactions that underlie learning of real-world functional tasks. Finally, not all neuroplasticity is good; thus, identifying if plasticity in the cerebello-cortical networks is related to better or poor motor recovery will be necessary for tailoring application of NiCBS.

Determine optimal NiCBS parameters: Of the 18 studies reviewed here, six utilized iTBS, eight utilized tDCS, and four used a combination of cerebellar stimulation combined with other neural stimulation techniques. Further, there is considerable variability in the parameters of each NiCBS technique. For example, two studies stimulated ipsilesional cerebellum (Chen et al., 2021; Wessel et al., 2023), while others stimulated contralesional cerebellum (Bonnì et al., 2020; Kumari et al., 2020; Liao et al., 2021; Picelli et al., 2018; Rosso et al., 2022; Xia et al., 2022; Xie et al., 2021). Determining the optimal NiCBS parameters and mechanisms to target a specific deficit will be crucial for optimal results. An important recognition in NiCBS application is its lack of focality. When applied, most NiCBS techniques are nonfocal; that is, the parameters needed to stimulate the motor parts of the cerebellum also influence the cognitive parts of the cerebellum. Thus, it is important to recognize that motor improvements with NiCBS may involve wider networks than those involving motor cerebellum and its connections (Hardwick et al., 2021). Combining computational modeling with modified electrode montage and neuroimaging may help optimize spatial location of NiCBS (Dutta, 2021). Another approach to preferentially target specific cerebellar pathways may involve paired associative stimulation of the cerebellum with prefrontal (cognitive), premotor (planning) and motor (execution) cortex to bias neural plasticity in specific cognitive or motor networks relevant to distinct behaviors (Wessel et al., 2023; Wessel & Hummel, 2018).

Participant selection: An emerging recognition in rehabilitation is that “no two patients are alike”; thus, selecting participants for intervention studies is critical. Participant selection can be optimally guided by the mechanism of action that the intervention is theorized to target. For example, the cerebellar mechanisms may differ depending on the stage of motor recovery. Early after stroke, cerebellum is likely recovering from diaschisis, while in the chronic stages, it may contribute to cognitive-motor processes of learning. Identifying time-driven mechanisms may inform the selection of NiCBS parameters in specific patient populations. Theoretically, to derive benefits from NiCBS, the integrity of the dentate-thalamo-cortical pathway is crucial. Given that a supratentorial stroke may lesion some of the thalamocortical fibers, determining how integrity of the dentate-thalamocortical pathway influences behavioral and physiologic effects of NiCBS will be crucial in identifying potential responders to NiCBS. Further, distinct neuroplastic mechanisms are instrumental depending on the severity of stroke. Future investigations of cerebellar NIBS will benefit from either theory-driven a-priori selection and/or detailed neuroanatomic, physiologic, and behavioral characterization of included participants with stroke. Finally, given that women have a higher lifetime risk of stroke and are more likely to suffer stroke-related disability than men, it is important to ensure equal representation of women in these trials.

Synergism between NiCBS and behavioral training: Noninvasive brain stimulation alone may not lead to clinically meaningful treatment benefits compared to a combined brain stimulation and behavioral approach (Page et al., 2015). Given the multitude of movement deficits in individuals with stroke and the nonfocality of current NiCBS methods, the specificity of behavioral intervention in targeting a specific clinical deficit will be key in improving outcomes. Current research has used non-specific descriptors (e.g., physical/occupational therapy or robotic therapy) to describe behavioral interventions. These descriptions identify the specialty of the provider or the mode of delivery; but do not define the critical ingredients, mechanisms or targets. For example, to improve individuation and minimize the influence of abnormal synergies (treatment target), behavioral intervention such as progressive shoulder abductor loading (Ellis et al., 2018) (active ingredient1) during reaching practice (McCabe et al., 2015) (active ingredient 2) that has shown to improve individuation may be combined with NiCBS to preferentially engage cortico-cerebellar and cerebellar-brainstem pathways (mechanisms). Such a theory-informed synergy between NiCBS and behavioral interventions has the potential to significantly augment movement recovery. To drive precision in NiCBS approach to stroke rehabilitation, future studies need to identify the treatment targets, active ingredients of behavioral and brain stimulation and underlying mechanisms being directed. The theory-driven framework proposed here will help identify such synergies between behavioral training and NiCBS.

4 Conclusion

There is emerging preliminary evidence for NiCBS as a promising adjunct in movement rehabilitation and recovery after stroke. A careful theory/mechanism-driven staged approach is needed to optimize the efficacy of NiCBS for improving movement outcomes in stroke rehabilitation. Establishing efficacy for combining NiCBS with behavioral interventions will pave way for future investigations to test effectiveness and infuse NiCBS in the clinic to improve patient outcomes.

Footnotes

Acknowledgments

During the time of writing this manuscript, SK’s time was funded by NIH R01-HD092481 and 1R01-HD104637 grants.

Conflict of interest

None of the authors have any conflict of interest to report.

Funding

The project was supported by MossRehab Peer Review Committee grant (FY22-2) to Shailesh Kantak.

The supplementary material is available in the electronic version of this article: .

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