Restricted accessResearch articleFirst published online 2023-10
Stimulation of the Premotor Cortex Enhances Interhemispheric Functional Connectivity in Association with Upper Limb Motor Recovery in Moderate-to-Severe Chronic Stroke
Transcranial direct current stimulation (tDCS) targeting the primary motor cortex is modestly effective for promoting upper-limb motor function following stroke. The premotor cortex (PMC) represents an alternative target based on its higher likelihood of survival and dense motor-network connections.
Objective:
The objective of this study was to determine whether ipsilesional PMC tDCS affects motor network functional connectivity (FC) in association with reduction in motor impairment, and to determine whether this relationship is influenced by baseline motor severity.
Methods:
Participants with chronic stroke were randomly assigned to receive active-PMC or sham-tDCS with rehabilitation for 5 weeks. Resting-state functional magnetic resonance imaging was acquired to characterize change in FC across motor-cortical regions.
Results:
Our results indicated that moderate-to-severe participants who received active-tDCS had greater increases in PMC-to-PMC interhemispheric FC compared to those who received sham; this increase was correlated with reduction in proximal motor impairment. There was also an increase in intrahemispheric dorsal premotor cortex-primary motor cortex FC across participants regardless of severity or tDCS group assignment; this increase was correlated with a reduction in proximal motor impairment in only the mild participants.
Conclusions:
Our findings have significance for developing targeted brain stimulation approaches. While participants with milder impairments may inherently recruit viable substrates within the ipsilesional hemisphere, stimulation of PMC may enhance interhemispheric FC in association with recovery in more impaired participants.
Trial Registration:
ClinicalTrials.gov Identifier: NCT01539096; Registration date: February 21, 2012.
Impact statement
This study reports that improved post-stroke proximal motor impairment following constraint induced movement therapy is associated with increases (a) inter-hemispheric connectivity in participants with moderate-to-severe impairments, and (b) intra-hemispheric connectivity in participants with mild impairments. As non-invasive brain stimulation of the ipsilesional premotor cortex was shown to enhance inter-hemispheric connectivity between homologous premotor cortex in participants with more severe impairments, we suggest that future studies of non-invasive brain stimulation should aim to personalize stimulation targets based on intrinsic mechanisms of recovery available to patients within different impairment ranges.
AndradeSM, BatistaLM, NogueiraLLRF, et al.Constraint-induced movement therapy combined with transcranial direct current stimulation over premotor cortex improves motor function in severe stroke: A pilot randomized controlled trial. Rehabil Res Pract, 2017; 2017:1–9; doi: 10.1155/2017/6842549
3.
BachmannLC, LindauNT, FelderP, et al.Sprouting of Brainstem-Spinal tracts in response to unilateral motor cortex stroke in mice. J Neurosci, 2014; 34(9):3378–3389; doi: 10.1523/JNEUROSCI.4384-13.2014
4.
BeallEB. Adaptive cyclic physiologic noise modeling and correction in functional MRI. J Neurosci Methods, 2010; 187(2):216–228; doi: 10.1016/j.jneumeth.2010.01.013
BeallEB, LoweMJ. SimPACE: Generating simulated motion corrupted BOLD data with synthetic-navigated acquisition for the development and evaluation of SLOMOCO: A new, highly effective slicewise motion correction. NeuroImage, 2014; 101:21–34; doi: 10.1016/j.neuroimage.2014.06.038
7.
BestmannS, SwayneO, BlankenburgF, et al.The role of contralesional dorsal premotor cortex after stroke as studied with concurrent TMS-FMRI. J Neurosci, 2010; 30(36):11926–11937; doi: 10.1523/JNEUROSCI.5642-09.2010
8.
BhattE, NagpalA, GreerKH, et al.Effect of finger tracking combined with electrical stimulation on brain reorganization and hand function in subjects with stroke. Exp Brain Res, 2007; 182(4):435–447; doi: 10.1007/s00221-007-1001-5
9.
BiswalB, YetkinFZ, HaughtonVM, et al.Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med, 1995; 34(4):537–541.
10.
BologniniN, Pascual-LeoneA, FregniF. Using non-invasive brain stimulation to augment motor training-induced plasticity. J Neuroeng Rehabil, 2009; 6(1):8; doi: 10.1186/1743-0003-6-8
11.
BorosK, PoreiszC, MunchauA, et al.Premotor Transcranial Direct Current Stimulation (TDCS) affects primary motor excitability in humans. Eur J Neurosci, 2008; 27(5):1292–1300; doi: 10.1111/j.1460-9568.2008.06090.x
12.
BradnamLV, StinearCM, BarberPA, et al.Contralesional hemisphere control of the proximal paretic upper limb following stroke. Cerebral Cortex (New York, NY: 1991), 2012; 22(11):2662–2671; doi: 10.1093/cercor/bhr344
13.
BroeksJG, LankhorstGJ, RumpingK, et al.The long-term outcome of arm function after stroke: Results of a follow-up study. Disabil Rehabil, 1999; 21(8):357–364.
14.
Burke QuinlanE, DodakianL, SeeJ, et al.Neural function, injury, and stroke subtype predict treatment gains after stroke. Ann Neurol, 2015; 77(1):132–145; doi: 10.1002/ana.24309
15.
CarmelJB, KimuraH, MartinJH. Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control. J Neurosci, 2014; 34(2):462–466; doi: 10.1523/JNEUROSCI.3315-13.2014
16.
ChenJL, SchlaugG. Increased resting state connectivity between ipsilesional motor cortex and contralesional premotor cortex after transcranial direct current stimulation with physical therapy. Sci Rep, 2016; 6(September 2015):1–7; doi: 10.1038/srep23271
17.
CunninghamDA, LinY-L, Potter–BakerKA, et al.Efficacy of noninvasive brain stimulation for motor rehabilitation after stroke. Stroke Rehabil, 2018; 249–265; doi: 10.1016/b978-0-323-55381-0.00018-4
18.
CunninghamDA, MachadoA, JaniniD, et al.Assessment of inter-hemispheric imbalance using imaging and noninvasive brain stimulation in patients with chronic stroke. Arch Phys Med Rehabil, 2015a;96(4):S94–S103; doi: 10.1016/j.apmr.2014.07.419
19.
CunninghamDA, Potter-BakerKA, KnutsonJS, et al.Tailoring brain stimulation to the nature of rehabilitative therapies in stroke. A conceptual framework based on their unique mechanisms of recovery. Phys Med Rehabil Clin N Am, 2015b;26(4):759–774; doi: 10.1016/j.pmr.2015.07.001
20.
CunninghamDA, VarnerinN, MachadoA, et al.Stimulation targeting higher motor areas in stroke rehabilitation: A proof-of-concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying mechanisms. Restorat Neurol Neurosci, 2015c;33(6):911–926; doi: 10.3233/RNN-150574
21.
DayanE, CensorN, BuchER, et al.Noninvasive brain stimulation: From physiology to network dynamics and back. Nat Neurosci, 2013; 16(7):838–844; doi: 10.1038/nn.3422
22.
Di PinoG, PellegrinoG, AssenzaG, et al.Modulation of brain plasticity in stroke: A novel model for neurorehabilitation. Nat Rev Neurol, 2014; 10(10):597–608; doi: 10.1038/nrneurol.2014.162
23.
DumRP, StrickPL. The origin of corticospinal projections from the premotor areas in the frontal lobe. J Neurosci, 1991; 11(3):667–689.
24.
ElsnerB, KuglerJ, PohlM, et al.Transcranial Direct Current Stimulation (TDCS) for improving function and activities of daily living in patients after stroke. Cochrane Database Syst Rev, 2013; 11(11):CD009645; doi: 10.1002/14651858.CD009645.pub2
25.
FengW, KautzSA, SchlaugG, et al.Transcranial direct current stimulation for poststroke motor recovery: Challenges and opportunities. PM&R, 2018; 10(9):S157–S164; doi: 10.1016/j.pmrj.2018.04.012
26.
FisherCM. Concerning the mechanism of recovery in stroke hemiplegia. Can J Neurol Sci, 1992; 19(1):57–63.
27.
GandigaPC, HummelFC, CohenLG. Transcranial DC Stimulation (TDCS): A tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol, 2006; 117(4):845–850; doi: 10.1016/j.clinph.2005.12.003
28.
HaywardKS, FerrisJK, LohseKR, et al.Observational study of neuroimaging biomarkers of severe upper limb impairment after stroke. Neurology, 2022; 99(4):e402–e413; doi: 10.1212/WNL.0000000000200517
29.
HaywardKS, NevaJL, MangCS, et al.Interhemispheric pathways are important for motor outcome in individuals with chronic and severe upper limb impairment post stroke. Neural Plasticity, 2017; 2017:1–12; doi: 10.1155/2017/4281532
30.
HummelFC, CohenLG. Non-invasive brain stimulation: A new strategy to improve neurorehabilitation after stroke?. Lancet Neurol, 2006; 5(8):708–712; doi: 10.1016/S1474-4422(06)70525-7
31.
KalénineS, BuxbaumLJ, CoslettHB. Critical brain regions for action recognition: Lesion symptom mapping in left hemisphere stroke. Brain, 2010; 133(11):3269–3280; doi: 10.1093/brain/awq210
32.
KangSY, KimJS. Anterior cerebral artery infarction: Stroke mechanism and clinical-imaging study in 100 patients. Neurology, 2008; 70(24 Pt 2):2386–2393; doi: 10.1212/01.wnl.0000314686.94007.d0
33.
KantakSS, StinearJW, BuchER, et al.Rewiring the brain: Potential role of the premotor cortex in motor control, learning, and recovery of function following brain injury. Neurorehabil Neural Repair, 2012; 26(3):282–292; doi: 10.1177/1545968311420845
34.
KononenM, TarkkaIM, NiskanenE, et al.Functional MRI and motor behavioral changes obtained with constraint-induced movement therapy in chronic stroke. Eur J Neurol, 2012; 19(4):578–586; doi: 10.1111/j.1468-1331.2011.03572.x
35.
KuypersHG, BrinkmanJ. Precentral projections to different parts of the spinal intermediate zone in therhesus monkey. Brain Res, 1970; 24(1):29–48.
36.
LefebvreS, JannK, SchmiesingA, et al.Differences in high-definition transcranial direct current stimulation over the motor hotspot versus the premotor cortex on motor network excitability. Sci Rep, 2019; 9(1):17605; doi: 10.1038/s41598-019-53985-7
37.
LefebvreS, LiewSL. Anatomical parameters of TDCS to modulate the motor system after stroke: A review. Front Neurol, 2017; 8:29; doi: 10.3389/fneur.2017.00029
38.
LemonRN. Descending pathways in motor control. Annu Rev Neurosci, 2008; 31:195–218; doi: 10.1146/annurev.neuro.31.060407.125547
39.
LiepertJ. Motor cortex excitability in stroke before and after constraint-induced movement therapy. Cogn Behav Neurol, 2006; 19(1):41–47.
40.
LiepertJ, BauderH, WolfgangHR, et al.Treatment-induced cortical reorganization after stroke in humans. Stroke, 2000; 31(6):1210–1216.
41.
LinY-L, Potter-BakerKA, CunninghamDA, et al.Stratifying chronic stroke patients based on the influence of contralesional motor cortices: An inter-hemispheric inhibition study. Clin Neurophysiol, 2020; 131(10):2516–2525; doi: 10.1016/j.clinph.2020.06.016
42.
LoweMJ, BeallEB, SakaieKE, et al.Resting state sensorimotor functional connectivity in multiple sclerosis inversely correlates with transcallosal motor pathway transverse diffusivity. Hum Brain Mapp, 2008; 29(7):818–827; doi: 10.1002/hbm.20576
43.
LoweMJ, KoenigKA, BeallEB, et al.Anatomic connectivity assessed using pathway radial diffusivity is related to functional connectivity in monosynaptic pathways. Brain Connect, 2014; 4(7):558–565; doi: 10.1089/brain.2014.0265
44.
LoweMJ, MockBJ, SorensonJA. Functional connectivity in single and multislice echoplanar imaging using resting-state fluctuations. NeuroImage, 1998; 7(2):119–132; doi: 10.1006/nimg.1997.0315
45.
MarconiB, GenovesioA, GiannettiS, et al.Callosal connections of dorso-lateral premotor cortex. Eur J Neurosci, 2003; 18(4):775–788.
46.
MaykaMA, CorcosDM, LeurgansSE, et al.Three-dimensional locations and boundaries of motor and premotor cortices as defined by functional brain imaging: A meta-analysis. NeuroImage, 2006; 31(4):1453–1474; doi: 10.1016/j.neuroimage.2006.02.004
47.
McCambridgeAB, StinearJW, ByblowWD. Revisiting interhemispheric imbalance in chronic stroke: A TDCS study. Clin Neurophysiol, 2018; 129(1):42–50; doi: 10.1016/j.clinph.2017.10.016
48.
NitscheMA, CohenLG, WassermannEM, et al.Transcranial direct current stimulation: State of the art 2008. Brain Stimulat, 2008; 1(3):206–223; doi: 10.1016/j.brs.2008.06.004
49.
PageSJ, FulkGD, BoyneP. Clinically important differences for the Upper-Extremity Fugl-Meyer scale in people with minimal to moderate impairment due to chronic stroke. Phys Ther, 2012; 92(6):791–798; doi: 10.2522/ptj.20110009
50.
PlowEB, CunninghamDA, BeallE, et al.Effectiveness and neural mechanisms associated with TDCS delivered to premotor cortex in stroke rehabilitation: Study protocol for a randomized controlled trial. Trials, 2013; 14:331; doi: 10.1186/1745-6215-14-331
51.
PlowEB, CunninghamDA, VarnerinN, et al.Rethinking stimulation of the brain in stroke rehabilitation: Why higher motor areas might be better alternatives for patients with greater impairments. Neuroscientist, 2015; 21(3):225–240; doi: 10.1177/1073858414537381
52.
RossiS, HallettM, RossiniPM, et al.Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol, 2009; 120(12):2008–2039; doi: 10.1016/j.clinph.2009.08.016
53.
RuddyKL, LeemansA, CarsonRG. Transcallosal connectivity of the human cortical motor network. Brain Struct Funct, 2017; 222(3):1243–1252; doi: 10.1007/s00429-016-1274-1
54.
SaadZS, GlenDR, ChenG, et al.A new method for improving functional-to-structural MRI alignment using local Pearson correlation. NeuroImage, 2009; 44(3):839–848; doi: 10.1016/j.neuroimage.2008.09.037
55.
SankarasubramanianV, MachadoAG, ConfortoAB, et al.Inhibition versus facilitation of contralesional motor cortices in stroke: Deriving a model to tailor brain stimulation. Clin Neurophysiol, 2017; 128(6):892–902; doi: 10.1016/j.clinph.2017.03.030
56.
StinearCM, BarberPA, SmalePR, et al.Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain, 2007; 130(1):170–180; doi: 10.1093/brain/awl333
57.
TaubE, UswatteG. Constraint-induced movement therapy: Bridging from the primate laboratory to the stroke rehabilitation laboratory. J Rehabil Med, 2003; (41Suppl.):34–40.
58.
WardNS, NewtonJM, SwayneOBC, et al.The relationship between brain activity and peak grip force is modulated by corticospinal system integrity after subcortical stroke. Eur J Neurosci, 2007; 25(6):1865–1873; doi: 10.1111/j.1460-9568.2007.05434.x
59.
WoodburyML, VelozoCA, RichardsLG, et al.Rasch analysis staging methodology to classify upper extremity movement impairment after stroke. Arch Phys Med Rehabil, 2013; 94(8):1527–1533; doi: 10.1016/j.apmr.2013.03.007
60.
WuJ, QuinlanEB, DodakianL, et al.Connectivity measures are robust biomarkers of cortical function and plasticity after stroke. Brain, 2015; 138(8):2359–2369; doi: 10.1093/brain/awv156
61.
ZhangY, BradyM, SmithS. Segmentation of brain MR images through a hidden markov random field model and the expectation-maximization algorithm. IEEE Trans Med Imaging, 2001; 20(1):45–57; doi: 10.1109/42.906424
62.
ZhaoJ, ZhangT, XuJ, et al.Functional magnetic resonance imaging evaluation of brain function reorganization in cerebral stroke patients after constraint-induced movement therapy. Neural Regen Res, 2012; 7(15):1158–1163; doi: 10.3969/j.issn.1673-5374.2012.15.006
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
