Neck rotation modulates flexion synergy torques, indicating an ipsilateral reticulospinal source for impairment in stroke

Abstract

The effect of reticular formation excitability on maximum voluntary torque (MVT) generation and associated muscle activation at the shoulder and elbow was investigated through natural elicitation (active head rotation) of the asymmetric tonic neck reflex (ATNR) in 26 individuals with stroke and 9 age-range-matched controls. Isometric MVT generation at the shoulder and elbow was quantified with the head rotated (face pointing) contralateral and ipsilateral to the paretic (stroke) and dominant (control) arm. Given the dominance of abnormal torque coupling of elbow flexion with shoulder abduction (flexion synergy) in stroke and well-developed animal models demonstrating a linkage between reticular formation and ipsilateral elbow flexors and shoulder abductors, we hypothesized that constituent torques of flexion synergy, specifically elbow flexion and shoulder abduction, would increase with contralateral head rotation. The findings of this investigation support this hypothesis. Increases in MVT for three of four flexion synergy constituents (elbow flexion, shoulder abduction, and shoulder external rotation) were observed during contralateral head rotation only in individuals with stroke. Electromyographic data of the associated muscle coactivations were nonsignificant but are presented for consideration in light of a likely underpowered statistical design for this specific variable. This study not only provides evidence for the reemergence of ATNR following stroke but also indicates a common neuroanatomical link, namely, an increased reliance on ipsilateral reticulospinal pathways, as the likely mechanism underlying the expression of both ATNR and flexion synergy that results in the loss of independent joint control.

reaching function following stroke can be profoundly impaired and has been historically described as being constrained, at least in part, to stereotypic multijoint movement patterns or synergies (Brunnstrom 1970; Foerster 1936; Twitchell 1951). Initial quantitative investigations thoroughly described the phenomena under isometric conditions highlighting the abnormal coactivation of brachialis, biceps brachii, and brachioradialis with deltoid (Dewald et al. 1995). The coactivation manifests as a “flexion synergy” and is significant for abnormal joint torque coupling of elbow flexion during shoulder abduction (Beer et al. 1999; Dewald and Beer 2001; Ellis et al. 2007). The resultant loss of independent joint control caused by synergistic coupling is now understood to severely impair both reaching distance when individuals with stroke attempt to lift the arm against gravity (Beer et al. 2000, 2004, 2007) and reaching workspace when individuals lift against various levels of shoulder abduction loading (Ellis et al. 2008; Sukal et al. 2007). The loss of independent joint control has also been quantified kinematically by other investigators who either calculated a joint individuation index during an outward reach against gravity (Zackowski et al. 2004) or calculated area and roundness during a circle drawing task with the arm supported on a horizontal surface (Krabben et al. 2011; Krebs et al. 1998). Although the behavioral characteristics and quantitative means for measuring this impairment have been well documented, human data supporting the underlying neurological mechanism responsible for its manifestation are limited.

Following a stroke-induced loss of corticospinal tract, it has been suggested that cortical reorganization may result in the increased reliance on brain stem pathways (Dewald et al. 1995). The reticulospinal tract is a brain stem pathway that originates in the gigantocellular reticular nucleus (lateral/medullary reticulospinal tract) and caudal and oral pontine reticular nuclei (medial/pontine reticulospinal tract) and descends in the brain stem both bilaterally and uncrossed, respectively (Kuypers 1964). Both tracts terminate in spinal gray matter bilaterally with minimal ipsilateral predominance (Sakai et al. 2009) across multiple spinal segments (Matsuyama et al. 1997).

Microstimulation studies of the reticular formation have demonstrated prevalent activation of limb flexors ipsilateral to and limb extensors contralateral to the side of stimulation in the cat (Drew and Rossignol 1990b; Sprague and Chambers 1954) and macaque monkey (Davidson and Buford 2006; Herbert et al. 2010). In these studies, stimulation of the reticular formation ipsilateral to the limb produced wrist flexor/elbow flexor/shoulder abductor activation reflecting flexion synergy, whereas stimulation of reticular formation contralateral to the same limb produced wrist and elbow extensor activation reflecting “extension synergy,” described in individuals with stroke. Intracellular recordings of spinal upper limb motor neurons (Riddle et al. 2009) and interneurons (Riddle and Baker 2010) following stimulation of medial longitudinal fasciculus in the macaque monkey have also demonstrated reticulospinal connections and convergence with contralateral corticospinal tract, respectively.

In humans, cortical stimulation via transcranial magnetic stimulation has provided evidence of a corticobulbospinal pathway in both individuals with intact nervous system (Ziemann et al. 1999) and individuals with stroke (Schwerin et al. 2008, 2011). Importantly, both of these studies investigated the presence of an ipsilateral (to the affected arm) cortical motor circuit, with the work by Schwerin et al. specifically demonstrating dominant ipsilateral oligosynaptic corticobulbospinal connections in individuals with stroke. The authors suggested the mechanism for the loss of independent joint control in the affected arm may involve an increased reliance on an ipsilateral bulbospinal pathway due to the loss of the contralateral corticospinal tract. All of these studies concluded that the reticulospinal tract, ipsilateral to the affected limb, is the most likely bulbospinal pathway involved, based on much of the same anatomical evidence in animals presented above. Considering the animal and human evidence, the ipsilateral projections and terminations of the ipsilateral medial/pontine reticulospinal and lateral/medullary reticulospinal tracts offer the most plausible anatomical mechanism for the coactivation of ipsilateral motor neuronal pools of elbow and shoulder muscles in the absence of contralateral (ipsilesional) corticospinal tract that occurs following stroke.

To identify the potential contribution of reticulospinal tract ipsilateral to the affected limb in humans following stroke, we investigated the effect of reticular formation excitability, through natural elicitation of the asymmetric tonic neck reflex (ATNR), on elbow and shoulder maximum voluntary torque (MVT) and associated muscle activation. This was performed with a maximum isometric torque generation task for the paretic upper extremity of individuals with stroke and the dominant extremity of individuals without neurological impairment. The ATNR is a primitive reflex normally present only during the first 2–3 mo of life, yet it can reemerge with acquired cortical injury and is classically described as a “fencing” posture where head rotation results in an asymmetric muscle activation pattern of limb extension ipsilateral to the direction of head rotation (direction face is pointing) and limb flexion contralateral to the direction of head rotation (see historical review, Shevell 2009).

The ATNR is an excellent noninvasive probe into reticular formation contributions in humans, since supportive neurophysiological/anatomical evidence is documented in animal models. In brief, cervical spine joint receptors (McCouch et al. 1950) and/or muscle spindle afferents from perivertebral muscles (Chan et al. 1987; Richmond and Bakker 1982) are excited from head rotation. These neck receptors project rostrally onto and result in the activation of, among others, the gigantocellular reticular nucleus (origin of lateral/medullary reticulospinal tract) (Srivastava et al. 1984). Rostral projections to vestibular motor nuclei (Boyle and Pompeiano 1980) and caudal projections to the cervical enlargement onto rotation-modulated segmental interneurons (Wilson et al. 1984) and propriospinal neurons (Brink et al. 1985) have also been identified; however, contributions from the supraspinal loop may be predominant in ATNR (Brink et al. 1985). Completing the reflex loop, descending projections from motor nuclei in the reticular formation then project bilaterally to spinal motor neurons and interneurons in the cervical enlargement, resulting in activation/facilitation of ipsilateral elbow flexors/shoulder abductors and contralateral elbow extensors/shoulder adductors as discussed above.

Importantly, since reticular formation facilitates elbow flexors and shoulder abductors in the ipsilateral arm, and since contralateral head rotation (face pointing away from the same arm) also facilitates elbow flexors and shoulder abductors in the same arm (ATNR), it is postulated that contralateral head rotation likely preferentially excites reticular formation ipsilateral to the affected limb. The same postulation can be made in the context of elbow extensors and shoulder adductors such that ipsilateral head rotation (face pointing toward the same limb) likely preferentially excites reticular formation contralateral to the affected limb. We therefore designed a protocol to probe for brain stem-mediated effects on MVT production and associated muscle activation by naturally eliciting ATNR via head rotation in individuals with stroke and an age-range-matched control group without neurological impairment. We hypothesized that the principally brain stem-mediated effects of ATNR would be greater in individuals with stroke than in individuals without stroke. Specifically, we expected that in individuals with stroke, there would be a greater MVT for elbow flexion and shoulder abduction and associated increased activation of elbow flexors and shoulder abductors, respectively, with contralateral head rotation (face pointing away from affected limb), indicating the reemergence of ATNR and, therefore, an upregulated reticular formation ipsilateral to the affected limb. Similarly, we expected to see an increased coupling of elbow flexion torque during shoulder abduction MVT and an associated increase in coactivation of elbow flexors with shoulder abductors during contralateral head rotation. With regard to ipsilateral head rotation, we expected to see an increase in elbow extension MVT and also an increase in elbow extension coupling during shoulder adduction MVT not due to changes in elbow extensor activation, but instead due to decreases in elbow flexor activation, indicating the lack of an increased reliance on reticular formation contralateral to the affected limb.

If these hypotheses are supported, the effects to flexion synergy torques (Brunnstrom 1970) (elbow flexion and shoulder abduction, external rotation, and extension) and isolated effects to the elbow flexors and shoulder abductors would implicate the ipsilateral reticular formation as the common anatomical source for flexion synergy and reemergence of ATNR activated via descending ipsilateral/contralesional corticoreticular projections and ascending spinoreticular projections, respectively. The results of this study indeed provide evidence for these hypotheses and further refine our understanding of the mechanism underlying the loss of independent joint control following stroke to be an upregulated ipsilateral reticular formation and subsequent increased reliance on the ipsilateral projections and terminations of the ipsilateral reticulospinal tract. It is anticipated that increasing our understanding of mechanisms underlying stroke-induced brain injury will provide new foundations for developing better diagnostic/prognostic tools and therapeutic interventions.

MATERIALS AND METHODS

Subjects.

A total of 26 individuals, with a mean (±SD) age of 59 ± 12 yr (range 38–81 yr), with chronic unilateral cortical and/or subcortical stroke, and 9 age-range-matched individuals without stroke, with a mean age of 57 ± 13 yr (range 37–82 yr), participated in the study. Data from eight participants with stroke were included from previous work that was presented in abstract form as pilot/preliminary data (Dewald et al. 2008). These data did not include electromyogram (EMG) acquisition or a control group. The pilot study was expanded to include an additional 18 individuals with stroke and 9 age-matched (by group mean and SD) individuals with no known neurological impairments and EMG acquisition and analysis (see Table 1 for summary demographic data).

Table 1.

Participant summary demographics

	Value	Range
Hemiparetic group
Age, yr	59 (11)	38–81
UE FMA	25 (8.7)	12–43
Sex (M/F)	19/7
Side affected (L/R)	15/11
Months poststroke	122 (16)	34–290
Control group
Age, yr	57 (13)	37–82
Sex (M/F)	3/6

Values are actual counts or means (SD) and range for participants in the hemiparetic (n = 26) or control group (n = 9). UE FMA, upper extremity motor Fugl-Meyer assessment (scale 0–66); M, male; F, female; L, left: R, right.

All participants were screened for the study prior to participation. Exclusion criteria for individuals with stroke were brain stem stroke, greater than mild impairment of upper extremity tactile sensation and proprioception, difficulty with sitting for long durations, recent changes in the medical management of hypertension, and any acute or chronic painful condition in the upper extremities or spine. The upper extremity portion of the Fugl-Meyer Motor Assessment (Fugl-Meyer et al. 1975) was administered to individuals with stroke as part of the initial screening measure for the paretic upper extremity to qualitatively determine the presence and extent of flexion synergy. The inclusion criteria for individuals with stroke required a broad range of impairment severity with exception of individuals without measurable impairment or individuals with near complete paralysis. The participants with stroke scored 25 ± 8.7 points (range 12–43 points) out of 66 on the Fugl-Meyer Motor Assessment. All subjects had passive range of motion to at least 90° of shoulder flexion and abduction, and neutral internal/external rotation that was required to participate in the study. All participants had pain-free active range of motion for right and left rotation of the cervical spine. Overpressure at the end of the range of motion was used as a screening measure to verify the absence of inflammation at the neck, shoulder, elbow, wrist, and fingers (Hertling and Kessler 1996). All participants had intact upper extremity sensation and proprioception as measured by a tactile localization task and an awareness of movement task (O'Sullivan and Schmitz 2001). Following screening, the subjects gave informed consent to participate in the study, which was approved by the Institutional Review Board of Northwestern University in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki for research involving human participants.

Setup.

Study participants were seated in a Biodex System 3 chair with tightened straps over the shoulders crossing the torso and around the pelvis to prevent movement of the upper body. The impaired arm, wrist, and hand of individuals with stroke or the dominant limb of individuals without stroke was immobilized with a fiberglass cast and fixed with a Delrin ring attachment piece located about the wrist to a 6 degrees-of-freedom (DOF) load cell (model no. 45E15A; JR3, Woodland, CA) that was mounted on the Biodex attachment pedestal. Forces and torques measured by the 6-DOF load cell were recorded with a personal computer-based data acquisition system (NI PCI-6031E; National Instruments, Austin, TX) with a sampling frequency of 1,000 Hz using Matlab data acquisition and graphical user interface toolboxes. The upper limb was positioned in a standardized configuration consisting of 85° of shoulder abduction, 40° of shoulder flexion (clinically; horizontal adduction), and 90° of elbow flexion. The head was then rotated 5° less than full active range of motion toward or away from the paretic (stroke) or dominant arm (control), and an LCD monitor was placed in front of the subject with the center of the display oriented at eye level with the medial sagittal plane of the head (Fig. 1). Throughout the entirety of this article, head rotation (direction the face is pointing) is defined in reference to the affected/dominant limb. Before data were collected in each head position, the load cell was calibrated/zeroed with the subject fully at rest (verified via quiescent EMG recordings). The monitor displayed a dial that provided real-time visual feedback of the elbow or shoulder torques generated by the participant. Head rotation angles were measured with a compass utilized to measure cervical rotation range of motion. Subjects were closely observed to verify maintenance of head position during each trial. Trials where unwanted or accidental head rotation occurred were eliminated.

Fig. 1.

Experimental setup of a participant seated in the Biodex seating system with the arm interfaced with the 6-degrees of freedom load cell via fiberglass casting while rotating the head ipsilateral to the paretic arm and visualizing the feedback monitor.

EMG signals were recorded during all trials from the brachioradialis; biceps brachii; lateral and long heads of triceps brachii; anterior, intermediate, and posterior deltoid; and vertical fibers of pectoralis major. Active differential electrodes (16-channel Bagnoli EMG system; Delsys, Boston, MA) with 1-cm interelectrode distance were used to record surface EMG from the upper limb muscles. The Delsys EMG system also provides preamplification (gain, 1,000) and single-pole high-pass filtering (cutoff frequency, 6 Hz). All EMG signals were filtered at 500 Hz (8-pole Butterworth, model 9016; Frequency Devices, Havelhill, MA) to prevent aliasing and were amplified in a second stage before data collection. The force/torque and EMG signals were collected at a sampling rate of 1,000 Hz via an analog-to-digital converter and stored on a computer for future analysis.

Experimental protocol.

Participants were instructed to generate isometric MVT in the directions of shoulder flexion, shoulder extension, shoulder abduction, shoulder adduction, shoulder external rotation, shoulder internal rotation, elbow flexion, and elbow extension without changing the position of their head/neck. MVTs were recorded for all subjects in two head positions (rotated/face pointing contralateral and ipsilateral to the paretic/dominant arm). The torque produced in the instructed direction was labeled as the primary torque, whereas the torques measure by the load cell in other DOFs at the same or other joint were labeled as secondary torques. For example, when an individual with stroke generates maximal isometric shoulder abduction, there is abnormal secondary torque coupling with elbow flexion (Dewald and Beer 2001).

For each primary torque direction (n = 8), participants rotated the head to maximal cervical rotation minus 5°, as measured with a compass, and then performed the strongest possible isometric contraction for 2–4 s within a 5-s trial. After each repetition, the participant rotated the head to facing forward as a resting position. The head position was randomized first, followed by the order of torque directions. A 1-min rest was taken after each repetition and a 2-min rest was provided between each torque direction to minimize muscle fatigue. Trials were performed until at least three trials, including the maximal trial, were within 10% and until the maximal trial was not the last trial. The next torque direction was performed after these criteria were met. Participants were consistently encouraged verbally to maximize the torque production while maintaining their head position.

Data processing.

Data recorded with the 6-DOF load cell were decoupled with the use of a calibration matrix and transformed to shoulder and elbow torques, which was possible in this isometric condition under the assumptions of a rigid body analysis. MVTs in the primary torque directions were determined using a 250-ms phase-compensated moving-average filter. Secondary torques were calculated from the same 250-ms time window in which the primary torque MVT occurred (Dewald and Beer 2001). MVTs and the concurrent secondary torques were calculated for each of the eight torque directions and both head rotation directions in all participants. Secondary torques were normalized to the maximum measured torque value across all trials. All processed data were transferred to Excel spreadsheets and stored for future statistical analysis.

A torque coupling ratio was then calculated for abduction MVTs and adduction MVTs in both head rotation conditions to quantify the abnormal torque coupling impairment. This was done by dividing the normalized secondary elbow flexion torque by the associated normalized abduction MVT to quantify expression of flexion synergy, as well as dividing the normalized secondary elbow extension torque by the associated normalized adduction MVT to quantify expression of extension synergy. All processed data were transferred to Excel spreadsheets and stored for future statistical analysis.

Individual muscle activation was determined for all muscles in all trials by using EMG. Raw EMG signals were rectified and averaged by employing a 250-ms time window. The EMG value for each muscle was identified as occurring 50 ms before the corresponding MVT to account for the electromechanical delay of the human skeletal muscle (Cavanagh and Komi 1979). All EMG values were normalized by the maximum EMG measured across all trials. The summation of EMG values was calculated for the elbow flexors (brachioradialis and biceps), elbow extensors (lateral and long head of triceps brachii), shoulder abductors (anterior, intermediate, and posterior deltoid), and shoulder adductor (one muscle; pectoralis major) for all trials. All processed data were transferred to Excel spreadsheets and stored for future statistical analysis.

Statistical analysis.

All statistical analyses were performed using IBM SPSS Statistics software version 20.0.0 for Mac OS X. An alpha level of 0.05 (P ≤ 0.05) was used for determination of significance. P values were rounded to the nearest second decimal place except in conditions where SPSS returned a value of 0.001 or 0.0001; in these cases, unrounded values are presented. Mixed-design three-factor ANOVAs were performed to test for main and interaction effects on MVT. Normality was confirmed using the Kolmogorov-Smirnov test, and sphericity was assessed using Mauchly's test with no violations found in any of the ANOVAs. Post hoc comparisons of interactions were not made as part of this study. Instead, a priori comparisons were decided in advance of data collection but were performed only for the most relevant within-group pairwise comparisons (discussed below) when the three-way interaction effect was significant. For the analysis of all shoulder and elbow MVT values, a mixed-design three-factor ANOVA was used to test for the effect of group (stroke, n = 25; control, n = 9), head rotation (contralateral, ipsilateral) and primary torque direction (n = 8), and the interaction effects of head rotation × group, primary torque direction × group, and head rotation × primary torque direction × group on MVT. One individual with stroke was removed specifically from analysis due to corrupted abduction torque and EMG data that were limited to only shoulder abduction MVT trials. In the case of a significant three-way interaction, the relevant a priori comparisons were between contralateral and ipsilateral head rotation for each torque direction (n = 8) within each group.

For the analysis of elbow muscle activation during elbow MVTs, separate mixed-design three-factor ANOVAs were used to test the effect of group (stroke, n = 18; control, n = 9), head rotation (contralateral, ipsilateral) and primary torque direction (elbow flexion and extension), and all interaction effects on summated elbow flexor and summated elbow extensor EMG.

For the analysis of shoulder muscle activation during shoulder MVTs, separate mixed-design three-factor ANOVAs were used to test the effect of group (stroke, n = 17; control, n = 9), head rotation (contralateral, ipsilateral) and primary torque direction (shoulder abduction and adduction), and all interaction effects on summated shoulder abductor and shoulder adductor EMG. One individual with stroke (same as mentioned above) was removed specifically from abductor analysis due to corrupted abduction torque and EMG data that were limited to only shoulder abduction MVT trials.

For the analysis of abnormal elbow torque coupling during shoulder MVTs, a mixed-design three-factor ANOVA was used to test for the effect of group (stroke, n = 25; control, n = 8), head rotation (contralateral, ipsilateral) and primary torque direction (abduction, adduction), and all interaction effects on the torque coupling ratio. One participant with stroke (same as mentioned above) and one control were excluded from torque coupling analysis due to corrupted abduction and adduction torque data, respectively.

For the analysis of abnormal elbow muscle coactivation during shoulder MVTs, separate mixed-design three-factor ANOVAs were used to test the effect of group (stroke, n = 17; control, n = 9), head rotation (contralateral, ipsilateral) and primary torque direction (shoulder abduction and adduction), and all interaction effects on summated elbow flexor and summated elbow extensor EMG. One individual with stroke (same as mentioned above) was removed from torque analysis due to corrupted abduction torque and EMG data.

RESULTS

Framework for the order of presentation of results.

The order of results presented herein reflects the overarching hypothesis of an upregulated ipsilateral reticular formation following a stroke-induced loss of contralateral/ipsilesional corticofugal tract. We lead off with the presentation of elbow and shoulder MVT data, hypothesizing increases in elbow flexion and shoulder abduction MVT during contralateral head rotation, particularly in individuals with stroke. This is followed by presentation of elbow and shoulder muscle activation data, hypothesizing increases in associated elbow flexor and shoulder abductor activation during elbow flexion and shoulder abduction, respectively, during contralateral head rotation, particularly in individuals with stroke. Importantly, only significant main effects were found for EMG data. Although there were no three-way interaction effects found for EMG data, nonsignificant results are presented for consideration, because the study was likely underpowered for this informative dependent variable. MVTs followed by the associated EMG data are presented, hypothesizing an overall reflection of prior behavioral observations of ATNR in individuals with stroke. Finally, we present torque coupling ratios, specifically elbow flexion torque coupling during shoulder abduction MVT and elbow extension torque coupling during shoulder adduction MVT, followed by the associated muscle coactivations, hypothesizing a reflection of prior behavioral observations of flexion and extension synergies, respectively, in individuals with stroke. Data are presented as means ± SD and with exact P values. All means are rounded to the nearest second decimal place.

Elbow and shoulder maximum voluntary torque.

Contralateral head rotation (face pointing away from the affected arm) resulted in an increase in elbow flexion, shoulder abduction, and shoulder external rotation MVT in individuals with stroke (Fig. 2). Importantly, these represent three of the four constituent torques of the flexion synergy described in individuals with stroke. Contralateral head rotation also resulted in a decrease in elbow extension MVT in individuals with stroke. The ANOVA for primary maximum voluntary torques found a significant main effect of head rotation (P = 0.01) and torque direction (P = 0.001) and significant interaction effects of primary torque direction × group (P = 0.001) and head rotation × primary torque direction × group (P = 0.01). A priori comparisons identified torque changes due to head rotation only in individuals with stroke. Elbow flexion was significantly greater with the head rotated contralateral (32.0 ± 13.5 Nm) than when rotated ipsilateral (28.8 ± 14.0 Nm) to the paretic arm (P = 0.001), demonstrating an 11% increase in strength during contralateral head rotation. In addition, elbow extension was significantly less with the head rotated contralateral (19.7 ± 11.0 Nm) than when rotated ipsilateral (23.0 ± 12.3 Nm) to the paretic arm (P = 0.0001), demonstrating a 14% decrease in strength during contralateral head rotation. Shoulder abduction was also significantly greater with the head rotated contralateral (21.3 ± 11.6 Nm) than when rotated ipsilateral (20.1 ± 12.0 Nm) to the paretic arm (P = 0.04) in individuals with stroke. This represented a 6% increase in abduction strength during contralateral head rotation. Finally, external rotation was significantly greater with the head rotated contralateral (7.7 ± 5.8 Nm) than when rotated ipsilateral (6.6 ± 6.0 Nm) to the paretic arm (P = 0.03), demonstrating a 17% increase in strength during contralateral head rotation. There were no other significant changes in MVTs for either group or torque direction. Summary data for the control group are provided in Table 2 for reference.

Fig. 2.

Maximum voluntary torque (MVT; Nm) for individuals with stroke during contralateral head rotation (C; face pointing away from affected arm) and ipsilateral head rotation (I; face pointing toward affected arm) for elbow flexion (EF), elbow extension (EE), shoulder abduction (ABD), shoulder adduction (ADD), shoulder flexion (SF), shoulder extension (SE), shoulder external rotation (ER), and shoulder internal rotation (IR). *P ≤ 0.05, significant difference found on pairwise comparisons. There was an 11, 6, and 18% increase in the flexion synergy constituent torques of EF, ABD, and ER, respectively, and a 14% decrease in EE with contralateral head rotation in individuals with stroke.

Table 2.

Statistical summary of primary torque values by head position for the control group

	Torque, Nm
Primary Torque Direction	Contralateral	Ipsilateral	P Value
Elbow flexion	51.75 (25.36)	52.39 (28.13)	0.65
Elbow extension	36.19 (21.90)	36.65 (21.45)	0.75
Abduction	41.21 (21.60)	39.93 (22.59)	0.29
Adduction	48.65 (31.88)	48.11 (34.38)	0.71
Shoulder flexion	49.78 (32.03)	51.45 (33.50)	0.23
Shoulder extension	28.24 (15.64)	33.86 (22.82)	0.09
External rotation	25.16 (13.16)	23.48 (14.32)	0.21
Internal rotation	22.36 (13.93)	20.90 (12.75)	0.08

Values are means (SD) of primary torque at contralateral and ipsilateral head positions for participants in the control group.

Elbow muscle EMG during elbow flexion/extension MVT.

Individual EMG and torque data trials are shown in Fig. 3, illustrating the impact of head rotation on elbow flexion MVT and associated elbow flexor and extensor activation representative of individuals with stroke and controls. The ANOVA for the elbow flexors during elbow flexion and extension found significant main effects for torque direction (P = 0.001), head rotation (P = 0.03), and group (P = 0.02). No significant interaction effects were found. However, mean elbow flexor activation during elbow flexion MVT was 11% greater in individuals with stroke when the head was rotated contralateral (1.37 ± 0.25) than when the head was rotated ipsilateral (1.23 ± 0.30) to the paretic arm. Furthermore, mean elbow flexor activation during elbow extension MVT was 21% greater in individuals with stroke when the head was rotated contralateral (0.23 ± 0.13) than when the head was rotated ipsilateral (0.19 ± 0.10) to the paretic arm. In the control group, mean flexor activation showed a lesser increase of 6% and 0% during elbow flexion (contralateral, 1.49 ± 0.13; ipsilateral, 1.40 ± 0.20) and extension (contralateral, 0.12 ± 0.06; ipsilateral, 0.12 ± 0.06), respectively, when the head was rotated contralaterally. The ANOVA for the extensors during elbow flexion and extension MVT found a significant main effect for only torque direction (P = 0.001). No significant interaction effects were found. Considering the lack of significant main effects of head rotation or group, or a significant three-way interaction effect, no mean EMG data for the extensors are presented.

Fig. 3.

Individual data acquisition trials taken from an individual without stroke (A, C, E) and an individual with stroke (B, D, F). Absolute torque (A and B) and rectified and normalized biceps long head (C and D) and triceps lateral head (E and F) electromyographs (EMG) are displayed during an elbow flexion MVT trial with the head rotated contralaterally (black) and ipsilaterally (red). A clear increase in biceps EMG from baseline quiescence (first 250 ms) and associated elbow flexion torque is representative of individuals with stroke during contralateral head rotation.

Shoulder muscle EMG during abduction/adduction MVT.

The ANOVA for shoulder abductors during abduction and adduction MVTs found a significant effect of torque direction (P = 0.0001) and group (P = 0.04). No interaction effects were found. However, mean shoulder abductor activation during shoulder abduction MVT was 10% greater in individuals with stroke when the head was rotated contralateral (1.91 ± 0.56) than when the head was rotated ipsilateral (1.74 ± 0.67) to the paretic arm. Furthermore, mean shoulder abductor activation during shoulder adduction MVT was 16% greater in individuals with stroke when the head was rotated contralateral (0.67 ± 0.38) than when the head was rotated ipsilateral (0.58 ± 0.37) to the paretic arm. In the control group, mean shoulder abductor activation showed a minimal change of 0% during shoulder abduction (contralateral, 1.68 ± 0.34; ipsilateral, 1.68 ± 0.43) and the opposite effect of a decrease of 26% during shoulder adduction (contralateral, 0.29 ± 0.04; ipsilateral, 0.35 ± 0.15) when the head was rotated contralaterally. The ANOVA for shoulder adductors found a significant main effect for only torque direction (P = 0.0001). There was an interaction effect of primary torque direction × group (P = 0.01), but not for the other three interactions. Considering the lack of significant main effects of head rotation or group, or a significant three-way interaction effect, no mean EMG data for the shoulder adductors are presented.

Elbow torque coupling during shoulder abduction/adduction MVT.

The ANOVA for the torque coupling ratio found a significant effect of primary torque (abduction and adduction) (P = 0.0001), head rotation (P = 0.03), and group (P = 0.007). A significant interaction effect was found only for primary torque direction × group (P = 0.03). There were no other significant interaction effects. However, in individuals with stroke there was a 12% increase of elbow flexion torque coupling during shoulder abduction MVT when the head was rotated contralaterally (0.86 ± 0.19) versus when the head was rotated ipsilaterally (0.74 ± 0.26). In addition, there was a 60% decrease in elbow extension torque coupling during shoulder adduction MVT in individuals with stroke when the head was rotated contralaterally (0.12 ± 0.42) versus when the head was rotated ipsilaterally (0.30 ± 0.48). In the control group, elbow flexion torque coupling during shoulder abduction MVT showed a lesser increase of 4% when the head was rotated contralaterally (0.52 ± 0.28) versus when the head was rotated ipsilaterally (0.50 ± 0.33). In addition, there was a similar but lesser decrease of 21% in elbow extension torque coupling during shoulder adduction MVT in the control group when the head was rotated contralaterally (0.27 ± 0.31) versus when the head was rotated ipsilaterally (0.34 ± 0.58).

Elbow muscle coactivation during shoulder abduction/adduction MVT.

The ANOVA for the elbow flexors found a significant effect of torque direction (shoulder abduction and adduction) (P = 0.0001) and group (P = 0.001) and an interaction effect of torque direction × head rotation (P = 0.04). There were no other significant interaction effects found. However, there was a 24% increase in elbow flexor coactivation during abduction MVT in individuals with stroke when the head was rotated contralaterally (1.28 ± 0.34) versus when the head was rotated ipsilaterally (1.03 ± 0.38). During shoulder adduction MVT, there was a 25% increase in elbow flexor coactivation in individuals with stroke when the head was rotated contralaterally (0.69 ± 0.33) versus when the head was rotated ipsilaterally (0.55 ± 0.33). The elbow flexor coactivations reflect the same pattern of results from the elbow/shoulder torque coupling data. In the control group, there was a 13% increase in elbow flexor coactivation during abduction MVT when the head was rotated contralaterally (0.93 ± 0.31) versus when the head was rotated ipsilaterally (0.82 ± 0.34) but a 28% decrease in elbow flexor coactivation during adduction MVT when the head was rotated contralaterally (0.28 ± 0.16) versus when the head was rotated ipsilaterally (0.39 ± 0.35). The ANOVA for the elbow extensors found a significant effect of torque direction only (P = 0.0001). Considering the lack of significant main effects of head rotation or group, or a significant three-way interaction effect, no mean EMG data for elbow extensor coactivation during shoulder adduction MVT are presented.

DISCUSSION

Brain stem projections and implications of current results.

The results of this study demonstrate a robust impact of head rotation on the flexion synergy constituents of elbow flexion, shoulder abduction, and shoulder external rotation. MVTs of these flexion synergy constituents were significantly greater during contralateral head rotation only in individuals with stroke. Importantly, it was also found that elbow extension increased during ipsilateral head rotation, demanding an inquiry into the underlying muscle activations. Although three-way interaction effects for EMG data were nonsignificant, main effects were found for head rotation and group for elbow flexors and shoulder abductors, suggesting that the statistical design was underpowered for EMG. However, consideration of the group means for EMG data provides some insight into the underlying mechanism of the significant effects of head rotation found on flexion synergy torques. During primary torque directions of elbow flexion and extension, elbow flexor activation was 11% and 21% greater during contralateral head rotation, respectively. There was little difference and no main effect of head rotation found on extensor activation during any condition. Considering the elbow torque changes found here, which are representative of the ATNR, one would expect facilitation/increase in extensor activation during ipsilateral head rotation. Instead, these data, although nonsignificant, suggest that torque changes consistent with the ATNR may be explained solely by changes in elbow flexor activation. Confirmation of a flexor bias in the context of ATNR needs to be investigated in a larger sample.

Similar to elbow flexors, shoulder abductors were 10% and 16% greater with contralateral head rotation during abduction and adduction MVT, respectively, in individuals with stroke, with no main effects of group or head rotation found for adductor activation. This would suggest that significant increases in abduction MVT that occur during contralateral head rotation in individuals with stroke might be explained solely by changes in abductor activation.

Ultimately, the concurrent increases in flexion synergy constituent MVTs, in addition to potential corroborative changes in muscle activation, strongly implicate an upregulated ipsilateral reticular formation as opposed to contralateral reticular formation in individuals with stroke. The ipsilateral reticulospinal motor system has been previously implicated in the abnormal coactivation of shoulder abductors with distal limb flexors (flexion synergy) and the resultant loss of independent joint control in individuals with stroke (Dewald et al. 1995, 2001; Ellis et al. 2007; Schwerin et al. 2008, 2011; Sukal et al. 2007). Furthermore, animal evidence has demonstrated the involvement of reticular formation neurons in general during reaching (Buford and Davidson 2004; Schepens and Drew 2006, 2004; Schepens et al. 2008). The means by which selective increased reliance on ipsilateral reticular formation occurs is unclear since corticoreticular projections are bilateral in both the cat and monkey (Keizer and Kuypers 1984, 1989). However, a predominant ipsilateral corticobulbospinal circuit has been demonstrated in humans following stroke (Schwerin et al. 2008, 2011; Yao et al. 2009) and in controls (Ziemann et al. 1999), further supporting a selective increased reliance on ipsilateral reticular formation.

In addition to descending ipsilateral corticoreticular projections, ascending projections (Srivastava et al. 1984) from cervical proprioceptors (Chan et al. 1987; Richmond and Bakker 1982) may also serve to excite the ipsilateral reticular formation in individuals with stroke. With a loss of descending contralateral corticofugal projections following stroke, descending efferents from the ipsilateral reticular formation may provide the common circuitry for concurrent activation of elbow flexor and shoulder abductor muscles observed with both contralateral head rotation (ATNR) and attempts to elevate the arm against gravity (flexion synergy). Of important consideration in differentiating these two phenomena is that volitional or cortical drive elicits flexion synergy whereas neck rotation elicits ATNR. Combining contralateral head rotation with volitional/cortical drive of the paretic arm during isometric torque generation merely exacerbates the expression of flexion synergy. Future work should investigate whether the exacerbation of flexion synergy with contralateral head rotation is substantial enough to further impair reaching abilities as measured using kinematics.

In the present study, abnormal elbow flexion torque coupling during abduction MVTs was 12% greater during contralateral head rotation in individuals with stroke while only 4% greater in the control group. An elbow flexion/shoulder abduction torque coupling ratio was calculated by dividing normalized elbow flexion torque by normalized shoulder abduction torque. Since both the numerator and denominator of the ratio increased significantly with contralateral head rotation in individuals with stroke, one would expect that the torque coupling ratio would remain the same. However, elbow flexion coupling during abduction MVT increased to a greater degree than did abduction MVT, resulting in a greater, although nonsignificant, torque coupling ratio. The derived variable of torque coupling ratio likely introduced greater variability, underpowering its statistical analysis. However, significant increases in abduction MVT considered in combination with the elbow flexion torque coupling data presented here further suggest a common drive from ipsilateral reticular formation to abductors and elbow flexors in individuals with stroke. Future anatomical work in animals along with behavior work in humans is necessary to determine whether common drive from ipsilateral reticular formation has differential effects from proximal to distal muscles. In summary, our data suggest that rotating the head away from the paretic arm exacerbates the expression of flexion synergy by further exciting the ipsilateral reticular formation via ascending proprioceptive projections, resulting in increased elbow flexion and shoulder abduction torques.

Although the animal reticular formation microstimulation evidence of ipsilateral facilitation of elbow flexors and shoulder abductors is in agreement with the observed increases in elbow flexion and shoulder abduction MVT observed in the present study, it is important to acknowledge a discrepancy observed in relation to head movement. Specifically, studies utilizing microstimulation of the reticular formation routinely observed that head movements were elicited ipsilateral to both the side of stimulation and the side of upper limb flexor activation (Drew and Rossignol 1990a; Quessy and Freedman 2004). The elicited ipsilateral head rotation direction is opposite to the classical ATNR that is described pairing contralateral head rotation with facilitation of elbow flexors and shoulder abductors. The discrepancy may be explained by the different mechanisms by which the ipsilateral reticular formation is excited: through direct microstimulation or through the reflex loop of ascending input from neck proprioceptors. For example, active contralateral head rotation lengthens antagonist perivertebral neck muscles, activating proprioceptive afferents that, in turn, project to and excite ipsilateral reticular formation, subsequently leading to facilitation of ipsilateral elbow flexors and shoulder abductors. On the other hand, direct microstimulation of the reticular formation activates the neck rotators that produce ipsilateral head rotation and ipsilateral elbow flexion and shoulder abduction. The neck rotators activated via stimulation would be, by definition, the same muscles that are antagonistic and lengthened during active contralateral head rotation, thus reconciling the head movement discrepancy. Future investigation of active head rotation versus elicited head rotation via direct microstimulation is needed to confirm this explanation.

Previous and potential future investigations of ATNR in stroke.

Unlike the present investigation, previous work studying the presence of ATNR in adults with stroke has failed to demonstrate an effect of head rotation on elbow flexion strength (Bohannon and Andrews 1989). The failure to detect changes in elbow flexion strength with head rotation was likely due to the use of hand held dynamometers by Bohannon and Andrews. The rigorous employment of a 6-DOF load cell and the rigid coupling of the arm to the load cell via fiberglass casting of the present study afforded the accuracy to significantly detect changes in maximum strength that may not be feasible with a hand-held dynamometer. This is especially true considering the wide range of strength of our participant pool. The lack of observed changes in elbow flexion strength by Bohannon and Andrews may also have been due to the supine testing position of all subjects. MVT for elbow flexion is reduced in supine compared with sitting in individuals with stroke (Krainak et al. 2011), possibly further minimizing observable effects of head rotation.

Partly similar to the present study, a three-way interaction effect [group × position (supine/sitting) × rotation method (passive/reinforced)] was not found for elbow flexor activation during contralateral head rotation (Warren 1984). Measurements of elbow flexor muscle activation by Warren were taken during active contralateral head rotation both passively and then in a “reinforced” condition involving forceful grasping of the nonparetic arm. Interestingly, Warren was able to detect a significant effect of the method of eliciting the reflex, demonstrating a greater activation of elbow flexor activation during the reinforced condition. Although Warren's reinforced method increased activation to the unaffected arm, the finding likely implicates the necessity of descending cortical drive, in general, to elicit the reflex. Despite maximal descending drive to the affected extremity as occurred during MVTs during the present study, a significant three-way interaction effect was not found for elbow flexor activation. However, main effects of group and head rotation were found, likely indicating inflated type II error. This is a strong possibility considering the significant findings of MVT data in combination with the twofold increase (although not statistically significant) in magnitude of elbow flexor activation with contralateral head rotation in individuals with stroke compared with controls. At a minimum, mean muscle activation changes with head rotation found in the present study warrant future investigation with larger sample sizes to corroborate the significant torque data.

Scientific significance and clinical implications.

The results of this study suggest that increased activation of reticulospinal pathways, anatomically plausible via ipsilateral projections and terminations of ipsilateral pontine and/or medullary (uncrossed fibers) reticulospinal tracts, are responsible for the reemergence of the ATNR and the loss of independent joint control in individuals with stroke. Ripe for future investigation, this neuroanatomical hypothesis dictates that volumetric loss of ipsilesional descending corticofugal projections would be proportional to the expression of both phenomena. Therefore, the clinical prognosis of a patient suffering a substantial loss of corticofugal projections would be poor with regard to ameliorating loss of independent joint control and even worse for recovering fractioned movement of the wrist/fingers (Miller and Dewald 2012). Future work investigating the relationship of corticofugal loss to utilization of contralesional neural resources to expression of motor impairment will greatly inform clinical practice as to the prognosis of patients with various levels of corticospinal tract loss. Quantitative intervention studies have demonstrated an improvement in the loss of independent joint control between the shoulder and elbow and attributed improvements to optimized utilization of residual ipsilesional corticospinal projections (Ellis et al. 2009a, 2009b). However, future clinical investigations will need to identify which patients will likely benefit from targeted shoulder/elbow/hand versus shoulder/elbow interventions on the basis of volumetric loss of corticospinal tract and subsequent increased reliance on ipsilateral corticoreticulospinal projections.

GRANTS

This work was supported by National Institute of Child Health and Human Development Grant R01 HD039343.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.D.E., T.K., and J.P.A.D. conception and design of research; M.D.E., J.D., C.C., and T.K. performed experiments; M.D.E. analyzed data; M.D.E. and J.P.A.D. interpreted results of experiments; M.D.E. and J.D. prepared figures; M.D.E. drafted manuscript; M.D.E. and J.P.A.D. edited and revised manuscript; M.D.E., J.D., C.C., T.K., and J.P.A.D. approved final version of manuscript.