Sound, Music and Movement in Parkinson's Disease - Marta M. N. Bienkiewicz

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REVIEW published: 02 December 2015 doi: 10.3389/fneur.2015.00251 Context-Dependent Neural Activation: Internally and Externally Guided Rhythmic Lower Limb Movement in Individuals With and Without Neurodegenerative Disease Madeleine E. Hackney 1,2 *, Ho Lim Lee 3 , Jessica Battisto 3 , Bruce Crosson 1,4 and Keith M. McGregor 1,4 1 Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Decatur, GA, USA, 2 Division of General Medicine and Geriatrics, Department of Medicine, Emory School of Medicine, Atlanta, GA, USA, 3 Emory College of Arts and Sciences, Emory University, Atlanta, GA, USA, 4 Department of Neurology, Emory School of Medicine, Atlanta, GA, USA Parkinson’s disease is a neurodegenerative disorder that has received considerable attention in allopathic medicine over the past decades. However, it is clear that, to date, pharmacological and surgical interventions do not fully address symptoms of Edited by: PD and patients’ quality of life. As both an alternative therapy and as an adjuvant Marta Bienkiewicz, Aix-Marseille University, France to conventional approaches, several types of rhythmic movement (e.g., movement strategies, dance, tandem biking, and Tai Chi) have shown improvements to motor Reviewed by: James Shine, symptoms, lower limb control, and postural stability in people with PD (1–6). However, Brain and Mind Research Institute, while these programs are increasing in number, still little is known about the neural Australia Lawrence Mitchell Parsons, mechanisms underlying motor improvements attained with such interventions. Studying University of Sheffield, UK limb motor control under task-specific contexts can help determine the mechanisms *Correspondence: of rehabilitation effectiveness. Both internally guided (IG) and externally guided (EG) Madeleine E. Hackney movement strategies have evidence to support their use in rehabilitative programs. mehack@emory.edu However, there appears to be a degree of differentiation in the neural substrates Specialty section: involved in IG vs. EG designs. Because of the potential task-specific benefits of rhythmic This article was submitted to training within a rehabilitative context, this report will consider the use of IG and EG Movement Disorders, a section of the journal Frontiers in Neurology movement strategies, and observations produced by functional magnetic resonance Received: 16 September 2015 imaging and other imaging techniques. This review will present findings from lower limb Accepted: 16 November 2015 imaging studies, under IG and EG conditions for populations with and without move- Published: 02 December 2015 ment disorders. We will discuss how these studies might inform movement disorders Citation: Hackney ME, Lee HL, Battisto J, rehabilitation (in the form of rhythmic, music-based movement training) and highlight Crosson B and McGregor KM (2015) research gaps. We believe better understanding of lower limb neural activity with respect Context-Dependent Neural Activation: to PD impairment during rhythmic IG and EG movement will facilitate the develop- Internally and Externally Guided Rhythmic Lower Limb Movement in ment of novel and effective therapeutic approaches to mobility limitations and postural Individuals With and Without instability. Neurodegenerative Disease. Front. Neurol. 6:251. Keywords: lower limb, motor control, neuroimaging, rhythm, externally cued, internally guided, Parkinson’s doi: 10.3389/fneur.2015.00251 disease Frontiers in Neurology | www.frontiersin.org 9 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement REHABILITATION IN PARKINSON’S EXTERNALLY GUIDED MOVEMENT IN DISEASE REHABILITATION Pharmacology and surgery do not fully address the motor, cog- Abundant evidence also demonstrates benefits of rehabilitative nitive, and psychosocial needs of those with Parkinson’s disease exercise that exploits external cueing, which likely specifically tar- (PD), a neurodegenerative disorder that is related to dopamine gets neural systems that support balance (4, 14). EG strategies have depletion in the substantia nigra pars compacta, which in turn improved movement initiation (15, 16). Other research has shown hinders processing in the basal ganglia (7). Several mobility pro- that people with PD have faster reaction times when externally grams are effective (e.g., mobility training, dance, tandem bik- cued compared to self-initiated (IG) movement (17). Synchroniz- ing, and Tai Chi) for improving motor symptoms, lower limb ing movement to rhythmic beats provided externally may enhance control, and postural stability in people with PD (2–6). These movement speed (18). There is also a well-known facilitating programs use a mixture of internally guided (IG) and externally effect of cues for alleviating freezing of gait (FOG) (19). Further- guided (EG) movement strategies, both of which have evidence more, gait training with regular external rhythmic auditory cues to support their use in rehabilitative scenarios. However, lit- has improved gait velocity, stride length, step cadence, timing of tle is known about rhythmic lower limb movement relating to EMG patterns, and mobility in persons with PD (20–22). Evidence locus of cue (EG vs. IG). Many rehabilitative programs pref- has begun to accumulate that suggests external cues access alter- erentially select one locus over another, which may or may nate neural pathways that remain intact in the individuals with not be optimal for long-term improvement of mobility. Better PD, including the cerebellar-thalamo-cortical (CTC) network. mechanistic understanding of beneficial exercise effects on neu- ral circuitry garnered under specific contexts could improve the CHARACTERIZATION OF THE NEURAL design of motor rehabilitation interventions for particular symp- toms (e.g., freezing and bradykinesia) and the various disease CIRCUITRY INVOLVED WITH INTERNALLY stages of PD. AND EXTERNALLY GUIDED MOVEMENT The goal of this review is to provide rehabilitative special- This review covers available literature focused on imaging studies ists and researchers with the state of the rehabilitation science involving IG and EG upper and lower limb movement paradigms regarding the potential neural underpinnings of IG and EG move- within the contexts of cortical and subcortical neural function. ments. Respective of this, IG movement neural dynamics will be Our goal is to summarize findings from the available lower limb contrasted with those of EG movements. As implemented, the literature to inform future research with goals of characterizing dichotomy provided in this review respective of movement locus neural areas involved in motor rehabilitation of PD. Numerous of cue is didactically necessary but practically difficult to realize neural systems likely produce IG and EG movement and could from a rehabilitative perspective. Ecologically speaking, human be modulated by rehabilitative training. However, the current movement is rarely, if ever, purely IG or EG, whether in the case of work is not intended to provide an encyclopedic reference to daily activities or in rehabilitative settings. That said, determining neural network function in motor systems, although we provide a the beneficial and most effective qualities and outcomes of IG reference in Table 1 that catalogs a number of studies that involve and EG motor training could inform rehabilitation particularly for IG and EG paradigms. Rather we will focus on the neural routes largely intractable conditions like PD. that likely assume multiple subcomponents to be explicated in future rehabilitation research. These routes are (a) cortically mod- INTERNALLY GUIDED MOVEMENT IN ulated (mainly in the frontal and parietal lobes), (b) subcortically REHABILITATION modulated including the basal ganglia and thalamus, and (c) the cerebellum. Proper completion of IG movements relies on efficient function In the neurotypical model, the investigation of IG and EG of subcortical loops involving the basal ganglia (8, 9). Due to movements of the upper extremity has received considerable dysfunction of the striato-thalamo-cortical (STC) circuit [also attention in neuroimaging (41, 46, 49, 51, 52). These studies have referred herein as the cortico-basal-ganglia-thalamic (CBGT)], suggested distinct cortico-cerebellar, cortico-cortico, and cortico- people with PD have particular difficulty with IG tasks (10–12). subcortical neural pathways for IG vs. EG in a variety of con- However, this impairment can be remediated by motor rehabil- texts. The following sections will address differences between itation that uses skills in which participants engage cognitively neural activity from both a region of interest (ROI) and neural in planning and selecting movements (5). Specifically for indi- network perspective. It needs to be noted that a vast majority viduals with PD, having complex movements broken down into of motor-related literature with such a focus has been done in simpler elements may facilitate motor performance. Employing upper extremity movements. Given the relatively young science a “movement strategy” that demands increased focus on move- of neuroimaging, this is somewhat understandable as there are ment plans and mentally rehearsing and/or preparing for self- considerable technical difficulties in controlling motion being initiated movement may be helpful. For example, focusing on translated from the legs to the head during movement. As such, critical movement aspects (e.g., longer steps, quicker movements) studies investigating neural correlates of movements of the lower helps individuals with PD to achieve nearly normal speed and extremity in humans in the context of IG vs. EG control are amplitude (13). Thus, IG training may be helpful for individuals rare. We will attempt to address the differences between upper with PD. extremity movements and lower extremity movements as available Frontiers in Neurology | www.frontiersin.org 10 December 2015 | Volume 6 | Article 251 TABLE 1 | A summary of the relevant imaging studies in the context of IG vs. EG movement in healthy controls and individuals with Parkinson’s disease. Frontiers in Neurology | www.frontiersin.org Hackney et al. Reference Population and N: (young Internally guided or Upper or lower Task Finding <40 years; older >50 years) externally guided limb movement (23) 12 Healthy young EG Lower limb Imagery and execution of EG movement execution and motor imagery shared a common network, including the ankle dorsiflexion premotor, parietal and cingulate cortices, the striatum, and the cerebellum (24) 4 Hemiparetic vs. 12 healthy EG Lower limb Ankle dorsiflexion EG-guided hemiparetic subjects (25–70 years) (25) 20 PD patients; 10 healthy EG Lower limb Ankle dorsiflexion PD-off: precentral gyrus, supplementary area, parietal opercular cortex, and ipsilateral (non-age matched) cerebellum activated; PD-on: similar activation pattern as off, with additional activation of insular cortex; healthy-off: contralateral precentral gyrus, central opercular, cortex, and ipsilateral cerebellum; healthy-on: activations in precentral gyrus, central and parietal opercular cortex, cerebellum, and posterior cingulate cortex – no sig. increased activation in on vs. off for controls (26) 8 Healthy (25–57 years) EG Lower limb Ankle dorsiflexion vs. EG dorsiflextion activated from medial M1S1 to SMA plantarflexion (27) 16 Healthy young EG Lower limb Ankle dorsiflexion vs. Both right and left ankle active movements activated SMA, contralateral M1, and primary plantarflexion somatosensory cortex (SI) (28) 13 PD, 13 age-matched healthy IG Lower limb Gait imagery During imagined movement, right dorsal premotor area (PMd), precentral, right inferior parietal lobule, and bilateral precuneus were more activated in PD compared to age-matched controls (29) 18 Healthy young IG and EG Lower limb Ankle dorsiflexion with and IG ankle movements has distinct network comprising the posterior parietal cortex and without visual cue lateral cerebellar hemispheres (30) 16 Healthy young EG Upper and Wrist and ankle flexion Lower extremity EG more bilaterally active than upper extremity EG 11 lower limbs (31) 24 Healthy young EG Upper and Foot and finger movement Relative overlap of cortical recruitment in M1 and SMA for lower extremity and upper lower limbs extremity movements (32) 23 Healthy young IG Upper and Adduction and abduction of Cerebellum: overlap of activations for foot and finger movement lower limbs finger vs. adduction and abduction of foot (33) 17 Healthy young, 21 healthy IG Upper and Hand and foot flexion Older adults recruited a more elaborate network of motor and non-motor regions younger older lower limbs adults (34) 13 Healthy young IG and EG Upper and Finger vs. toe flexion Finger and toe movements showed differential cerebellar recruitment; more bilateral during Internally/Externally Guided Rhythmic Leg Movement lower limbs complex tasks (35) 11 Healthy young EG Upper limb Hand force production Caudate nucleus is involved in planning motor force, but not force execution in EG tasks (36) 10 Healthy young EG Upper limb Finger button press and Cognitive and motor processes activate segregated areas of the cerebellum motor imagery December 2015 | Volume 6 | Article 251 (37) 9 Healthy young EG Upper limb Finger tapping EG finger tapping recruited cerebellum: right lobules IV–V and right lobules VIIIA and VIIIB (38) 7 Healthy young EG Upper limb Finger button press Finger specific BOLD patterns showed overlapping sensory and motor representations in cerebellum (39) 11 Healthy young EG Upper limb Hand force production Only the caudate nucleus increased activation when the subjects mapped force (40) 10 PD; 10 age-matched healthy EG Upper limb Hand force modulation Off medication PD subjects have novel area recruitments of the bilateral cerebellum and primary motor cortex as compared to healthy adults (41) 10 Healthy young IG and EG Upper limb Drawing vs. tracing with hand Results indicated that compared to tracing (EG), drawing (IG) generated greater activation in the right cerebellar crus I, bilateral pre-SMA, right dorsal premotor cortex, and right frontal eye field (Continued) Hackney et al. Internally/Externally Guided Rhythmic Leg Movement During EG, the hMT/V5+, the superior parietal cortex, the premotor cortex, the thalamus, literature can inform. However, the scarcity of data involv- and cerebellar lobule VI showed higher activation. During IG: the basal ganglia, the SMA, Our results show that the putamen is particularly involved in the execution of non-routine Compared to PD patients, healthy adults showed greater activation of SMA and anterior PD patients showed increased recruitment of ipsilateral CTC circuit during EG task than IG: anterior basal ganglia more heavily recruited; EG: cerebellum more heavily recruited ing lower extremity movements does not afford us a complete Differential recruitment of CBGT and CTC circuits respective of mapping of “what” or An upper extremity task reveals differential striatocortical involvement for successful Differential activation between PD and older adults during synchronous movements cingulate motor cortex, the inferior parietal, frontal operculum, and cerebellar lobule understanding of the potential variability explained by contrast- Eg movement showed decreased activation in the M1S1, cerebellum, and medial cingulate, left putamen, left insular cortex, right DLPFC, and right parietal area 40 ing upper vs. lower limb movements. While Keele et al. (53) demonstrated that finger tapping, forefoot tapping, and heel tapping are highly correlated in light of timing mechanisms (53), differences between hand and foot movements in func- tional brain anatomy have been reported in imaging studies (54, premotor system in PD subjects compared to healthy controls 55). An important example of these differences was recently reported by Volz et al. (30) who used functional magnetic res- movements with PD patients with and without FOG onance imaging (fMRI) to assess cortical network function in IV–V/dentate nucleus showed increased activity younger adults performing unimanual hand or foot tapping. movements, especially if those are self-initiated The authors reported significant differences in premotor con- nectivity with hand movements having a much stronger cor- tical representation in the motor planning areas. Additionally, upper extremity performance appears to be highly lateralized “when” during IG vs. EG tasks as compared to lower limb movements. With respect to disease models, the examination of motor control in conditions like PD has largely focused on upper limb control. Respective of this, healthy older adults where applicable and available, we will attempt to differentiate reports involving lower extremity from upper extremity research (Figure 1). Finding Finger flexion during positron Phasic movements of hand Hand force production emission tomography Finger button press Task Finger tapping Finger tapping Finger tapping Finger flexion Finger flexion vs. foot limb movement Upper or lower Upper limb Upper limb Upper limb Upper limb Upper limb Upper limb Upper limb Upper limb Upper limb Internally guided or externally guided IG and EG IG and EG IG and EG IG and EG IG and EG IG and EG IG and EG IG and EG IG 5 PD and 5 age-matched healthy FIGURE 1 | A representative synopsis of the connectivity reported in 10 PD; 10 age-matched healthy 10 PD; 13 age-matched healthy <40 years; older >50 years) 32 PD patients; 16 w/FOG, 16 the current review comparing neural connectivity in internally guided Population and N: (young vs. externally guided movements. The top panel represents connectivity 35 Healthy (21–67 years) within internally guided movements whose initiation from cortical regions (SMA, M1, and CMA) is mediated by the striatum (caudate for movement 6 PD and 6 healthy 14 Healthy young 12 Healthy young 10 Healthy young selection; putamen for execution) and thalamo-cerebellar bidirectional processing for movement execution. By contrast, the bottom panel represents connectivity during externally guided movements, which originate w/o FOG from sensorimotor integration (M1S1, SMA, and precuneus) due to the TABLE 1 | Continued external cue for initiation. The progression of motor execution engages the lentiform nuclei (putamen, GP), which then influence cortico-thalamo- cerebellar processing during task execution. Abbreviations: SMA, Reference supplementary motor area; M1, primary motor cortex; S1, primary somatosensory cortex; STN, subthalamic nucleus; CMA, cingulate motor area; GP, globus pallidus; Thal, thalamus. (42) (43) (44) (45) (46) (47) (48) (49) (50) Frontiers in Neurology | www.frontiersin.org 12 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement INTERNALLY GUIDED NEURAL and putamen activity during IG movements. The caudate is linked CIRCUITRY – CORTICAL, SUBCORTICAL, to motor learning and sensory processing of proprioceptive input in this context (52, 67). Vaillancourt et al. (39) reported on IG force AND PD production at different levels during fMRI (39). Interestingly, the caudate was selectively activated only during the process of Cortical Activity identifying and selecting the proper force to produce. Later, the Cortical initiation of IG movements has received a fair amount group exquisitely showed that the caudate was selectively engaged of study with neuroimaging over the past 20 years. Prior to this, in the processing of force for production but did not activate based on primate models, the role of the supplementary motor during force production (35). As such, the caudate is likely directly cortex (SMA) was considered crucial to the initiation of IG move- involved in the mapping of higher cortical motor process [input to ments. Single unit recordings of neurons in macaque SMA showed the gray bridges is through premotor, SMA and M1 connectivity greater spiking during IG movements rather than those prompted in IG movements (68)]. However, the caudate does not appear to by external cues, which were thought to involve premotor areas assist in timing of IG movement execution. Instead, this function (rostral to the anterior commissure in BA6) (56, 57). However, appears to be fulfilled by the putamen. as our understanding of neural circuits improved with neural Many imaging studies have probed the function of the puta- pathway tracings in primates, anatomical differentiation of these men and its role in timing of IG movements. For years, this regions informed the functional distinction of premotor cortex, structure has been reported as active during execution of IG pre-SMA, and SMA (58, 59). When neuroimaging techniques tasks using fMRI (9, 35, 39, 49, 67, 69). Recently, these reports were applied to probe the anatomical substrates involving IG have been informed by alternate modalities indicating the neural movements, a much different picture with respect to cortical timing of activity in the putamen with respect to regulation of involvement emerged. Multiple labs used fMRI during upper IG movement. Using local field potential (LFP) recordings in extremity tasks to identify cortical activity during IG movement macaques, Bartolo et al. recently investigated tuning of spiking paradigms and found that the SMA (medial BA6, posterior to the potentials respective of movement state, either EG or IG cued anterior commissure) was not significantly driving the execution (70). While the putamen is involved in both types of activity, of movements in IG conditions (49, 60). Instead, there was a the waveforms of the spike potentials tuned differentially to the strong influence of a complex cortical and subcortical initiation locus of cue. These waveforms were characterized by frequency and gating network that has since been largely confirmed by consisting of beta (13–30 Hz) and gamma frequencies (30–70 Hz) network-based modeling analysis (39, 50). Moreover, recent work and were compared during the execution of IG and EG tasks. has identified functionally distinct networks respective of the tim- IG movements were strongly aligned with the beta band of the ing of the IG movements with alteration of cortico-basal ganglia LFPs. Alternately, during EG movements, LFP activity was char- involvement during initiation and then execution of the move- acterized by gamma frequency oscillations. Importantly, when ment. During movement initialization (i.e., the process of identifi- sampling across larger distances the beta frequency coherence cation/selection of motor responses), the anterior cingulate motor was high indicating a possible functional coordination of the area (which may be considered an extension of pre-SMA) and putamen during IG tasks. Conversely, the spatial coherence of pre-SMA appear to be critically involved as their damage results gamma frequencies was very low, which could be interpreted in improper suppression of selected motor responses (50, 61). to indicate local, single event processing (70, 71). The authors However, the transition into direct engagement of skeletal mus- concluded that the gamma frequency activity potentially indicated cle recruits additional cortical resources including lateral BA6, local computations directly related to external stimulus process- inferior parietal regions, and lateral inferior frontal areas (Broca’s ing. In contrast, the beta band preference in the putamen was area – left BA44) (62). This lateral frontal recruitment could be the result of a larger scale entrainment of CBGT circuits as these interpreted as selective movement organization, as Broca’s area is were associated with IG movement timing. The authors provided crucial for proper syntactic discourse (63, 64). For example, in the additional evidence for this in a recent paper investigating LFP English language, syntax is heavily dependent on word order, and oscillations during different task types (reaction time vs. internally even more so in German. Broca’s area is critical in identifying the timed tapping) (72). sequential order of word placement (63). In an analogous motor role, activation in Broca’s area may indicate order selection for organized movement (65). Cerebellum Although we have thus far focused on the STC circuit in its role for IG movement, the cerebellum has been implicated in IG move- Subcortical ment as well. While this may be surprising given the literature rec- The cortical components of IG are strongly gated and in some ognizing cerebellar involvement in explicitly EG tasks (41, 45, 47, cases are dependent on reciprocal input from subcortical struc- 60, 73), IG tasks have been reported to recruit cerebellar regions. tures, primarily the striatum. The caudolenticular gray bridges, fMRI studies involving IG movements of the upper extremity have topographically interposed between the caudate and the putamen, reported regional recruitment of cerebellum, including lobulus V function as the primary efferent center from pre-SMA to the (anterior cerebellum) and lobules VIIB and VIII (inferior cere- basal ganglia (66). As such, the striatum plays a critical role in bellum) (74). During arm pointing movements (using both left modulating movement, and its activity is largely dependent on and right arms), activations were found ipsilateral to movement movement state. A functional dichotomy exists between caudate in lobule V and lobule VIIA (34). While studies employing lower Frontiers in Neurology | www.frontiersin.org 13 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement extremity movement during IG tasks are scarce, a study from movement initiation by disruption of physical state monitoring Schlerf et al. (34), in which they attempted to characterize cere- required for movement. bellar activity during IG upper and lower extremity movements, Deficient gating of sensory signals in the basal ganglia (80) is worth noting. The group investigated differential cerebellar may lead to abnormal processing of proprioceptive input in motor involvement when modulating task difficulty of both the upper regions, such as the SMA (81). In a related study, Goble et al. and lower extremities (fingertip and toe, respectively). Toe tapping (82) examined how brain activity resulting from stimulation activated more anterior areas of the cerebellum compared to finger of proprioceptors is related to performance in a proprioceptor- movements regardless of movement difficulty. Interestingly, the related task (82). Subjects lying in an fMRI scanner received group also found greater bilateral cerebellar activity during more vibrations on their foot, allowing for proprioceptive brain map- difficult lower extremity movements compared to analogously ping via muscle spindle stimulation. Exposure to foot vibra- difficult conditions during finger tapping. Other groups have tions showed an association of the basal ganglia structures with further investigated the possibly differential cerebellar represen- structures involved in postural control. Movement studies show tations of lower limb movement as contrasted to upper extremity the basal ganglia play a significant role in motor learning. In movement. A recent study by Kuper et al. (32) aimed to identify a study by Jueptner and Weiller, positron emission tomography overlapping or distinct cerebellar activity when contrasting finger (PET) measurements of regional cerebral blood flow (rCBF) were and foot tapping at the joints’ maximum movement range (32). used for studies of motor learning, visuomotor coordination, and Interestingly, while overlapping cerebellar finger and foot activity sensory movement control (9). Furthermore, the basal ganglia were present [cf., Ref. (34)], Kuper et al. found activity appeared to have been shown to be involved in controlling ongoing move- follow a somatotopy with foot activation occurring more rostrally ments, including feedback processing (83). Maschke et al. exam- compared to finger movement. ined the role of the basal ganglia in kinesthesia, the conscious However, the attribution of cerebellar recruitment with respect awareness of limb position, with a passive elbow movement task to IG vs. EG locus of cue is incomplete without proper conceptu- in participants with PD, participants with spinocerebellar ataxia alization of timing within a movement context. In a recent con- (SCA), and age-matched healthy control participants. The PD sensus paper (75), Richard Ivry denoted an important qualifier of participants showed significant kinesthetic deficit to control par- cerebellar activity respective of movement timing, by noting that ticipants, whereas the SCA participants showed no kinesthetic much work using imaging of the cerebellum has difficulty teasing deficit, allowing the conclusion that CBGT loops are important in apart externally cued movement and its transition to emergent kinesthesia (84). timing. The difficulty is partially explained by the challenge that Symptoms associated with PD provide some insight into the lies in differentiating absolute time vs. perceived time and the role disease process on neural circuits and inform rehabilitation strate- that the cerebellum plays in optimizing the coordination of the gies of lower limb-related problems. FOG is a common and dan- two. Taken in this light, the role of cerebellar recruitment during gerous condition in individuals with PD whereby the person suc- IG vs. EG movement becomes somewhat mottled in the imaging cessfully initiates walking, but it is transiently unable to complete literature. What may be deemed “internally guided” may be con- the gait cycle, frequently resulting in imbalance and increased fall tinuously informed by an emergent timing within the participant risk. FOG is functionally distinct from bradykinesia and postural when this individual is trying to synchronize internal timing to rigidity and is only conditionally affected by pharmacological his/her perception of absolute timing. treatment (85, 86). Although FOG is challenging to character- ize as EG or IG, we will consider FOG a failure to continue a INTERNALLY GUIDED MOVEMENT IN self-initiated movement, the primary manifestation of the con- PARKINSON’S DISEASE dition. FOG very likely represents a disrupted sense of internal rhythmic timing (87). Peterson et al. (88) informed upon the brain As PD is caused by the loss of endogenous dopamine, the disease regions that are involved in PD patients with and without FOG. In profoundly affects basal ganglia function. The most immediate this study, PD patients imagined walking during fMRI acquisition. impact of dysfunction in IG movement in PD relates to impaired The results showed significantly lower activity in supplementary cortico-basal ganglia communication driving initiation of move- motor regions, globus pallidus, and cerebellum in individuals ment. One such behavioral manifestation of this disruption is the with PD who experience FOG compared to those who did not presence of bradykinesia in PD during IG movement (76). As report FOG. Furthermore, the authors reported decreased activity stated above, cortical initiation of IG movements relies on basal in the mesencephalic regions associated with postural stability ganglia modulation (particularly at the striatofrontal interconnect (88). These widespread activity differences between groups indi- at the post-commisural putamen) and signal augmentation that cate that individual discrete neural circuits do not easily account is highly sensitive to disruption when filtered through dysfunc- for the motor dysfunction exhibited by FOG. Rather, cortical, tional lentiform connections (77). However, this physiology is subcortical, and cerebellar loops are all affected in FOG. This complicated by the importance of sensory feedback required for finding may explain the large variability of pharmacological and proprioception and kinesthetic integration. These afferent inputs surgical outcomes relating to FOG in PD (85, 86, 89). Impor- are directly modulated by thalamo-cortical relays involving the tantly, this study indicates rehabilitative strategies that are focused subthalamic nucleus, ventrolateral, and centromedian thalamic on IG movements need to be holistic in approach because no nuclei (68, 78, 79). As such, disruption of the sensory integration single sub-circuit or structure is preferentially involved in these back to motor planning cortex further complicates successful movements. Frontiers in Neurology | www.frontiersin.org 14 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement EXTERNALLY GUIDED NEURAL within the SMAs [see also Ref. (98)], while at movement auto- CIRCUITRY – CORTICAL, CEREBELLAR, maticity (maximum performance accuracy), the dominant corti- cal activity was in the parietal lobe (95). Work involving fMRI has AND PD also shown this anterior to posterior shift in cortical recruitment Externally guided movements involve both overlapping and dis- as tasks become well practiced (96) with an overall reduction of crete brain regions for successful task completion. While studies volume of cortical regions recruited after automaticity is achieved. vary widely in terms of the methodology employed, externally Importantly, the paradigms denoted thus far have only cued movement of differing types involves similar cortical, sub- employed upper extremity movements. Much less is known about cortical, and cerebellar substrates. We will explore these areas cortical execution of EG movements in contrast to IG respective as they are associated with EG movements and discuss how PD of lower extremity movement. Bruce Dobkin’s laboratory has may disrupt proper execution with implications for rehabilitation published much of the rehabilitation-focused imaging research programs to follow. on the lower extremity. In a series of studies involving the use of lower extremity EG movement, this team denoted reliable recruit- ment of left SMA, bilateral sensorimotor areas (M1S1), and right Cortical Involvement in EG Movement parietal lobules (24, 99). Other labs have also approached lower Prior to modern neuroimaging, the initial cortical origin of IG limb movement with considerations for rehabilitative outcome. movements was thought to be SMA (57), as cortical activity in For example, Trinastic et al. (26) attempted to differentiate cortical EG was viewed in the context of the motor planning and, as such, recruitment in motor cortex during EG plantarflexion as com- focused on the relationship between premotor areas with primary pared to dorsiflexion. Findings showed that although dorsiflexion motor cortex (90–92). This work in the non-human primate recruited additional cortical areas as compared to plantarflexion, model still provides invaluable insight into cortical function, but the tasks commonly recruited medial SMA (26). Kapreli et al. it has been updated in the human model with functional neu- (100) approached lower limb movements relating to motor overlap roimaging. The following text details the differential recruitment of the somatosensory network shown in upper extremity move- of cortex in EG as contrasted to IG in light of modern imaging ments. In this study, the group reported similar regions of activity techniques. between tasks; however, lower limb movements were much less In 2006, Elsinger and colleagues published an important paper lateralized and tended to recruit both hemispheres during motor differentiating IG and EG cortical dynamics during an upper activity (100). Laterality differences between upper and lower extremity button press task in fMRI (60). Indeed, this group did extremities have been reported during visual monitoring (101) show that lateral premotor areas were more active during EG and motor tracking tasks (102) comparing movements of the hand response; however, this activity was likely part of a spatial reaction vs. the foot. This increased bilateral response [also reported by network associated with the monitoring of external stimuli. This Trinastic et al.(26) during dorsiflexion as compared to plantarflex- network involves the right hemisphere parietal–premotor–frontal ion] in lower extremity tasks as compared to those involving eye field regions (93). This monitoring network can be inter- the upper extremity has likely been noted because locomotion preted exquisitely due to the task-selective nature of the regions requires bilateral coordination to maintain balance (26, 103). This recruited. The frontal eye fields are critical in processing saccades differentiation also provides an opportunity for rehabilitation spe- and act as a visual motor integration respective of higher-level cialists to design interventions that take advantage of the greater visual input. The spatial processing of object location is strongly cortical recruitment of lower limb movements. associated with right parietal regions, which would necessarily inform premotor areas to prime selection and then execution of accurate motor response. It has been shown that increased task Subcortical Recruitment in EG complexity corresponded to an increase in network coherence Although there exists regional differentiation of cortical recruit- (60). Because the task was mapping of specific finger movements ment respective of EG vs. IG movements, the neural system does to external stimuli, the increased activation of this circuit as a not function as wholly discrete neural compartments as char- result of increased complexity may be interpreted as multisensory acterized thus far. Understanding the integration of subcortical integration of proprioceptive, visual, and kinesthetic information. and cerebellar structures in light of movement circuits is crucial Cortical recruitment in EG tasks can also be described in the to properly inform rehabilitation using IG and EG strategies in context of movement entrainment or sequence learning. Much movement. attention has been paid to the role of EG in movement training As stated earlier, sensory integration during EG task execution to automaticity (94–97). Using PET, Jenkins et al. (95) was one of is a central component to neural activity in this modality. Without the first groups to use neuroimaging techniques to probe motor continuous state monitoring (postural, positional, visual, audi- skill acquisition and the neural correlates that underlie the stages tory, etc.), coordinating movement with external cues would be of motor learning (novel stimulus, movement entrainment, and impossible. As such, the basal ganglia and thalamic sensory relay automatic movement). Overall, the cortical representation pattern centers are critical components to successful EG task execution. was characterized as moving from anterior frontal regions to To this end, in healthy individuals performing EG tasks, a com- more posterior areas after continued task practice. Specifically, the plex interaction of thalamic (pulvinar, ventroanterior lateral, and group denoted that novel motor learning was the only task con- ventroposterior lateral), cerebellar, and cortical regions form sen- dition to show activity in the prefrontal cortex. The entrainment sory circuits, which allow for selected task actions to coordinate phase of motor practice was associated with consistent activity with cues. Frontiers in Neurology | www.frontiersin.org 15 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement Taniwaki et al. (104) used fMRI to characterize discrete cortico- cortex, and motor execution recruited the sensorimotor cortex. subcortical circuits associated with IG vs. EG movements in the Slow movements recruited frontopolar and right dorsomedial upper extremity. The group employed a structural equation mod- prefrontal areas bilaterally in execution and motor imagery. Fast eling (SEM) approach with a priori network structures identified movements strongly activated the sensorimotor cerebral cortex. to test for path strength between ROIs during EG compared to IG. However, the anterior vermis, lobules VI/VII and VIII of the The group identified discrete ROIs of active structures regardless cerebellum were activated in fast movements, in imagery and exe- of movement type before entering the regions into a confirma- cution (23). Fast movements are similar to ballistic movements, tory structural equation model. In reference to previous literature which have also been implicated in cerebellum imaging stud- and task-based activation in the study (left hand movements), ies (107). These findings indicate regional functional specificity the group identified IG movements with right putamen, globus potentially exclusive to the execution of EG tasks in the upper and pallidus, ventrolateral thalamus, dorsomedial thalamus, bilateral possibly in the lower. ventroposterior lateral thalamus, cerebellum, and SMA. However, Bostan et al. (108) recently showed that in the cebus monkey, the EG movements were associated with right ventral premotor, the cerebellum is connected disynaptically with the subthalamic left ventroposterior lateral thalamus, right dorsomedial thalamus, nucleus via the pontine nuclei. While previous work by the group and bilateral cerebellum. The group tested output path coefficients had insinuated structural isolation of the cerebellum from the respective of whether each movement type was associated with basal ganglia and STN (68), the findings of this paper clearly CBGT loops or cortico-cerebellar loops. IG involved stronger path show a bidirectional connectivity of these regions in higher order links with the CBGT structures listed above. However, EG was primates. As such, modulation of the STN via cerebellar control is associated with stronger cerebellar connectivity to ventral premo- likely implicated in pathophysiology like PD. As described above, tor cortex via the thalamus. The cortico-cerebellar connectivity the STN exerts powerful effects on the basal ganglia. Given the did not involve mediation by the striatum in EG, while IG was critical involvement of the cerebellum in EG movements, it is strongly associated with putamen activity of the right (contralat- possible that additional cerebellar input accounts for a portion of eral) side. So, although EG tasks appear to be less dependent the behavioral differences of PD patients when comparing IG vs. on the CBGT loops, they rely strongly on cerebellar input (104). EG task performance. Additional work since Taniwaki et al. (104) has largely confirmed Unfortunately, few studies compare EG and IG movements in this conclusion (43, 73). the lower extremity, which could help delineate the cerebellar components involved with each movement type. Currently, find- Cerebellum ings indicate EG movements of the lower limb, when employing Unsurprisingly, the cortico-cerebellar system is perhaps the most comparable cues to those used to cue upper limb movements, cited neural pathway to be associated primarily with EG move- tend to recruit both overlapping and discrete cortico-cerebellar ments (41, 43, 45–47, 60, 73, 104). The importance of cerebellar neural structures (30, 34). Just as the cerebellum is involved in IG feedback during EG tasks likely indicates the role of the cerebellum movements (in addition to the STC circuit), subcortical striatal as a modulator of complex motor dynamics and proprioception. structures are involved in EG foot movements. Sixteen healthy The cerebellum acts as a de facto servo system to modulate gross subjects performed dorsi-plantar flexion of the foot actively motor action into controlled and coordinated movement. This (responding to auditory cues at 1.25 Hz) and passively. Passive is also reflected in the cortical networks upstream of cerebellar movements activated cortical regions similar (but reduced) to activity in EG, as the frontal eye fields perform an analogous those activated by the active task. Activations during active and role in saccades and transitions to smooth pursuit. Additionally, passive movement were found not only in the contralateral M1 these structures serve in concert with the semicircular canals and and S1 cortices but also in the premotor cortical regions (bilateral the cerebellum (particularly the flocconodular lobe) to regulate rolandic operculum and contralateral SMA) and in subcortical postural stability and vestibular state (105). regions (ipsilateral cerebellum and contralateral posterior puta- Imaging studies have expounded upon our understanding of men) (27). Additionally, differential activation has been noted in cerebellar function in cued movements that had previously been the cerebellum depending on whether movements are IG or EG, largely derived from literature related to cerebellar damage (106). regardless of presence or absence of visual feedback and activation Functional MRI of upper extremity movement has indicated dis- related to proprioceptive input (29). Clearly, this area of inquiry crete lobes of the cerebellum that appear responsible for facili- requires additional carefully planned studies to identify cerebellar tating movement in response to external cues. For example, 10 circuits and auxiliary structures that can be preferentially targeted healthy right-handed subjects, while fixating on a visual cross, by EG interventions. were cued to press a button in response to hearing a sound, causing activations in lobules V and VI in the right anterior cerebellum PARKINSON’S DISEASE AND EG (36). With a finger-tapping task similar to the one described above, activations were found in right lobules IV–V and right lobules Parkinson’s disease affects both IG and EG movements. How- VIIIA and VIIIB (37). Sauvage et al. (23) compared the neural ever, EG movements may be less impaired in early stages of the substrates involved in execution vs. mental imagery of sequen- disease as compared to IG movements (44). Interestingly, PD is tial movements (fast and slow) of the left foot in 12 volunteers. associated with alterations in recruitment of cortico-cerebellar Overt movement execution and motor imagery shared a com- networks despite only mild overt performance differences. For mon network: premotor, parietal and cingulate cortices, striatum, example, Elsinger et al. (48) used the paced finger-tapping task and cerebellum (23). Motor imagery recruited the prefrontal (PFT) (with the right hand) and observed that PD participants Frontiers in Neurology | www.frontiersin.org 16 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement had decreased accuracy and increased variability on the task beta frequency range. In turn, combining the three techniques, compared to controls. Whether the PD participants were on or while methodologically challenging, may help account for the off dopamine supplementation did not affect task performance. varying reports of cortical involvement using fMRI. However, decreased activation in the left sensorimotor cortex, At present, due to the dearth of research involving lower limb cerebellum, and medial premotor system was noted in PD subjects movement and imaging, drawing any conclusions about the effect compared to controls (48). In another study, PD participants of PD on neural circuits respective of EG movements in the lower (tested both on and off anti-parkinsonian medication) and age- extremity is challenging. Table 1 lists a summary of the relevant matched controls participated in an EG sinusoidal force task with imaging studies in the context of IG vs. EG movement in healthy visual cues and varying speeds while gripping a squeeze bulb controls and individuals with PD, which were considered in the in their right hand. The group reported that off-medication as text above. Clearly, there are many questions to be answered, opposed to on-medication PD participants recruited the bilat- making this investigation important for consideration for motor eral cerebellum and primary motor cortex as compared to on- and rehabilitation scientists. medication PD participants and controls (40). Cerasa et al. (47) described findings from a right hand, finger-tapping paradigm of IG and EG movement with visual cues in PD patients. Both PD REHABILITATION PROGRAMS FOCUSED and healthy subjects engaged somewhat similar neural networks ON RHYTHMIC MOVEMENT in both EG and IG movement, yet the PD group showed greater activity in sensory and associative cortices. For example, in the Until this point, this review has attempted to elucidate the neural EG condition, PD subjects showed increased activation of the mechanisms that are involved with IG and EG movements respec- calcarine cortex bilaterally, potentially indicating an increased tive of the hand and foot respective of both healthy individuals and reliance on visual input for task performance. In the IG condition, individuals with PD. We now turn to modern rehabilitative pro- the cerebello-thalamic pathway was shown to be involved to a grams that may select for a movement modality or their interac- greater degree in PD subjects, possibly denoting a compensatory tion. These programs selectively engage and optimize movement modality shift to EG mapping, which is perhaps more robust to using internal or external cues, or in many cases, both. failure in PD than neurotypical IG pathways (47). Therapy programs that include external guidance through con- With respect to lower extremity function, recent findings sistent rhythmic auditory stimulation (RAS) (e.g., a metronome have been mixed regarding cerebellar changes in PD. For exam- or music) can facilitate movements and are recommended for ple, Schwingenschuh and colleagues, using an EG ankle dorsi- people with PD. RAS has been used to improve gait in those flexion task, found that people with PD activated lobules I–V with PD via external sensory cues consisting of metronome beats. in the ipsilateral cerebellum during EG movement, and simi- Studies have shown the positive effects of RAS on FOG and gait lar cerebellar activations were found for healthy controls. After parameters (112). Although other sensory cues such as visual and oral administration of levodopa, the PD participants showed proprioceptive cues have been examined, auditory cues appear to increased activity in subcortical structures (contralateral puta- be most effective in improving gait in PD (113). Coupling gait to men and thalamus), compared to control participants who rhythmic auditory cues may rely on a neural network engaged showed no alteration of function. These findings suggest that the in both perceptual and motor timing in individuals with PD cortico-subcortical motor circuit in PD is sensitive to exogenous (114). In fact, some individuals with PD may have an impaired dopamine administration (25). Externally cued motor imagery perception of beat timing. Leow et al. (115) examined the impact has also been employed during fMRI to probe changes in cortico- of beat salience in effectively improving gait cadence and other cerebellar structures in gait. Cremers et al. (109) reported that peo- parameters by comparing “high groove” (i.e., music with a strong ple with PD compared to healthy controls had decreased activity underlying beat) to “low groove” music. Individuals with poorer in cerebellar vermis and SMA. Importantly, individuals with PD perception of beat timing were helped by high groove music who exhibited greater gait disturbance were less likely to recruit because of the salience of the beat. Such musical support might cerebellar and cortical regions characterized by the healthy control help facilitate gait in those with PD. This finding is highly relevant group during gait visualization (109). This finding is in contrast to dance- or music-based rehabilitation because poor or good beat with results of Spraker et al. who noted increased recruitment perception affects gait performance when synchronized to music of cerebellar structures and pathways with disease progression (115). Leow et al. also showed that more familiar music elicited (110). Interestingly, what might account for the varied results less variable strides and faster stride velocity and better synchro- between studies is the relative difficulty with which studies using nization with the music (116). Salience of a beat (as mentioned fMRI can quantify modulation of cortical structures by the basal above) and familiarity with music are therefore considerations for ganglia. Recently, Cagnan et al. (111) demonstrated using LFPs rehabilitative purposes. with people with PD that phasic synchronization of basal ganglia Indeed, music therapies may have some utility in ameliorat- structures is more associated with tremor and motor dysfunction ing some function in individuals with PD. Recently, Bella et al. in PD. Interestingly, when on dopaminergic treatment, the phase trained PD participants on musically cued gait therapy, consist- locking in beta waveforms in STN and globus pallidus abated to a ing of synchronizing movement to familiar folk music without more dynamic oscillation and, importantly, the individuals with lyrics (a bell cued participants’ movement). Findings included PD exhibited improved motor function. Possibly, were LFPs in not only increased gait speed and stride length but also strong STN to be acquired in concert with EEG, alteration of cerebellar gains in motor synchronization (tapping) and perceptual aware- and cortical activity may indeed reflect oscillatory activity in the ness on just noticeably different tasks (117). Findings from stroke Frontiers in Neurology | www.frontiersin.org 17 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement literature and the application of music-supported therapy (MST) PD (126). Other forms of dance have been investigated for efficacy might also shed light on possible beneficial effects of rhythmic for those with PD. A study that investigated the feasibility of movement with auditory support for people with PD. MST uses Irish set dancing, in comparison to standard physiotherapy, found musical instrument playing to treat paresis of the upper limb the dancing safe and feasible. Furthermore, participants tended and adheres to four principles: massive repetition, audio-motor to improve more in gait, balance, and FOG after dancing, than coupling, shaping, and emotion–motivation effects. After 4 weeks after the standard care (128). Dance may have an immediate effect of MST in combination with usual care, chronic stroke partici- on mobility in those with PD as improvements have been found pants assigned to MST showed improvements on the Wolf motor in as little as 2 weeks of tango (129) and contact improvisation function test in comparison to a control group (118). Additionally, training (130). The very popular “Dance for PD” method has been a case study revealed audio-motor coupling when a patient was investigated for its efficacy, and it was found to improve the motor exposed to a passive listening task with unfamiliar and trained subscale of the UPDRS after 16 sessions (20 h of treatment) in an melodies. Before MST, only the auditory cortices were activated; uncontrolled study (131). after MST, motor regions were also activated (119). Given that Because several studies have been conducted on the efficacy participants actually play an instrument, MST is an intriguing of tango, it will be examined and considered for its qualities, to form of musical therapy that can exploit benefits of both EG and serve as an exemplar with qualities that can relatively easily be IG strategies, and their accompanying neural circuitry. identified within the IG/EG dichotomy. Argentine tango has steps, A meta-analysis recently demonstrated that music-based ther- patterns, music, and importantly, partnering that may address apy, including dance, positively affects PD gait and gait-related specific impairments associated with PD. Partner dancing is a activities (120). Recently, dance has indeed gained attention as sophisticated, yet accessible system of tactile communication that a music-based therapy that may be able to effectively address conveys motor intentions and goals between a “leader” (plan- impairments related to PD. An understudied aspect of dance ner of movement) and “follower” (externally cued mover). An interventions is the interplay of external vs. internal guidance “embrace” or “frame” between the leader and follower is the posi- across multiple sensory modalities. Proprioceptive and kines- tion maintained by the arms throughout all steps in adapted tango. thetic inputs based on tactile cues are crucial for motor adap- In adapted tango classes (121, 123, 125), participants consistently tation and dance performance. Visual cues no doubt play a role both led and followed all dance steps with healthy partners, and in postural control, navigation, and emotional understanding, therefore alternated between two motor training approaches (a) as well as having a curious positive effect on FOG. However, leading, consisting of internally guiding movement plans and (b) auditory cues (e.g., percussion or other musical rhythms) play a following, consisting of responding to external guidance. Thus, strong role in guidance of movement and can be EG (e.g., bass qualities of effective rehabilitative programs are found in both percussion) or IG [e.g., fermata pause (notes held longer than leading and following within the context of adapted tango. While music’s tempo)] or even delivered as disruptive asynchrony (e.g., in the role of leader, participants practice self-directed, internally syncopation). We believe rehabilitation regimens like dance and generated movements; while, in the role of follower, participants other rhythmic training likely provide a synergistic multisensory practice responding to external cues from the partner. There are adjuvant to motor skills training in both aging and disease mod- key differences between leading and following that may address els. However, in consideration of the discussion of the neural specific needs and result in distinct training gains in mobility, pathways associated with IG and EG motor training strategies, because as we have outlined above the neural circuitry that drives answering the question why dance may be effective is helpful. At leading and following movement likely differs. this point, it is unclear to what extent external musical auditory Individuals who perform the leading role in dance are thought or visual (and tactile, in the case of any sort of partnered/contact to adopt a world-centric reference frame. To lead a dance suc- dance) cues play to elicit therapeutic effects vs. the improvements cessfully, these individuals need to multi-task by focusing on gained by increased attention and cognitive engagement used to environment, follower, music, and both current and future motor plan and enact movement. Studies are needed to answer these plans. Leading, which should be using IG cognitive and motor questions when considering the research that has accumulated skill, is thought to involve employing a “movement strategy” supporting beneficial effects of rehabilitative methods involving that demands increased focus on movement plans and mentally rhythmic training. rehearsing and/or preparing for movement. Leaders in partnered dances must determine precise spatiotemporal movement param- Dance Therapy eters of a dance sequence, e.g., amplitude, direction, timing, and In the last 10 years, a series of studies have investigated the rotation. As such, leading may pose a challenge for individu- effects of adapted Argentine tango dance (adapted tango) for als with PD, given that many have impaired executive control, individuals with PD. Participants experienced significant gains in specifically in cognitive processes involved in planning and exe- mobility, balance, and QOL (121–124). These improvements were cuting complex, goal-directed behavior (11, 132). Importantly, maintained 1 month later, (123) and up to 3 months later (125, the individual who follows in adapted Argentine tango is not 126). After participating in 1 year of tango classes offered in the required to plan precise spatiotemporal parameters of movement community, participants with PD also demonstrated decreased (e.g., direction, length of step, timing, and amount of rotation). disease severity (127). Recently, a study demonstrated a 12-week From moment to moment, the follower receives movement guid- adapted tango program, which was disseminated to several novice ance regarding the afore-mentioned parameters from the leader instructors and offered in the community, improved spatial cogni- via tactile cues. Because followers are not devoting attentional tion, as well as disease severity in participants with mild-moderate resources to planning movement, potentially they can attend more Frontiers in Neurology | www.frontiersin.org 18 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement to their postural control, which becomes more and more necessary to social interaction between student and teacher. Interestingly, as a person ages or contends with a neurodegenerative movement recent work has approached the interpersonal dynamics involving disorder. adapted tango. A research group at Emory University and Georgia Although the adapted tango dichotomy of leading and follow- Tech has been investigating the ability of robots to act as leaders ing roles provides a convenient analog to the “ideal” EG and and followers in a simple tango step pattern. The robots are able to IG motor training vehicle, it must be admitted that underly- maintain a stable distance from their human partner, characteris- ing strongly rhythmic movements that characterize dance forms tics of a human counterpart. While experiments using these robots continuously employ both EG and IG strategies. Whether these are ongoing, a recent report demonstrated that expert dancers rhythms are internally created or manifested from external guid- have indicated reasonable ecological validity of the leading and ance (from music and tactile cues of a leader), dance movements following performance of the robots (133). This line of work offers obey their inherent timing. As such, rhythmic cues may be very unique insights as to the effects of interpersonal dynamics on responsible for any gains seen in PD rehabilitation as a result of rehabilitative outcome using dance therapy. Furthermore, these dance participation. However, in practice, it can be challenging investigations could serve as an interesting platform upon which to both train a person with PD (or even a “healthy” individual) to test ideas about IG and EG movement schemas. in complex shapes of a dance form and also teach them the sophisticated rhythms that make up most dances. As such, the consideration of shape vs. timing must be acknowledged. RHYTHMIC MOVEMENT IN The “shape” of a movement sequence is the simple biomechan- REHABILITATION OF INTERNALLY AND ics of the steps, irrespective of speed or timing. Rhythm usually EXTERNALLY GUIDED MOVEMENT refers to a repetitive pulse that is repeated in cycles through a musical or movement form. Even IG movement, which does not At this time, few studies offer evidence of neural changes as a appear to “obey” a particular repeated rhythm has an intrinsic result of focused training in people with PD or healthy controls. A timing, and occupies a temporal space [see Ref. (75)]. In a dance study utilizing PET showed improved vocal intensity after training class for people with motor challenges, there are a number of in the Lee Silverman voice training (LSVT) LOUD program for stages through which a dancer may go in order to achieve dance speech improvement. These motor improvements were correlated mastery, which includes a mastery of coordinating movement to with modification in motor, auditory, and prefrontal areas, but music. This movement entrainment may or may not be the same as there was no effect on the basal ganglia (134). However, in healthy reports from Wu et al. (96) investigating finger movement training participants lying supine, increased activity in the putamen was to automaticity, as coordinated rhythmic movements involve a noted using PET when tango movements were performed with a much more complex interplay of IG and EG timing. During single limb to a metered beat (135). In a related finding, after a rhythmic training, in the first/novice stage, the individual begins week of tango lessons, healthy adults exhibited increased activity to understand a dance pattern, and puts their body through novel of supplementary motor (SMA) and premotor cortices during motions that will occupy some sort of temporal space, but may imagined tango-style walking. In participants who had completed not align precisely with a dictated rhythm/timing given by an a week of locomotor attention training involving physical and instructor. With practice the dancer enters a second stage, in which mental practice, activation was examined during an overt foot he/she has the motor control to coordinate his bodily timing to motor task consisting of ankle dorsiflexion. Posttraining the foot the musical timing. As the steps become more complex, there is task showed reorganization of sensorimotor areas, in keeping vacillation between the first and second stages. But whether or with other studies on lower limb motor learning, suggesting not the dancer (a) benefits from precisely moving to the beat of that functional connectivity of the sensorimotor network may the music, or the dance rhythm (b) from listening to the music, be modulated by focusing attention on the movements involved and/or – thinking – they are moving precisely to the beat and in ambulation (136, 137). Dobkin et al. (24) assessed how ankle obeying a dance rhythm, or (c) benefits mostly from concentrating dorsiflexion could be utilized as an fMRI paradigm to measure on the shape of the movement, while creating their own internal the efficacy of a rehabilitative strategy – body weight-supported rhythmic timing, is unclear. treadmill training – for hemiparetic subjects. During voluntary The role of the instructor is extremely important with respect ankle movement, the subjects completed two sets of five isolated to properly implementing adapted rhythmic training programs, movements of 10°. The study observed reorganization in the brain as the trained instructor becomes the model by which the indi- with training; specifically, decreased activity in the ipsilateral pri- vidual gages performance. During initial instruction, the student mary sensorimotor cortex (S1M1) as therapy gains increased and models performance externally by visual approximation of his or by 2–6 weeks of training, three of the four subjects saw increased her own movement to that idealized by the instructor. As the activity in the contralateral S1M1 (24). More studies are clearly student progresses and achieves additional kinesthetic feedback needed to examine neural changes in combination with observed and motor flow during the rhythmic movement, motor adaptation clinical motor and cognitive changes, particularly with respect to translates from externally derived imitation to IG motor flow. particular motor training strategies. However, despite this transition, the role of the instructor to provide the movement template is central to successful training. LIMITATIONS In these regards, the student’s interpersonal relationship with their instructor has great import on their training trajectory; As stated earlier, there is a paucity of research investigating the however, this relationship necessarily introduces variability due neural correlates of lower limb movements in aging and disease. Frontiers in Neurology | www.frontiersin.org 19 December 2015 | Volume 6 | Article 251 Hackney et al. Internally/Externally Guided Rhythmic Leg Movement As such, much of the research concerned with initiation of move- for today’s population with PD. As with the case of deep brain ment from an IG vs. EG perspective is derived from work in stimulation, suppression of abnormal downstream network activ- the upper extremity. While we have noted overlap of cortical, ity produced by the malfunctioning basal ganglia may result from subcortical, and cerebellar structures when comparing IG against stimulating the subthalamic nucleus (139). Rehabilitation may EG movements of the hand and foot, considerable variation has also create changes downstream of basal ganglia structures. If the also been reported particularly regarding laterality of movement. mechanism of improvement resulting from IG motor training is While this variation might, in part, limit interpretation in the similar, there may be a reduction in abnormal neural activity along current review, its presence provides a direct opportunity for the STC circuit, which likely mediates IG motor tasks and includes inquiry in both basic science and applied rehabilitation investiga- the putamen, ventral anterior thalamus, rostral SMA, and pri- tions. In addition, a challenge that Dobkin et al. have described mary motor cortex. An alternative possibility could be increased in imaging-related literature in rehabilitation is the problem of activity in the basal ganglia, which have been demonstrated to be describing neural activity using BOLD imaging respective of time hypoactive in drug-naïve individuals in early stages of PD (140). of data acquisition – both post-onset of pathology and progression Moreover, when examining twins discordant for PD performing through the rehabilitation regimen (24). The group has provided right hand, finger sequencing tasks for task specific influences on evidence that neural activity during early training tends to be the STC and CTC pathways before and after levodopa adminis- larger in volume. However, with increasing exposure, despite tration, it was noted that levodopa corrected hypoactivation in similar task performance, neural activity appears to be consol- the contralateral STC, but over-corrected activation in the ipsi- idated to smaller cortical volumes. This presents a challenge in lateral STC and bilateral CTC pathways; therefore, standard PD the review of rehabilitation literature as simple static statistical pharmacology affects compensatory changes (51) and effective IG threshold comparisons of activity volumes across studies conflate or EG motor training as well. Nevertheless, currently, insufficient the neurological variability of the substrates under consideration evidence exists to determine the mechanisms by which IG and due to both age and the rehabilitation regimen. Again, due to EG motor training are efficacious, and future work is necessary the low number of rehabilitation studies comparing IG vs. EG in to do so. Furthermore, to understand the mechanisms underly- the imaging literature, we lack the statistical tools to describe this ing impairments and training effects in whole-body balance and variability properly in the current review. Perhaps most impor- mobility tasks, lower limb neural activity must be investigated first tantly, in the current review, we have not discussed the critical within the context of IG and EG tasks in individuals with and aspect of dosing of rehabilitative regimens engaging in EG and IG without PD. Knowledge about neural changes that may occur after movement strategies. The identification of an optimized amount repeated and targeted training with IG or EG tasks will allow us to of treatment has been overlooked in rehabilitation research. This develop better rehabilitation training strategies for those with PD may have been of necessity given the field has been engaged in and supplement pharmacological and surgical developments. identifying specific regimens for efficacy. However, given recent success in identifying programs, it is appropriate to begin to ask the question, “how much?” and to probe for differences between AUTHOR CONTRIBUTIONS IG and EG motor training with respect to dose. Furthermore, this MH and KM drafted the manuscript, performed literature review, review has only very briefly outlined the investigation into music- and edited the final manuscript for submission. HL and JB con- based and dance-based therapies within the PD population and tributed literature search and review and tabular organization. BC has likely not thoroughly covered the rhythmic and cognitively performed final review and critical appraisal of the manuscript. driven (IG) aspects of other forms of exercise (e.g., spinning, Tai Chi, walking, swimming, and boxing), which deserve attention. FUNDING CONCLUSION This work is supported by the US Department of Veterans Affairs’ Underlying mechanistic commonalities may exist among thera- Rehabilitation Research and Development grants: #0870-01A1- pies that effectively target symptoms of individuals with PD (138). MH and E-0956W-KM. 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This is an open- correlates of efficacy of voice therapy in Parkinson’s disease identified by access article distributed under the terms of the Creative Commons Attribution License performance-correlation analysis. Hum Brain Mapp (2010) 31(2):222–36. doi: (CC BY). The use, distribution or reproduction in other forums is permitted, provided 10.1002/hbm.20859 the original author(s) or licensor are credited and that the original publication in this 135. Brown S, Martinez MJ, Parsons LM. The neural basis of human dance. Cereb journal is cited, in accordance with accepted academic practice. No use, distribution Cortex (2006) 16(8):1157–67. doi:10.1093/cercor/bhj057 or reproduction is permitted which does not comply with these terms. Frontiers in Neurology | www.frontiersin.org 24 December 2015 | Volume 6 | Article 251 Review published: 11 November 2015 doi: 10.3389/fneur.2015.00234 Effects of Auditory Rhythm and Music on Gait Disturbances in Parkinson’s Disease Aidin Ashoori1 , David M. Eagleman2 and Joseph Jankovic3* 1 Columbia University College of Physicians & Surgeons, New York, NY, USA, 2 Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA, 3 Department of Neurology, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, USA Gait abnormalities, such as shuffling steps, start hesitation, and freezing, are common and often incapacitating symptoms of Parkinson’s disease (PD) and other parkinsonian disorders. Pharmacological and surgical approaches have only limited efficacy in treating these gait disorders. Rhythmic auditory stimulation (RAS), such as playing marching music and dance therapy, has been shown to be a safe, inexpensive, and an effective method in improving gait in PD patients. However, RAS that adapts to patients’ movements may be more effective than rigid, fixed-tempo RAS used in most studies. In addition to auditory cueing, immersive virtual reality technologies that utilize interactive computer-generated Edited by: Cathy Craig, systems through wearable devices are increasingly used for improving brain–body inter- Queen’s University Belfast, UK action and sensory–motor integration. Using multisensory cues, these therapies may be Reviewed by: particularly suitable for the treatment of parkinsonian freezing and other gait disorders. Graziella Madeo, University of Rome Tor Vergata, Italy In this review, we examine the affected neurological circuits underlying gait and temporal Maria Stamelou, processing in PD patients and summarize the current studies demonstrating the effects University of Athens, Greece of RAS on improving these gait deficits. *Correspondence: Joseph Jankovic Keywords: Parkinson’s disease, gait, freezing, music, rhythm josephj@bcm.edu Specialty section: INTRODUCTION This article was submitted to Movement Disorders, a section of the Gait disorders, particularly freezing of gait (FOG), are among the most disabling features of journal Frontiers in Neurology Parkinson’s disease (PD) (1). Rhythmic auditory stimulation (RAS), such as listening to marching Received: 17 September 2015 music, has been used to ameliorate this motor abnormality (2). The observation that sensory input, Accepted: 22 October 2015 such as RAS, can help overcome freezing suggests that the motor program for gait is relatively intact Published: 11 November 2015 in patients with PD but cannot be appropriately accessed without the sensory input (3). In this Citation: review, we will examine the role of auditory rhythm and music on parkinsonian gait. Ashoori A, Eagleman DM and Jankovic J (2015) Effects of Auditory Rhythm and Music on Gait …there’s something about the temporal structure of the music, the emotional content of Disturbances in Parkinson’s Disease. the music, that arouses areas of the brain that are still functioning and allows a lost ability Front. Neurol. 6:234. to become present as they participate in the music. – Dr. Concetta Tomaino, Executive doi: 10.3389/fneur.2015.00234 Director/Co-Founder, Institute for Music and Neurologic Function (4) Frontiers in Neurology | www.frontiersin.org 25 November 2015 | Volume 6 | Article 234 Ashoori et al. Music-Based Gait Therapy for PD A recent success story for music therapy from a neurological beneficial in preventing injuries in runners with PD or in athletes perspective is the speech recovery of Congresswoman Gabrielle with “runner’s dystonia” (31). Giffords after suffering a gunshot wound to the head in 2011. Giffords was unable to speak due to severe damage in the left GAIT IMPAIRMENTS IN PARKINSON’S hemisphere of her brain. However, remarkably, Giffords was able to sing parts of songs. After working for several years with music AND CURRENT THERAPIES therapy, she slowly regained the natural rhythm of speech through Parkinson’s disease, the second most common neurodegen- vocalizing musical phrases (5). In Giffords’s words, “music therapy erative disorder (32), is a complex neurological disorder that was so important in the early stages of my recovery because it can negatively impacts both motor and non-motor functions (33). help retrain different parts of your brain to form language centers The disease is caused by the degeneration of dopaminergic in areas where they weren’t before you were injured” (6). Through (DA) neurons in the substantia nigra associated with neuronal singing, Giffords’s undamaged brain regions were able to rewire inclusions called Lewy bodies, leading to DA deficiency in the themselves to recover her ability to speak. Indeed, research has basal ganglia (BG) (34). This deficiency results in four cardinal shown that music not only helps patients recover from stroke symptoms of PD that can be remembered by the tremor at but may improve gait in patients with PD, and learning to play rest, rigidity, akinesia (or bradykinesia), and postural instabil- a musical instrument may induce neuroplastic changes that may ity (33–35). These symptoms are often accompanied by gait translate into improved motor and cognitive function (7). This impairments (36) that are particularly prominent in the pos- was emphasized by the late Oliver Sacks in his book Musicophilia, tural instability gait difficulty (PIGD), in contrast to the tremor entirely devoted to this topic (8). Rarely, however, playing a dominant, subtype of PD (37). Gait abnormalities become also musical instrument may uncover underlying motor abnormality more severe in the late-stage PD (38). which becomes manifested as task-specific dystonia (9, 10). Gait disorders in PD are characterized by stooped posture, Rhythmic stimulation through music and sound has been shuffling steps, flexed knees, narrow base, reduced arm-swing, shown to improve motor deficits in a variety of movement turning en bloc, and FOG, which is one of the most debilitating disorders. Rhythm is defined as the time-based pattern of music features of PD (1, 39). While walking, patients suddenly lose or sound that consists of perceptible groupings of notes, beats, the ability to lift their feet and become stuck in place for several accents, and phrases (11). Beat is the unit of rhythmic pulse (11). seconds or even minutes despite their efforts to initiate forward Tasks requiring melody perception and production recruit movement (40). FOG can be provoked by perceived obstructive both the auditory and the motor areas of the brain (12–17). environmental cues, such as attempting to walk through nar- Passively listening to rhythmic stimuli, even in the absence of row doorways. Compared to healthy adults, PD patients have motor actions or intent, recruits the auditory systems as well as a shorter stride length, slower velocity, and more unpredictable the mid-premotor cortex (PMC) and the supplementary motor fluctuations between consecutive strides (1, 38, 41–46). Indeed, area (SMA) (18). Through a process called rhythmic entrainment FOG has been shown to be associated with marked disruption to (19), humans naturally move in synchrony to external rhythmic internal rhythmic timing (47). Table 1 lists and summarizes the cues. The evidence of rhythmic entrainment can be observed basic parameters used to measure the quality of gait. when humans spontaneously move or dance to the beats of Emergence of gait abnormalities often indicates a poor prog- music, even without being consciously aware of their action. nosis for PD patients as they correlate with bradykinesia, rigidity, However, rhythmic entrainment is not limited to auditory cues. and cognitive impairment associated with cortical Lewy bodies As humans walk side by side, they naturally synchronize their (36, 48) and leads to more frequent falling, a major cause of death footsteps without instruction or conscious intent (20–22). This among patients with PD (1). Several studies have shown that FOG bipedal locomotion relies on our innate internal timing, which in patients with PD correlates with poor quality of life, disease may control our conscious and subconscious abilities to extract severity, apathy, and exposure to anticholinergic drugs; it may, rhythm from the external world (23). but not always, improve with DA therapy (49). The strong connections between gait, innate internal timing, and rhythmic perception are demonstrated by humans’ rhythmic preference in music. Although humans’ perceptible temporal Table 1 | Basic parameters of gait and their definitions and range is 40–300 bpm (24–27), the preferred musical tempo is at units of measurement. 120–130 bpm (28). This preferred tempo is at the middle of the Gait parameter Definition range of the average gait cadence of males (103–150 strides per Walking speed (m/s) Distance walked per unit of time minute) and females (100–149 strides per minute) across different Cadence (steps/min) Number of steps per unit of time age groups (29). Accordingly, humans’ natural musical rhythmic Stride time (s) Time between two successive ground contacts preferences may have been influenced by their natural sponta- of the same foot neous gait rhythm. This powerful connection between rhythm Stride length (m) Distance covered between two successive ground and locomotion has led rhythmic entrainment to be clinically contacts of the same foot employed for gait rehabilitation in patients with neurological Step time (s) Time between two successive ground contacts disorders including stroke, traumatic brain injury, cerebral palsy, of the opposite feet and PD (7, 19). Rhythmic entrainment through music tempo has Step length (m) Distance covered between two successive ground also been used to improve running cadence (30), which may be contacts of the opposite feet Frontiers in Neurology | www.frontiersin.org 26 November 2015 | Volume 6 | Article 234 Ashoori et al. Music-Based Gait Therapy for PD The mechanisms of PD-related gait disorders, and FOG in severity increases (66–69). The underlying neural networks of particular, are not well understood. Impaired functional con- implicit and explicit timing are distinct. While implicit timing nectivity between the BG and the dorsolateral prefrontal cortex mainly recruits the cerebellum and is less dependent on the BG and the posterior parietal cortex has been suggested by recent and the SMA (70–72), explicit timing recruits the BG, the SMA, connectivity studies (50, 51). Although DA deficits clearly play the PMC, and the cerebellum (73). an important role in gait disturbances associated with PD, FOG The BG–SMA–PMC network is directly involved in rhythm often does not respond well to DA therapy, suggesting extranigral perception in the presence or absence of motor actions (18, 74, pathology in this particular gait disorder. In a cross-sectional 75). In this network, the dorsal striatum (caudate and putamen) study involving 143 PD patients using positron emission tomog- of the BG serves the most crucial role since it generates the raphy imaging, patients with FOG had lower DA striatal activity, internal pacing required for time estimation (73, 76). Thus, the decreased neocortical cholinergic innervation, and greater neo- BG is directly involved in perceptual and motor timing (77–79). cortical deposition of β-amyloid compared to non-freezers (52). The D2 receptors in the striatum mediate the DA signaling that Conventional therapeutic interventions for PD, such as phar- controls the speed of this internal pacing (80–85). The lack of macotherapy and deep brain stimulation (DBS), can be effective DA innervation to the BG in PD causes slower internal pacing for treating the cardinal motor symptoms but have shown limited (76), which leads to impairments in motor and perceptual timing efficacy in gait abnormalities (53). Levodopa, a DA precursor and abilities (17, 69, 72, 86, 87). In further support of the BG’s crucial one of the main pharmacotherapies of PD, has limited therapeu- role in timing, non-PD patients with focal lesions in the BG have tic effects on balance and gait disturbances (40). Furthermore, similar difficulty with motor rhythmic synchronizations and have anti-PD medications may produce side effects including light- difficulty adapting to tempo changes (88). headedness, drowsiness, and dyskinesias which can exacerbate Given that gait and other motor deficits in PD are strongly gait abnormalities (1). Although DBS typically improves tremor, associated with timing impairments, RAS is a promising strategy rigidity, bradykinesia, and levodopa-related motor complications for gait rehabilitation. Although PD patients have impairments (54), this therapeutic modality results in only minimal benefits in with external timing due to internal pacing dysfunction, patients patients whose primary symptoms are PIGD (1, 55, 56). still have the ability to make temporal predictions through implicit timing. In other words, PD patients can still use external rhythmic cues to inform temporal-based decisions, such as when NEURAL MECHANISMS OF CUED GAIT the next footstep should occur. Since implicit timing is still mostly TRAINING intact in PD patients, they compensate for the disruption in the BG–SMA–PMC (explicit timing) by recruiting the cerebellum In recent years, there have been numerous studies demonstrating (89) (essential for implicit timing). the therapeutic efficacy of RAS in gait abnormalities associated Although internal pacing is disrupted in PD patients, this with PD. An increasing body of research suggests that PD involves timing alteration can be corrected and recalibrated through a deficit in temporal processing (57) and that internal rhythmic motor–sensory interaction with the world (3, 90). Cued gait timing is more disrupted among PD with gait deficits than among training utilizes the implicit timing abilities still present in PD patients without gait deficits (47). It has been proposed that patients to recalibrate the internal clock. In RAS, PD patients internal timing is dependent on striatal DA levels (58), and that are instructed to walk while synchronizing their footsteps to the timing problems may be a potential marker for frontal and striatal salient beats of the music or metronome. RAS can be combined dysfunctions in PD (59). Accordingly, we hypothesize that the with visual cues such as patterned tiles or stripes placed along the temporal deficits in PD are a major contributor to gait impair- walkway for multisensory cueing. ments. This is supported by the finding that DA replacement The schema in Figure 1 summarizes the basic neural path- therapy reduces the timing deficits in PD (60), and that timing ways involved in gait training. In the absence of external cueing, deficits are induced by changes in the expression levels of striatal internal cueing signals generated by the BG–SMA–PMC circuit D2 receptors (61). Furthermore, timing deficits are also found in feed into the motor programs, which are carried out in the medial other DA-related disorders including schizophrenia (58, 62, 63). motor areas comprised of the SMA and the cingulate motor area To understand temporal dysfunction, one must consider the (91). During locomotion, the spinocerebellar, the spinothalamic, two fundamental modes of timing: explicit and implicit timings. the spinoreticular, and the spinohypothalamic tracts carry Explicit timing is required to make deliberate estimates of dura- somatosensory information, such as proprioception back to the tion and relies on internal sense of time (64). Implicit timing brain (3, 92). The information carried by the somatosensory utilizes external cues and relies less on conscious time-based feedback modulates the internal clock of explicit timing (62) in judgments, engaging automatic timing systems. An example of the BG–SMA–PMC circuit and helps plan and predict future an implicit timing task is the serial prediction task, which requires cued motor tasks. the subject to use a regularly timed stimulus to make temporal The motor programs of gait appear to be relatively intact in PD predictions about future stimuli (64, 65). Patients with PD have patients, but due to impaired internal timing, the programs can- greater difficulty with explicit timing than with implicit timing. not be easily accessed without external cues (1, 3, 33). External More specifically, PD patients have problems with explicit tem- rhythmic cues include visual and auditory sensory stimuli and poral discrimination tasks involving tactile, visual, and auditory can serve as surrogate cues for the impaired internal timing (93, stimuli, and explicit timing performance decreases as disease 94). Accordingly, auditory and visual stimuli can bypass the Frontiers in Neurology | www.frontiersin.org 27 November 2015 | Volume 6 | Article 234 Ashoori et al. Music-Based Gait Therapy for PD Figure 1 | Neurological schema of cued gait training. BG, basal ganglia; CMA, cingulate motor area; PMC, premotor cortex; SMA, supplementary motor area. damaged BG and help the patients improve their gait by inducing While the studies in healthy subjects suggest that cues with motor–sensory feedback signals that recalibrate internal pacing. music are more effective than with a metronome at increasing After the correct temporal scheme is re-established with RAS gait velocities, a study by Leow et al. (99) reports that cues with a and potentiated through the BG–SMA–PMC circuit, patients metronome rather than with music elicit better gait synchroniza- can sustain improved locomotion for a period of time in the tion in healthy young adults. The same study further compares absence of external cueing. Gait rehabilitation through RAS has the effects of two types of music on gait: high-groove music (high been recognized to benefit PD patients for almost two decades. beat salience) and low-groove music (low beat salience). Between In 1996, Thaut et al., using renaissance style instrumental music these two types of musical cues, high-groove music elicited better as the rhythmic cues, 3-week gait training with RAS significantly gait synchronization and faster gait velocity. Low-groove music improved gait velocity, cadence, and stride length in PD patients was not as effective, and even had a detrimental effect on gait in (44). One year later, a similar study showed that RAS with cues weak beat-perceivers (99). Music familiarity is also an important that were 10% faster in tempo than the patients’ baseline cadence factor in RAS. RAS with familiar songs results in faster gait veloc- had even a greater improvement on gait deficits (95). Since then ity and less stride variability than with unfamiliar songs. This is there have been numerous reports on the effect of music- or likely due to the fact that synchronizing footsteps to a familiar metronome-based gait training in PD patients. Below, we will beat structure require less cognitive demand. Enjoyment of famil- discuss some of the recent key studies on cued gait training to iar music may also have had a role in eliciting a faster gait (100). better understand the challenges of gait therapy and to formulate A variety of devices have been developed to provide custom- a future direction for RAS in PD. ized fixed-temp RAS. Recently, a research group in Madrid, Spain (Brainmee™) developed Listenmee®, an intelligent glasses’ Optimal Auditory Cues for Gait Training system, that employs RAS to improve gait (101). The glasses are Gait-training studies in PD patients have used either music or portable and contain built-in headphones that allow the user simple isochronous sounds, such as a metronome, as cues for to listen to isochronous (metronome-like) auditory cues while RAS. Cue type can affect gait parameters differently depending on walking. The sounds are customizable to various styles, such as factors, such as the participants’ health and age. Although there ambient, percussive, electronic, and vocal. The user controls the has not yet been a published direct comparison between music device via Bluetooth with the Listenmee® smartphone applica- and metronome in gait rehabilitation in PD patients, several stud- tion. The research groups plan to turn the device into an auditory ies have done this with healthy participants. One study reports feedback system by integrating feedback to spatial movements. that healthy young adults walked faster with music than with The device will include a built-in video camera and a laser emitter metronome cues (96). Another similar study in healthy older to assess motion in the visual field and provide responsive visual adults (age >65) demonstrated that both music and metronome cueing. The group has yet to publish the results of the efficacy of cues significantly increased cadence, but that only music signifi- this integrated visual and auditory feedback system. cantly increased stride length and gait velocity (97). Contrary to An experiment showing the efficacy of the non-feedback these results in healthy participants, Huntington’s disease patients device involved 10 PD patients between the ages of 45 and walked faster when cued by the metronome rather than with 65 years (101). Inclusion factors consisted of a history of frequent music (98). FOG and falling as well as failure to respond to medication and Frontiers in Neurology | www.frontiersin.org 28 November 2015 | Volume 6 | Article 234 Ashoori et al. Music-Based Gait Therapy for PD physical therapy. Five of the patients received DBS with minimal gait improvement prior to the study. In this study, patients were instructed to walk while off DA therapy. Cadence, stride length, and walking speed were measured with and without RAS. Patients showed significant improvement for all three gait parameters while listening to auditory cues. Musically Cued Gait Training: Sustained Benefits Beyond Gait Rehabilitation A recent study by Benoit et al. (102) shows that musically cued gait training significantly improves multiple deficits of PD, including in gait, motor timing, and perceptual timing. The study consisted of 15 non-demented patients with idiopathic PD (Hoehn and Yahr stage 2). The patients had no prior musical training and maintained their DA therapy regimen during the trials. There were three 30-min training sessions per week for 1 month. During each session, the participants walked to the salient beats of German folk music without explicit instructions to synchro- nize their footsteps to the beat. Compared to pretraining gait performance, the PD patients showed significant improvement Figure 2 | Self-improving relationship between beat perception and gait training efficacy. in gait velocity and stride length during the training sessions. The gait improvement was sustained for 1 month post-training, indicating a lasting therapeutic effect for uncued gait. This RAS training also significantly improved motor and DA therapy and on 16 healthy controls (109). The device utilizes perceptual timing. Pretraining, immediately post-training, pressure sensors in the shoes that feed gait timing data into a and 1 month post-training, patients participated in a battery computer system, and adjust the metronome cueing tempo in of motor and perceptual timing tests of duration discrimina- real-time. The efficacy of WalkMate on gait was compared with tion, beat alignment, paced tapping, and adaptive tapping. fixed-tempo RAS and a silence-control condition. Gait dynamics Prior to training, 73% of the patients displayed timing deficit were analyzed using the detrended fluctuation analysis (DFA) that decreased to 67% immediately post-training and only 40% fractal-scaling exponent, which is associated with gait adaptability 1 month post-training. Thus, in addition to gait, RAS improves and one of the best measures of predicting falling (46, 109, 110). perceptual timing with continued therapeutic effect even in In a silent-control condition the PD patients had significantly the absence of auditory cueing. This study in the context of the lower fractal scaling (higher variability) in stride than the healthy previously mentioned study by Leow et al. suggests a circular subjects. During fixed-tempo RAS, PD patients’ stride had even relationship between rhythm perception and gait performance: lower fractal scaling than during the silent-control condition, improved beat perception increases the efficacy of gait training consistent with past findings (107). With WalkMate, PD patients’ (99) and improved gait training increases beat perception ability fractal scaling became significantly better than the silent-control (102) (Figure 2). condition and reached the DFA baseline of healthy subjects in the silent-control condition. Furthermore, gait improvement Interactive Cueing Systems persisted in the absence of the adaptive WalkMate cues 5 min Although the efficacy of gait training with RAS has been proven, after the training sessions (Figure 3) (109). the rigid, fixed-tempo of the cues implemented by most stud- More recently, a similar device named D-Jogger was tested on ies has limited applications to PD patients. Fixed-tempo RAS healthy subjects to study the synchronization of gait to adaptive requires increased demand for attention to synchronize footsteps rhythmic cues (111). D-Jogger is a music player that adjusts the with auditory cues, thus invoking higher-level cognitive pro- musical tempo to the listeners’ gait rhythm (Figure 4) (112). cesses (103). This can be problematic for PD patients, in whom In the most effective adaptive strategy (out of the four adaptive multitasking while walking can trigger or exacerbate their gait strategies tested), the participant initially begins walking in the difficulties (104–106). Even in healthy participants, fixed-tempo absence of music. The music then begins by the first beat matching RAS can result in random and unpredictable stride intervals the footfall and continues with a tempo equal to the average gait (107). Therefore, attempts have been made to improve RAS tempo sampled from the previous 5 s. The results from healthy by integrating an adaptive system that provides feedback from participants motivate further testing of D-Jogger on patients with human rhythm to determine cueing rhythm. A cueing system PD or other movement disorders. that aligns to the patients’ movements would demand less atten- tion, which may lead to greater gait improvements than with Virtual Reality: A Potential for Combined fixed, non-adaptive cueing (108). Visual and Auditory Cueing WalkMate, an interactive RAS device developed by Yoshihiro In PD patients, locomotion and postural control have an Miyake and colleagues, was tested on 20 PD patients undergoing increased dependence on perceptual vision (113, 114) that can Frontiers in Neurology | www.frontiersin.org 29 November 2015 | Volume 6 | Article 234 Ashoori et al. Music-Based Gait Therapy for PD Figure 3 | Interactive rhythmic auditory stimulation using WalkMate. (A) Parkinson’s patients during rhythmic treatment, (B) Healthy participants during rhythmic treatment, and (C) Parkinson’s patients’ carry-over effect during a silent trial 5 min after the rhythmic treatment. The cueing conditions are unassisted silent control, interactive WalkMate rhythmic auditory stimulation (RAS), and fixed-tempo RAS. Error bars represent six SEM. *P < 0.05; n.s., non-significant. Reproduced from Hove et al. (109). Figure 4 | Smart music player: person–machine interaction loop and the main components involved. Reproduced from Moens et al. (112). be corrected using visual cues (115, 116). Multiple studies have patients who wish to train at home in a daily basis. Furthermore, shown that matching footsteps to visual cues such as equidistant as with auditory cueing, fixed walkway strips may be less effec- horizontal lines along a walkway improves gait and reduces tive than an interactive system that adjusts cueing based on the FOG in PD patients (117–119). Although visual cueing can be patient’s movement and gait parameters. Instead, an ideal cueing beneficial, replicating clinical scenarios would be unfeasible for system would involve adaptive feedback and include both visual Frontiers in Neurology | www.frontiersin.org 30 November 2015 | Volume 6 | Article 234 Ashoori et al. Music-Based Gait Therapy for PD and auditory stimuli. Immersive virtual reality (VR) technology device via Bluetooth. Furthermore, VR devices are capable could fill this gap by optimizing visually cued gait training. VR of measuring the users’ performance via tracking technology is an immersive and interactive computer-generated environ- (125), which would allow VR systems to provide feedback of ment that simulates the real-world experience (120) and can be the users’ improved gait performance during and following operated using a custom-made or commercially available head- training (126). Thus, a multisensory and adaptive VR device mounted display. The use of VR with visual cueing for clinical with performance tracking should be explored as a superior rehabilitation is still in its infancy, though multiple studies have gait-training therapy. found that in chronic stroke patients VR-based training improves cadence, step length, stride length, symmetry, and other gait CONCLUSION parameters (120–123). Recently, immersive VR was shown to be effective for gait Similar to how the metronome helps musicians maintain a steady rehabilitation in PD (124). The study uses a pair of VR glasses that tempo during a musical performance, RAS provides an effective projects a virtual checkered tile floor into the user’s visual field. approach for reducing gait impairments in PD patients. The The user is instructed to walk along the floor, and the VR floor efficacy of RAS reflects the overlapping neurological domains adapts to the user’s body movements by simulating the visual involved in gait and beat perception. Importantly, RAS is safe effect of walking. Twenty PD patients with a mean age of 71.25 (127), inexpensive, non-invasive, and free of adverse health participated in the study. While wearing the device, the patients effects. One major limitation to most RAS methods is the fixed- tried to match their steps with the adjacent tile to regulate their tempo design that requires increased cognitive demand and can gait via the VR visual feedback. When cued by the VR display, negatively impact gait. However, an interactive cueing system that the patients showed significant improvement in walking speed adapts to the patients’ gait parameters may be able to resolve this (P = 0.002) and stride length (P = 0.002) compared to baseline. limitation and maximize gait improvement from RAS. For RAS Fifteen minutes post-training and without the device, the patients to be successful, the intervention should be initiated early in the showed even greater improvements in walking speed (P = 0) and progression of PD to maximize a participant’s ability to adapt to stride length (P = 0) compared to baseline (Figure 5). the demands of the training before the development of cognitive Although these findings are promising, more well-controlled impairment. studies are needed to demonstrate the efficacy of VR-based ther- Further investigation of mechanisms of gait impairment apies for PD. A potential expansion of VR gait training should in various parkinsonian disorders is needed. For example, an involve adaptive, multisensory visual (e.g., virtual tiles or strips) unresolved question is whether lower body parkinsonism, and auditory (e.g., metronome and music) cues. Simultaneous which is frequently associated with FOG, is a subtype of PD multisensory cues could have a stronger combined effect than (37) or whether it represents a separate entity, such as vascular each cue alone. VR systems can be portable, enabling patients to parkinsonism (128, 129), cortical Lewy Body disease (48), or train their gait in the comfort of their home. VR devices already atypical parkinsonism such as progressive supranuclear palsy have the computing capacity required for the integration of or normal pressure hydrocephalus (1). The long-term impact of simultaneous adaptive cueing and can be internally processed RAS on gait impairment and other motor and cognitive deficits or remotely processed in a smartphone connected to the VR should be objectively assessed by randomizing subjects to either participate in RAS by a trained therapist at least once a week for 6 months or participate in routine gait training. Novel methods and instruments, such as quantitative stepping-in-place with a concurrent mental task using a fourth generation iPod Touch sensor system (130), are needed to assess the effects of RAS on gait and mental function. The type of music and rhythm needed to optimize response to RAS should also be further evaluated. For example, in one study of healthy individuals’ strikingly prominent (salient) commercially available music increased measures of cadence, velocity, and stride length, but simple music tempo did not (131). We suggest that different types of music, rather than the traditional rhythmic auditory cues, are carefully evaluated in patients with PD to determine which music most effectively improves PD-related gait disorders. Another approach to gait rehabilitation is the use of VR for PD. While initial research to this immersive approach is promising, further studies are required and should integrate RAS. VR technol- Figure 5 | Rehabilitation of gait using virtual reality feedback cues. ogy holds the potential to deliver more effective rhythmic cues by Measurements of walking speed and stride prior to the sessions (baseline), combining RAS and visual cueing, which we term rhythmic audi- VR display off, VR display on, and 15 min after end of the session (15-min tory and visual stimulation. With modern technology, VR-based residual). Error bars represent SEM. *P < 0.01; **P < 0.001. Adopted from rehabilitation could be made portable, and smartphones could Badarny et al. (124). be programed to process adaptive cue algorithms. Portability and Frontiers in Neurology | www.frontiersin.org 31 November 2015 | Volume 6 | Article 234 Ashoori et al. Music-Based Gait Therapy for PD ease of use could increase the frequency of gait-training sessions and tactile cues in a VR device could further enhance the efficacy and improve compliance. Adaptive auditory and visual cueing of this therapy. could also be combined with tactile stimulation as a more sali- ent gait therapy for PD patients. Concepts of tactile stimulation ACKNOWLEDGMENTS could be informed by recent innovations, such as the versatile extrasensory transducer (VEST), a non-invasive, low-cost vibra- We would like to thank Amanda M. Buch, a research scientist at tory VEST developed by Novich and Eagleman (132). Thus, RAS Columbia University Medical Center, for her editing and valuable is a promising therapy for the gait impairments in PD and other comments. We also thank the National Parkinson Foundation for movement disorders, and combining adaptive RAS with visual their support of the Baylor College of Medicine Center of Excellence. REFERENCES 20. Zivotofsky AZ, Hausdorff JM. The sensory feedback mechanisms enabling couples to walk synchronously: an initial investigation. J Neuroeng Rehabil 1. Jankovic J. Gait disorders. 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Frontiers in Neurology | www.frontiersin.org 35 November 2015 | Volume 6 | Article 234 Mini Review published: 20 January 2016 doi: 10.3389/fneur.2016.00001 A Technological Review of the Instrumented Footwear for Rehabilitation with a Focus on Parkinson’s Disease Patients Justyna Maculewicz* , Lise Busk Kofoed and Stefania Serafin Sound and Music Computing Group, Department of Architecture, Design and Media Technology, Aalborg University Copenhagen, Copenhagen, Denmark In this review article, we summarize systems for gait rehabilitation based on instrumented footwear and present a context of their usage in Parkinson’s disease (PD) patients’ auditory and haptic rehabilitation. We focus on the needs of PD patients, but since only a few systems were made with this purpose, we go through several applications used in different scenarios when gait detection and rehabilitation are considered. We present developments of the designs, possible improvements, and software challenges and requirements. We conclude that in order to build successful systems for PD patients’ Edited by: gait rehabilitation, technological solutions from several studies have to be applied and Marta Bienkiewicz, Aix-Marseille University, France combined with knowledge from auditory and haptic cueing. Reviewed by: Keywords: instrumented footwear, rhythmic rehabilitation, Parkinson’s disease, gait rehabilitation, auditory Yoshihiro Miyake, feedback, haptic feedback Tokyo Institute of Technology, Japan Vladimir Ivkovic, Massachusetts General Hospital and Harvard Medical School, USA 1. INTRODUCTION *Correspondence: Justyna Maculewicz The purpose of this review article is to present a context of usage of instrumented footwear in jma@create.aau.dk Parkinson’s disease (PD) patients’ auditory and haptic rehabilitation. We present developments of the design, possible improvements, and software challenges and requirements. We summarize Specialty section: existing technological solutions and applications. Literature on rhythmic auditory rehabilitation This article was submitted to provides design requirements for the hardware and software, which is necessary to build successful Movement Disorders, rehabilitation wireless systems for PD patients with instrumented footwear as a data collector and a section of the journal feedback device. Frontiers in Neurology Received: 30 September 2015 2. A CONTEXT OF INTERACTIVE SHOE USAGE Accepted: 04 January 2016 Published: 20 January 2016 Interactive shoes with embedded sensors have been used in many different scenarios. Gait analysis Citation: is the prominent one. Tao et al. (1) reviewed gait analysis challenges and presented a selection of Maculewicz J, Kofoed LB and wearable sensors, which can be used for gait analysis. In the context of PD, it is necessary to collect Serafin S (2016) A Technological information about patients’ balance (2), gait cadence, velocity, and stride length (3). Interactive shoes Review of the Instrumented Footwear for Rehabilitation with a Focus on give opportunities for collecting data about users’ current state. This can be followed by notifying Parkinson’s Disease Patients. users or supervising persons (e.g., doctors and physiotherapists). Data gathered by sensors can send Front. Neurol. 7:1. information to rehabilitation systems when a specific problem or need occur and activate cueing doi: 10.3389/fneur.2016.00001 stimuli in the form of auditory signals or vibrations. Frontiers in Neurology | www.frontiersin.org 36 January 2016 | Volume 7 | Article 1 Maculewicz et al. A Review of the Instrumented Footwear for Gait Rehabilitation 2.1. Gait Impairments in PD mood of the walking person (23). Complex walking sounds, Gait impairments have received a lot of attention in recent years such as footsteps on gravel, may convey both temporal (step since they are a common cause of disability in people with PD duration) and spatial (step length) properties of gait (16). (4). Various aspects of gait have been found to be affected by PD, but they can be influenced and improved through rehabilitation 2.3. The Advantages of Haptic Stimulation based on auditory or haptic cueing. The most common ones are Little research has focused on foot-based vibrotactile systems. freeze of gait (5), balance (6), gait velocity, cadence, stride length The sensitivity of the sensory system of the feet is sufficient for (3), increased spatio-temporal variability (7), and difficulties vibrotactile guidance (24). Signals from mechanoreceptors in the with gait initiation (8). These disturbances are lead to restricted foot are one of the main sensory sources for gait generation and mobility, weakened balance, and consequently to increased risk modification (25). It is likely that mechanoreceptive afferents in of falling (9). Such disturbances have been found to influence the sural nerve provide rich information about contact patterns patients’ general quality of life (10). between the foot and the environment during stance and locomo- tion (24). When exposed to audio and haptic stimulation, subjects 2.2. Rehabilitation through Auditory are able to best recognize different materials delivered haptically or as a combination of auditory and haptic feedback (26). Both audi- Stimulation tory and haptic feedback are represented as temporal variations, 2.2.1. Metronome-Like Rhythmic Stimulation which can be simulated with similar patterns, at different frequency It has been shown that following a rhythmic auditory cue helps ranges. Since most of the pedestrians wear shoes when walking it gait performance in patients with PD (11–15). The PD patients makes it an excellent platform for mounting actuators (27). are usually provided with an auditory metronome, or markedly rhythmic music, and asked to match consecutive footfalls with the onset of each beat (16). External rhythms presented by audi- 3. THE EXISTING TECHNOLOGIES tory cues may improve gait characteristics (13–15) and can also This section presents studies describing foot plantar measurement be used to identify deficits in gait adaptability (17). Spaulding systems and their usage in auditory and haptic rehabilitation and et al. (3) in their review pointed that the auditory cueing elicited focuses on main advantages coming from their possible usage. positive changes in gait cadence, velocity, and stride length. 3.1. Foot Plantar Measurement Systems 2.2.2. Mutual Entrainment In this subsection, we will mention a few interesting instrumented The aforementioned way of stimulation lacks the interactivity insoles which followed by a review by Abdul Razak et al. (28). component where the system could adapt to the user. In this Amjadi et al. (29) presented a flexible foot pad containing case, mutual entrainment between system and user happens. force-sensitive resistors arrays for the foot sole distributed force Miyake (18) proposed the Walk-Mate to implement the mutual detection. Stassi et al. (30) described an easy and cost-effective entrainment for the rehabilitation of PD and hemiplegic patients. approach used to fabricate the conformable insole based on a Baram (19) suggested that gait rehabilitation must be performed piezoresistive material. It measures both the pressure distribu- in a closed-loop system to avoid constant vigilance and need of tion under 64 nodes arranged in the main plantar regions and the attention strategies to prevent reversion to impaired gait patterns mean plantar pressure during walking activity with a sampling caused by repetitive stimuli. Hove et al. (20) reported that ran- frequency of 20 Hz. While developing instrumented insoles, dom, disconnected stride times (low fractal scaling) predicts fall- Tamm et al. (31) focused mostly on accuracy, long-term stability ing for PD patients. Fixed rhythmic auditory stimulation lowers and reproducibility, and time resolution. They proposed a thin, fractal scaling and requires attention. Gait rehabilitation should light weight self-contained platform for mobile wireless pressure lead to achieving the more stable and not random stride times sensing insole system with 24 separated points of measurement structure, which can be observed in healthy gait (20). Systems on the foot. Suresh et al. (32) demonstrated a proof-of-concept of based on mutual entrainment principles can emergently respond a new high-resolution plantar pressure monitoring pad based on to unpredictable changes in human behavior (21). The studies fiber Bragg grating (FBG) sensors. Motha et al. (33) introduced by Hove et al. (20) and Uchitomi et al. (22) showed that the gait a unique approach to measure applied pressure. The change in fluctuation of the patients gradually returned to a healthy stride capacitance is entirely led by variation of relative permittivity of times fluctuation level in the interactive conditions. This effect the surrounding dielectric medium with applied pressure. Tan did not occur in fixed tempo and no-cue conditions. et al. (34) presented another low-cost design for plantar pres- sure measurements. They proposed a system based on carbon- 2.2.3. Improvements through Ecological Stimuli embedded piezoresistive material sandwiched between two layers Rhythmic sounds (metronome-like) only specify step duration of of electrodes to form a pressure sensing insole. gait, with no information relating to spatio-temporal properties of walking actions. Rodger et al. (16) recently proposed the use 3.2. Foot Plantar Measurement Systems of ecological signals as a new approach to auditory rehabilitation. with Its Tested Applications Ecological signals, defined as those stimuli, which are encountered Redd and Bamberg (35) presented a simple system of two force- in everyday life, have the potential to convey richer information. resistive sensors per insole, connected to a mobile application that Listeners, based on footstep sounds, can determine gender and delivers feedback. Their tests showed that the feedback system Frontiers in Neurology | www.frontiersin.org 37 January 2016 | Volume 7 | Article 1 Maculewicz et al. A Review of the Instrumented Footwear for Gait Rehabilitation is capable of influencing the gait of the user, without the need supports walking by reducing asymmetries and fluctuations in for direct supervision by a rehabilitation specialist. The system foot contact rhythm. proposed by Santoso and Setyanto (36) consists of a sensing unit and a signal processing unit. The sensing unit is based on 3.5. More Complex Systems piezoelectric stress sensor module (two in each insole) and data Watanabe and Ando (27) introduced a system called Pace-synch acquisition module both wirelessly connected. The system is able shoes. Pressure sensors embedded in a shoe sole served as step to differentiate running from walking in athletes performance. detectors and provided data for a vibration motor to be activated. Madavi and Giripunje (37) proposed a wearable device for the The users reported that when the vibration was presented at heel- diabetic person of sensory neuropathy. It identifies the ulcerous strike timing, it was perceived as natural, while the vibrations at the condition, which may be created in foot plantar surface area. other timings caused odd feelings. They also reported that, when Temperature sensors or pressure sensors are used to detect the they walked matching their step cycles to the vibration at the heel- infected area. The output data can be transmitted wirelessly to the strike timing, their way of walking did not subjectively change. As hospital system. Grenez et al. (38) described the development of a the authors claimed, their method would be applicable for training hardware system simulating a shoe, which consists of three pres- and coaching in sports and for rehabilitation in health care. sure sensors, two bending sensors, an accelerometer, an Arduino The system described in Zanotto et al. (6) allows for synthesiz- mini, and a Bluetooth module. The developed prototype is able ing continuous audio-tactile feedback in real time, based on the to differentiate between healthy gait and imperfect gait. Holleczek readings of piezoresistive and inertial sensors embedded in the et al. (39) described the development of textile pressure sensors, footwear. The system contains 4 piezoresistive sensors, a 9-degree- which are more comfortable in usage than standard ones. The of-freedom inertial measurement unit, and five actuators in each textile pressure sensors were developed using the principle of a shoe. All information is stored and processed in the belt unit. The variable capacitor. These sensors were attached to the socks (three results of this preliminary experiment indicated that ecological in each sock at relevant positions under the heel and the ball of underfoot feedback may alter the natural gait pattern of healthy the foot) of a snowboarder for the monitoring of the in-shoe subjects. pressure distribution. The prototype proposed by Tajadura-Jiménez et al. (44) allows for the dynamic modification of footstep sounds, as people walk, 3.3. Instrumented Footwear Systems with and measures changes in walking behavior. This sandals-based Vibrating Stimulation system captures sounds of a person’s footsteps via a microphone Hijmans et al. (40) described a technology, which could be used attached to the sandals. Two force-sensitive resistors are attached in the future to improve balance in healthy young and older to the front and the rear part of the sandal insole that detect the people and in patients with a stroke or diabetic neuropathy. The exerted force by feet against the ground as well. A triple axis accel- system uses cork insole covered with a leather layer. A C2 elec- erometer was attached to the walker’s left ankle. Augmenting the tromechanical actuator and a piezo actuator or the VBW32 skin high frequencies of the sound leads to the perception of having transducer, activated by a custom-made noise generator, were a thinner body and enhances the motivation for physical activity chosen to provide tactile stimulation to the feet. inducing a more dynamic swing and a shorter heel strike. The goal of the application called Gilded Gait is to simulate the perception of a range of different ground textures and serve as 3.6. Existing Application for PD Patients the navigation in the city (41). The system contains six vibrations The work presented by Winfree et al. (45) is one of the most inter- panels to present the feedback patterns, push-down switch, and esting studies in the context of this review. These authors described an accelerometer to detect user’s steps. Three different patterns of a prototype of a shoe-based system, which contains FSR sensors vibrations were designed to simulate different ground textures. and an actuator, which are activated in the certain situations. The Recognition of the patterns was possible only if they were asked system was used in a short intervention study with PD patients. to choose from the list rather than recall a material. The most crucial aspects of the system are its portability, wireless Velázquez et al. (42) described the development of a tactile communication, low-cost development, adjustable automatic communication system (16 actuators embed into a shoe insole) software, ease of learning, and presentation of appropriate audio and a pilot study on recognition of different information (direc- and haptic signals. The core of the system operates in a way that tion, pattern, emotion recognition, and language learning) if only the ball or toe of the foot is in contact with the ground, assigned arbitrary to vibration patterns, which as was shown can the toe actuator vibrates. When both the heel and ball or toe are be easily learnt and understood. concurrently in contact, both tactors vibrate. This condition is met during stance phase of ambulation. The Berg Balance Scale 3.4. A System Based on Accelerometer (46), Timed Up and Go (47) performance tests, and the FOG Walk-Mate (43) is a system mainly used as a gait compensation questionnaire (48) were used to obtain measurement data dur- device and as a gait rehabilitation training device by analyzing ing pre-and post-treatment. It was shown that this stimulation improvements in locomotion before, during, and after rehabilita- provoked significant changes to all measures except time on toe tion in hemiparetic patients and comparing it with a previous gait sensor and step duration. training method. Walk-Mate generates a model walking rhythm Bächlin et al. (49) aimed to develop a system, which overcomes in response to the user’s locomotion in real time, and by indicat- the limitations of previous systems, such as the continuous nature ing this rhythm using auditory stimuli, provides a technology that of the cueing intervention, manually triggered cueing or provided Frontiers in Neurology | www.frontiersin.org 38 January 2016 | Volume 7 | Article 1 Maculewicz et al. A Review of the Instrumented Footwear for Gait Rehabilitation only during training sessions, but not provided at the time of potential candidate to be stimulated by an actuator. Although episodic gait disturbances. The challenge set by these authors is Kennedy and Inglis (50) indicated that the ball and the arch are to detect freeze of gait episode and apply automatically interactive the most sensitive areas to vibrotactile stimulation. rhythmic auditory stimulation to overcome the problem. This The placement of an accelerometer is quite optional, but it system consists of a wearable computer, a set of acceleration sen- should be hidden in the shoe and well protected from the dis- sors and headphones. The study was the first one in which FOG placement. Accelerometers collect data about feet acceleration is automatically detected, and the results are very promising. in three-dimensional space. They give more precise information The system detected FOG with high sensitivity and also received about feet movement than FSR sensors, and they are crucial in acceptance from the users. detecting balance problems. An accelerometer was successfully used for FOG detection in Bächlin et al. (49). 4. EMERGING GUIDELINES FOR 4.2. Software/Application INTERACTIVE SHOES DESIGN FOR PD Few studies consider the use of ecological signals, despite their AND DISCUSSION richness of information and acceptance from the users’ perspec- tive. Bächlin et al. (49) demonstrated the need for a context-aware Identifying non-invasive treatments to alleviate the symptoms system. The ideal system should be adaptive to the participant’s of PD is important to improving PD patients’ life quality (45). speed (19, 20) and able to present cueing signals constantly or in Several studies exploring rhythmic auditory stimulation (RAS) ad hoc manner (49). The overall goal is to design a system, which and its modified interactive versions in PD rehabilitation showed patients would like to wear everyday and feel comfortable with improvements in gait cadence, stride length, and gait velocity it. For example, auditory cueing should be used by patients only (3). It is promising to use all above mentioned knowledge and during short sessions every day. The haptic stimulation could technology to build an instrumented footwear system for the serve constantly, especially when a person would like to go out of PD rehabilitation based on data collected from the instrumented their home. According to the patients’ needs, it should be able to footwear and feedback presentation through auditory and tactile choose constant or ad hoc stimulation by choosing program on channels. This kind of a system gives a lot of opportunities for a the main computer unit. Each system should be personalized and remote communication between a patient and a doctor or thera- be programed for specific needs such as FOG, loss of balance, or pist. System interactivity allows for not only presenting feedback slowed pace, to be mentioned among others. but also giving cues for patients based on their performance. The system could detect the events such as FOG, loss of balance and impaired gait patterns and subsequently present cues to correct it 5. SUMMARY and help patients overcome these issues. In this review, we summarized systems for gait rehabilitation based on instrumented footwear. We focused on the need of 4.1. Hardware PD patients, but since only a few systems where made with Our literature review shows that from the hardware perspective this purpose, we went through several applications used in pressure sensors, actuators and accelerometer need to be embed- different scenarios when gait detection and rehabilitation is ded into the instrumented footwear system. Pressure sensors will considered. Future designs could benefit from this knowledge. allow for step detection, and for monitoring balance, and pressure We outlined the hardware and software needs to run rehabilita- applied to selected parts of the feet. Important is the choice of tion with the use of haptic and auditory cueing and feedback. the pressure sensors with adequate accuracy and durability. The There is still work to be done, but since technology for foot aforementioned studies exhibit that it is possible to use a wide plantar measurement and feedback presentation is developing variety of pressure sensors and materials from which they are very fast, we should focus on specific applications and build made. Moreover, they present high diversity in the number of customized systems for everyday use. The future trends out- data collecting points, ranging from 2 (35) to 75 (34). It is pos- lined as well by Bächlin et al. (49) are: (1) miniaturization of sible to find low-cost solutions in both categories. However, the the system and the main operating unit, which could be a part number of the sensors embedded in a shoe sole depends on the of the patients everyday clothing and hidden to make user feel available calculating power of each system. These data can be eas- comfortable; (2) specific calibration and customization of the ily used as a basis for calculating velocity, stride length, cadence, rehabilitation programs based on patient-specific problems; and temporal variability. (3) possibility of outdoor usage, so patients will be more secure The actuators present haptic feedback or cues to the users. and independent. Haptic feedback has three main advantages: it can be hidden in the shoe, can motivate users to perform a step by detecting FOG AUTHOR CONTRIBUTIONS or gait initiation, and can increase the perceived naturalness of the auditory stimuli, which can serve as a higher motivation JM is the most responsible person for this article. Since the type for rehabilitation. There are no sufficient studies to indicate the of article is mini review, she was responsible for literature search best placement of actuators in a shoe sole; based on the study and selection and writing part. Both LK and SS were consulted at by Watanabe and Ando (27), we believe that a heel is the best each step of article preparation, writing and corrections. Frontiers in Neurology | www.frontiersin.org 39 January 2016 | Volume 7 | Article 1