Adaptive motor cortex plasticity following grip reconstruction in individuals with tetraplegia

Abbreviation

1Introduction

Patients with a cervical spinal cord injury suffer severe upper limb function loss resulting in tetraplegia. In tetraplegia, there is injury to one of the eight cervical segments of the spinal cord and the lack of motor control and strength varies, depending on the level and severity of injury. Spinal cord lesions at the C6 or C7 level result in paralysis of the finger flexors, the finger extensors, the intrinsic muscles of the hand and partial or total triceps paralysis. The vast majority of spontaneous recovery (77%) takes place within three months after the injury (Fawcett et al., 2007). Despite intensive rehabilitation therapy with the aim to enhance functional ability and independence, permanent upper limb function loss severely impairs the quality of life for affected individuals (Bryden et al., 2012). Consequently, restoring hand function is considered to be the highest priority among patients with tetraplegia, being prioritised above bowel, bladder, sexual function, or walking ability (Fridén & Gohritz, 2015; Lo et al., 2016). Due to minimal loss of strength in elbow flexors and wrist extensors after spinal cord lesions at the C6 or C7 level, several highly successful surgical interventions have evolved. Surgical reconstruction of grip function in tetraplegia has constantly been developed since its introduction in the early 1970s. The basis for surgical restoration of the tetraplegic hand lies in mobilizing paralyzed joints where tendon transfers are the core traditional procedures (Bryden et al., 2012; Dunn et al., 2016; Fridén & Gohritz, 2015; Skirven et al., 2011). Here, the distal end of a functionally intact muscle and its tendon are detached from its normal insertion, rerouted and reattached to the distal tendon of a paralyzed muscle to replace its original function (Skirven et al., 2011). Reconstruction of thumb flexion to create key pinch is preferably achieved by transferring one of the three elbow flexor muscles, the tendon of Brachioradialis (BR) to the tendon of the paralyzed thumb flexor; Flexor Pollicis Longus (FPL). Innovative single-stage combined procedures have developed from basic scientific research and clinical studies, and have been proven to offer considerable advantages over traditional approaches (Fridén & Gohritz, 2015). Specifically, grip reconstruction is achieved through a combination of surgical procedures including the BR-FPL tendon transfer (Fridén et al., 2011).

Following surgery, patients are subjected to an intense rehabilitation program (Wangdell et al., 2016). Three weeks after surgery the patient is encouraged to use their restored grip functions in daily activities (Wangdell et al., 2016). Previous studies show that the restoration of grip function in tetraplegia leads to recognized functional benefits in activities of daily living and enhanced quality of life in individuals with tetraplegia (Bunketorp-Käll et al., 2017; Wangdell et al., 2013).

Based upon neuroimaging studies, the central nervous system (CNS) is now considered to be functionally dynamic. The CNS is adaptive, or plastic, and has some capacity to adapt or re-organize itself to compensate for the loss of function and/or maximize remaining functions in the event of an injury to the central nervous system. More specifically, the functional topography of the motor cortex (commonly called the motor homunculus or motor map) can be modified by a variety of manipulations such as peripheral or central injury, electrical stimulation, and behavioral experience (Nudo et al., 2001). Behavioral experiences that typically induce long-term plasticity in motor maps appear to be limited to those that entail the development of new motor skills (Nudo et al., 2001).

The execution of motor tasks involves several brain areas, in particular the primary motor cortex (M1). Somatotopic organization of M1 illustrates the fundamental organizational principle of functional specificity in the brain. Somatotopic organization refers to the anatomic mapping of motor functions within the CNS. Advances of brain mapping and neuroimaging have enabled studies of neural plasticity in the human brain (Kokotilo et al., 2009). A large body of literature has examined neuroplasticity changes and motor cortex reorganization as a consequence of SCI (Freund, P. et al., 2013; Kokotilo et al., 2009; Moxon et al., 2014; Nardone et al., 2013). Several studies have examined cortical reorganization of motor and sensory systems following SCI, showing that the CNS is adaptive, or plastic, and has some capacity to re-organize itself. (Freund, P. et al., 2013). With the exception of possible expansions of limb-specific activations (Curt et al., 2002; Jurkiewicz et al., 2007), the topography of the primary sensorimotor regions seems to remain largely intact (Corbetta et al., 2002; Shoham et al., 2001; Turner et al., 2003). However, due to varying protocols and conflicting results it is not possible to draw definite conclusions regarding the effects of SCI on brain reorganization (Kokotilo et al., 2009).

The human hand represents one of the most complex biological motor systems (Bezuhly et al., 2007). The way in which individuals with tetraplegia gain voluntary control over paralyzed functions following surgical tendon transfer, is an area of intense interest. Reconstructive surgery amounts to a unique, focused stimulus for brain plasticity and therefore yields a rare opportunity to characterize cortical plasticity in relation to the process of regaining limb function. Although tendon transfer has been performed in patients since the 1970s (Dunn et al., 2016), no previous studies have sought to delineate neuroplasticity in the restoration of upper limb function following tendon transfers in tetraplegia.

Given the preserved topography (Kikkert et al., 2016) and retained functionality of neuronal networks in spinal cord injured patients (Hotz-Boendermaker et al., 2008), it seems likely that regained limb control may be mediated by activation of that limb’s specific cortical sensorimotor region. Supporting this view, acute stage cortical sensorimotor fMRI activation reductions due to SCI progressively enlarge during recovery, and ultimately normalize when motor ability is regained (Jurkiewicz et al., 2007). In this study, we used functional Magnetic Resonance Imaging (fMRI) with the aim to examine whether restoration of voluntary grip control through tendon transfer in patients with tetraplegia follows the topographic pattern. Specifically, we examined the hypothesis that regained thumb control after surgical BR-FPL transfer activates the thumb region of the primary motor cortex.

2Materials and methods

2.3Motor tasks and experimental design

Participants were positioned supine on the bed of the MRI scanner with their head immobilized in a tight-fitting head coil in order to minimize motion artifacts. A wedge pillow was positioned under the legs of participants. The right arm was held such that the elbow was resting against the scanner wall, the wrist straight, and the elbow was immobilized in a plastic splint at about 60°of flexion (Johanson et al., 2006). The palm was positioned towards the midline of the body, and a small cube was attached to the index finger by a small strip of Velcro tape, in order to keep the thumb stabilized and somewhat elevated in relation to the index finger (Fig. 1A).

Fig.1

(A) Experimental setup. (B) Activation center of gravity for thumb (blue) and elbow (red) flexion activations in control participants and patients. The central sulcus is indicated by the dotted line. (C) Mean cortical distance between thumb and elbow flexion activation centers of gravity for control participants and patients. Error bars indicate standard error of the mean. Significance of the planned comparison (one-tailed t-test) is shown.

Two isometric motor tasks were examined: thumb flexion and elbow flexion. Activation of a restored key pinch produces articulations mainly in the metacarpophalangeal joint due to balancing procedures including fusion of the carpometacarpal joint and a tenodesis in the interphalangeal joint (Fridén et al., 2011). Prior to the experiment, the maximal voluntary contraction during isometric activation of the key pinch was measured using a Pinch Gauge (North Coast Medical, Gilroy, USA) (Vanden Berghe et al., 1991). All subjects then trained to exert target forces corresponding to approximately 20% of the MVC for both motor tasks. Each scanning session in the fMRI protocol consisted of six runs, each including 10 pseudo-randomized 10 s blocks, with equal numbers of each movement. Each of the two motor tasks lasted 1 second, a speed that was found to be easy and comfortable to perform in pilot trials. The duration of each run was approximately 250 seconds. Across runs, each motor task was repeated 300 times. Participants were guided by auditory and visual cues presented on a screen viewed through a head-coil mounted mirror. A blinking graphic illustration was presented depicting either a key pinch or a flexed elbow, paced by digitized sound effects. The blocks were separated by an inter stimulus interval (ISI) of 12–15 s, during which subjects were instructed to visualize a fixation ring and to remain motionless. All participants performed an in-scanner practice session prior to data collection and were reminded, between runs to avoid any movements not associated with the required tasks.

3Results

3.4Brain activations

Thumb and elbow movements elicited extensive precentral gyrus activations in all participants (FWE p < 0.05). Consistent with the previously demonstrated topographic organization of the motor cortex (Meier et al., 2008), control participant thumb CoGs were significantly more distal (one-tailed paired t-test, p = 0.017, Bonferroni corrected for three comparisons) and ventral (corrected p = 0.032) than their elbow flexion CoGs. There was a trend towards a more anterior location (uncorrected p = 0.029, corrected p = 0.086) (Fig. 1B). The k-means clustering algorithm correctly assigned the elbow and thumb flexion CoGs to topographically separate clusters (p = 0.014).

In patients, the thumb flexion CoGs were not more distal (one-tailed paired t-test, p = 0.098, Bonferroni corrected for three comparisons) or anterior (corrected p = 0.246) than their elbow flexion CoG, but the thumb CoG was more ventral (one-tailed paired t-test, corrected p = 0.020) (Fig. 1B). Consistently, the k-means clustering algorithm failed to correctly assign the CoGs (p = 0.247).

For elbow flexion activations, patients’ and control participants’ CoGs did not differ in any dimension (all uncorrected p > 0.4) (Fig. 1B). For thumb flexion activations, patient CoG were significantly more medial (one-tailed t-test p = 0.049, corrected for three multiple comparisons) than control participants thumb CoGs, and there were trends towards a more posterior (one-tailed t-test, uncorrected p = 0.070) and dorsal (one-tailed t-test, uncorrected p = 0.050) location. That is, patient thumb CoG was located towards control participant elbow CoG (Fig. 1B).

The distance between the thumb and elbow flexion CoG was smaller in patients (mean 4.72 mm, SD 3.80) than in control participants (mean 9.57 mm, SD 5.53) (one-tailed t-test, p = 0.053) (Fig. 1C). There was no correlation between thumb to elbow CoG distance and duration since surgery in patients (r = 0.248, p = 0.636).

Patients’ elbow CoGs were located closer to the average control participants’ elbow CoGs than the thumb CoGs: the Euclidian distance between patients’ and average control participants’ elbow CoGs was significantly smaller than the distance to the control participants’ thumb CoGs (one-tailed paired t-test, p = 0.003) (Fig. 2). However, patients’ thumb CoGs were not located closer to the average control participant thumb CoG than their elbow CoG (one-tailed paired t-test, p = 0.695) (Fig. 2).

Fig.2

Average cortical distances between patients’ elbow and thumb flexion activation centers of gravity (CoGs) and control participant’s CoGs, showing that the distance from patient’s elbow CoG to the average control participant’s elbow CoG was significantly smaller than the distance from patient’s elbow CoG to the average control thumb CoG, whereas patient’s thumb CoG was not more near neither the average control’s thumb or elbow CoG. Error bars indicate standard error of the mean. Significance of planned comparisons (one-tailed t-tests) are denoted as follows: ^*p < 0.05, n.s. p > 0.05.

4Discussion

We examined primary motor cortex plasticity associated with re-established motor function after surgical tendon transfer in tetraplegia, and tested the hypothesis that regained thumb control is mediated by reactivations of the corresponding topographic area of the motor cortex. Our results do not support this hypothesis: patients’ thumb activations were not topographically distinct from their elbow activations. In patients, the activation did not match the topographic organization of controls. Our findings thus suggest plasticity in which the cortical region for elbow flexion may have adapted to also control the paralyzed thumb muscle. The average number of years elapsed since surgery and the post-surgical rehabilitation did vary between 1–10 years, but we found no correlation between time elapsed since surgery and cortical alterations.

Patient cortical thumb flexion representation was significantly more patchy, seemed similar to the elbow representation, and located more lateral and ventral than in controls. This suggests a functional remapping of elbow neurons corresponding to the transferred BR muscle area. The BR exerts a flexion moment at the level of the elbow (Johanson et al., 2011). A well-controlled recruitment for a key pinch restoration requires a synergistic co-contraction of either the triceps or transferred posterior deltoid. This is necessary to prevent excessive elbow flexion generated by the BR (Johanson et al., 2006; Johanson et al., 2011; Waters et al., 1990). In healthy subjects, the BR does not contract during thumb flexion (Waters et al., 1990). We found no difference in elbow flexion between patients and control participants, despite the surgical alteration of BR in patients. Since the neurological level of injury was C6 and C7 among patients, the function of their elbow flexors was unaffected. Thus, the resisted elbow flexion task recruits all elbow flexors in the arm in a similar way in both patients and controls.

To facilitate motor re-education and voluntary recruitment of transferred tendons, early active postoperative training is required (Fridén & Gohritz, 2015; Wangdell et al., 2016). Early mobilization also helps in preventing adhesions. Starting the day after surgery, patients perform intermittent exercises. The aim is to isolate recruitment of the transferred donor muscle in its new location and coordinate movements with new synergists during ADL. This motor re-education sheds light on the brain’s capacity to adapt to peripheral changes. Moreover, previous studies demonstrate that immobilization of the upper extremity in healthy subjects causes deprivation of the sensorimotor network by specific neuroanatomical changes in the cortical regions responsible for the sensorimotor control of the upper limb (Langer et al., 2012). This further supports the importance of early active training after tendon transfer (Wangdell et al., 2016).

It is noteworthy to mention that the functional organization of M1 is much more complex than has previously been described (Plow et al., 2010; Schieber, 2001). More recently, muscle representations are shown to overlap; individual muscles have multiple representations that intermingle with representations of related movements or parts forming a complex mosaic pattern (Graziano & Aflalo, 2007; Hosp & Luft, 2011). There are individual corticospinal neurons that diverge to multiple motor neuron pools and horizontal fibers that interconnect distributed representations. This complex organization may underlie functional plasticity in local sub-regions of the motor cortex (Nudo et al., 2001). There are studies on complete spinal cord injuries that show activation in the motor network several years after a spinal injury when they mentally imagine themselves moving a paralyzed body part (Sabbah et al., 2002). Thus, the mental representation of the movement remains, despite the complete spinal cord injury. However, it has been shown that activation of the sensory and motor cortex is considerably weaker if one only imagines the movement, and activity in the cerebellum is missing (Nyberg et al., 2001). In addition, a previous neurophysiological study in individuals with SCI demonstrated long-lasting involuntary activity at rest in muscles innervated from close to, within or below the level of the injury (Zoghi et al., 2016). This indicates a high state of central excitability and may reflect a loss of discrete activation of the transferred BR muscle in its new role of controlling two different movements.

There are a number of limitations to this study. As a result of the rarity of tetraplegia combined with the strict inclusion criteria, only six patients were examined. Taking into account the number of people who sustain a SCI worldwide, restorative surgery is an underutilized procedure, although widely advocated (Fridén & Gohritz, 2015). The reason for this is suggested to be skepticism among patients, therapists, and rehabilitation physicians due to inadequate information as well as inadequate referral networks (Curtin et al., 2005). Nevertheless, the resulting homogenous patient group and highly focused hypothesis allowed a within-subject analysis with comparatively robust results, suggesting that motor cortex plasticity is largely consistent across patients. Conversely, the study design did not allow exploration of brain regions or circuits outside the motor cortex, and additional studies in larger samples are required to examine brain-wide mechanisms of plasticity following tendon transfer.

In addition, we observed that patients moved more than the control group. However, rigorous control for movement was included in the analysis of results so selective effects of motion are unlikely. Despite these limitations, this study suggests that the gain of limb function following surgical tendon transfer and early active training is mediated through adaptive changes in the central nervous system that do not follow pre-existing topographic maps. This finding reflects adaptive changes in the central nervous system as a response to extrinsic stimuli (Chen et al., 2003; Cramer et al., 2011), and has a number of clinical implications. Cortical adaptation is a critical facilitator of successful motor relearning, and delineation of the underlying mechanisms may lead to improved rehabilitation approaches and biomarkers (Nardone et al., 2013). Our findings also suggest that successful tendon transfer restoration of voluntary limb control is possible despite any atrophy of cortical regions associated with the unused limb (Freund, Patrick et al., 2013; Freund et al., 2011; Haefeli et al., 2016; Wrigley et al., 2009). Surgical reconstruction of grip functions remains possible, even decades after cervical spinal cord paralysis (Fridén & Gohritz, 2015). All persons living with impaired upper limb functions resulting from SCI should therefore be assessed and informed of possible reconstructive options (Bunketorp-Käll et al., 2017; Fridén & Gohritz, 2015).

Finally, our results are particularly relevant to neuroprosthetics research (Davis et al., 2016). The finding that the motor cortex may adapt to allow body-part specific regions to gain control over other limbs suggests that cortical implants in one region may effectively control multiple types of robotic movements. Indeed, such cortical adaptation may underlie the ability of tetraplegic patients with implants in the hand area of the motor cortex only to perform sophisticated reaching movements with robotic arms (Hochberg et al., 2012).

5Conclusion

Findings from the current study suggests that restored thumb flexion following surgical transfer of an elbow flexor is mediated through adaptive changes in the central nervous system that do not follow pre-existing topographic maps. Our results suggest a neuroplastic mechanism in which cortical areas previously dedicated to elbow flexion may have adapted to control thumb flexion.