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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

What startles tell us about control of posture and gait

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Jorik Nonnekes a,∗ , Mark G. Carpenter b , J. Timothy Inglis b , Jacques Duysens c , Vivian Weerdesteyn a,d a

Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Rehabilitation, Nijmegen, The Netherlands School of Kinesiology, University of British Columbia, Vancouver, BC, Canada Research Center for Movement Control and Neuroplasticity, Department of Kinesiology, KU Leuven, Leuven, Belgium d Sint Maartenskliniek Research, Nijmegen, The Netherlands b c

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Article history: Received 8 September 2014 Received in revised form 12 March 2015 Accepted 3 April 2015 Available online xxx

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Keywords: Startle StartReact Postural control Gait

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Contents

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Recently, there has been an increase in studies evaluating startle reflexes and StartReact, many in tasks involving postural control and gait. These studies have provided important new insights. First, several experiments indicate a superimposition of startle reflex activity on the postural response during unexpected balance perturbations. Overlap in the expression of startle reflexes and postural responses emphasizes the possibility of, at least partly, a common substrate for these two types of behavior. Second, it is recognized that the range of behaviors, susceptible to StartReact, has expanded considerably. Originally this work was concentrated on simple voluntary ballistic movements, but gait initiation, online step adjustments and postural responses can be initiated earlier by a startling stimulus as well, indicating advanced motor preparation of posture and gait. Third, recent experiments on StartReact using TMS and patients with corticospinal lesions suggest that this motor preparation involves a close interaction between cortical and subcortical structures. In this review, we provide a comprehensive overview on startle reflexes, StartReact, and their interaction with posture and gait. © 2015 Published by Elsevier Ltd.

1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Startle reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Neural pathways and characteristics of the startle reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Modulation of startle reflex expression by posture and gait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Modulation of posture and gait by startle reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. StartReact effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Acceleration of reaction times by a startling stimulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Mechanisms underlying StartReact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Differences between startle reflexes and StartReact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. StartReacts effects observed during gait initiation and online step adjustments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. StartReact effects and postural responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction All of us have experienced the startling sensation of unexpected stimuli. Startling stimuli can result in a startle reflex, which is the

∗ Corresponding author. Tel.: +0031649732697. E-mail address: [email protected] (J. Nonnekes).

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fastest generalized motor reaction in humans and animals (VallsSole et al., 2008). Startling stimuli also have the ability to accelerate motor responses, a phenomenon termed StartReact (Carlsen et al., 2004b; Valls-Sole et al., 1999). Recently, there has been an increase in the number of studies evaluating startle reflexes and StartReact, many in tasks involving postural control and gait. These studies have helped to improve our understanding on the neural mechanisms underlying startle reflexes and StartReact, and also provided

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insight into the neural control of posture and gait. Here, a comprehensive review on startle reflexes, the StartReact effect, and their interaction with posture and gait is provided. 2. Startle reflexes 2.1. Neural pathways and characteristics of the startle reflex

A startle reflex is an involuntary motor reaction to unexpected sensory input and consists of a generalized flexion response 55 56 that follows a rostro-caudal progression (Brown et al., 1991a; 57 Chokroverty et al., 1992; Wilkins et al., 1986). Startle reflex activity 58 is most prominently seen in the sternocleidomastoid muscle. Sub59 sequently, the descending volley may activate more distal muscles 60 in the trunk and upper and lower extremities. A pure generalized 61 startle reflex is not always seen in both proximal and distal muscles 62 (Brown et al., 1991a). Startle reflex activity is thought to result from 63 the activation of reticulospinal motor tracts in the pontomedullary 64 reticular formation (pmRF), which in the case of auditory startle, 65 is triggered by direct synaptic activation from the cochlear nucleus 66 (Koch, 1999; Yeomans and Frankland, 1995). Importantly, neurons 67 of the pmRF are not modality specific, and therefore respond to 68 different types of afferent information (Wu et al., 1988). For exam69 ple, startle reflexes can be elicited by acoustic stimuli (Brown et al., 70 1991b), tactile stimuli (Gokin and Karpukhina, 1985), high inten71 sity visual stimuli (Bradley et al., 1990), and by stimulation of 72 the vestibular system via unexpected vertical drops of the body 73 (Bisdorff et al., 1995; Gruner, 1989). Startling stimuli do not only 74 result in startle reflexes, but also in blink responses due to acti75 vation of the orbicularis oculi muscle. Pathways underlying blink 76 responses are thought to be different from startle reflexes, involv77 ing neurons of the inferior colliculus and mesencephalic reticular 78 formation (Hori et al., 1986). 79 Habituation and prepulse inhibition are important characteris80 tics of startle reflexes. Habituation of startle reflexes is observed 81 when startling stimuli are given in repetition. Startle reflexes 82 decrease in amplitude with repeated exposure, and eventually only 83 the blink response will remain (Brown et al., 1991b). Habitua84 tion occurs most often after two to six presentations of a startling 85 stimulus, and is presumably the result of synaptic depression at 86 the pmRF (Chokroverty et al., 1992). Prepulse inhibition is the 87 inhibitory effect of a weak sensory signal given 30–500 ms prior to 88 the startling stimulus (Graham, 1975; Koch et al., 1993; Swerdlow, 89 2013). The neural pathways involved in prepulse inhibition likely 90 include the pedunculopontine nucleus (PPN) (Inglis and Winn, 91 1995; Koch, 1999), as studies in rats showed that PPN-lesions 92 abolish prepulse inhibition (Swerdlow and Geyer, 1993). For more 93 detailed information about prepulse inhibition and habituation of 94 startle reflexes, we refer to excellent reviews by Valls-Sole et al. 95Q3 (2008) and Carlsen et al. (2011). 54

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2.2. Modulation of startle reflex expression by posture and gait Studies that evaluated startle reflexes during gait and various postures have shown that the expression of startle reflex activity is modulated by afferent input. During gait, a phase dependent modulation of startle reflexes is observed, with more prominent startle reflexes in the stance leg compared to the swing leg (Nieuwenhuijzen et al., 2000; Schepens and Delwaide, 1995). Startle reflexes in lower leg muscles are more prevalent while standing compared to sitting, whereas rates of occurrence of reflex EMG activity in the sternocleidomastoid muscle do not differ between both postures (Brown et al., 1991a; Delwaide and Schepens, 1995). Moreover, shorter latencies of reflex EMG activity in leg muscles are observed while standing (70–95 ms) compared

to sitting (120 ms) (Brown et al., 1991a; Delwaide and Schepens, 1995). Finally, a recent study found that more subtle changes in posture, such as weight-bearing asymmetry, also influence startle reflex expression in leg muscles (Nonnekes et al., 2013d). It has been suggested by these authors that afferent loading information plays a critical role in the observed modulation of startle reflexes. Such information is provided by Ib-afferents from Golgi tendon organs and cutaneous mechanoreceptors in the foot soles (Dietz and Duysens, 2000; Duysens et al., 2000; Kavounoudias et al., 2001). Modulation of startle reflex activity by afferent loading information likely takes place at the spinal cord, as studies in cats indicated that symmetrical volleys from the pmRF are gated at premotoneural level by spinal interneuronal networks (Drew, 1991b; Schepens and Drew, 2006). 2.3. Modulation of posture and gait by startle reflexes Startle reflexes likely contribute to the large amplitude postural responses that are observed when balance is perturbed unexpectedly or for the first time in a series of perturbations (Campbell et al., 2013; Siegmund et al., 2008). Amplitudes of postural responses to balance perturbations are significantly larger during the first trial compared to subsequent trials involving the same postural stimulus, a phenomenon known as first trial effect (Allum et al., 2011). First trial effects are observed in whole body postural responses that occur when standing balance is perturbed (Allum et al., 2011; Bloem et al., 1998; Chong et al., 1999; Keshner et al., 1987; Oude Nijhuis et al., 2009, 2010; Tang et al., 2012), but also in postural responses in neck and trunk muscles that occur during seated perturbations (Blouin et al., 2006, 2007). These first trial effects have been suggested to result from summation of startle reflex activity on the basic postural response (Blouin et al., 2006; Campbell et al., 2013; Nanhoe-Mahabier et al., 2012; Siegmund et al., 2008). This hypothesis is supported by three observations. First, postural responses habituate after the first trial in a series of repeated perturbations, just like habituation of startle reflexes (Campbell et al., 2013; Oude Nijhuis et al., 2010). Habituation of postural responses could as such consist of the extinction of startle reflexes, leaving only the postural response (Siegmund et al., 2008). Second, early masseter activity after first trial perturbations might be indicative of a startle-like component contributing to balance responses (Visser et al., 2010), as early activation of this muscle is indicative of the presence of a startle reflex (Brown et al., 1991b). A third observation in support of startle-like components contributing to balance responses relates to coherence in EMG activity between bilateral neck muscles during rear-end perturbations (Blouin et al., 2006). An increased coherence in the 10–20 Hz bandwidth is observed after startling auditory stimuli, and is thought to represent increased reticulospinal activity (Grosse and Brown, 2003). During rear-end forward perturbations, an increased coherence in the 10–20 Hz bandwidth was seen during the first trial (Blouin et al., 2006). During subsequent habituated trials the synchrony between bilateral neck muscles decreased significantly, but reappeared when a startling acoustic stimulus was superimposed on the whiplash-like perturbation. Hence, these results also indicate a superimposition of startle reflex activity on the postural response during first trial perturbations. The above observations raise the question whether the summation of startle reflex activity on the basic postural response results in functional benefits. The function of the startle reflex could lie in the rapid accomplishment of a defensive posture (Brown et al., 1991a; Nonnekes et al., 2013d), yet in modern life, summation of startle reflexes and postural responses might have disadvantages as well. The expression of startle reflexes following rear-end collisions has been suggested to contribute to increased forces and strains in neck tissues, leading to whiplash injuries (Mang et al.,

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2012). In the same way, a startle reflex overlaid onto a normal postural response may be detrimental to balance, if it interferes with the planned amplitude, direction and inter-segmental coordination between limbs. Indeed, center of mass deviations are larger during first trial perturbations compared to habituated postural responses (Oude Nijhuis et al., 2010). Hence, the generalized startle reflexes induced by highly unexpected perturbations appear to reduce the net effect of appropriate corrective responses, which comes to the detriment of postural stability.

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When a startling stimulus is presented in a reaction time task together with the imperative stimulus, reaction times are significantly accelerated, a phenomenon known as StartReact (Carlsen et al., 2012; Valls-Sole et al., 2008, 1999). In addition to an acceleration of reaction times, an increase in EMG amplitudes and muscle force has also been reported for StartReact experiments (Anzak et al., 2011; Kumru et al., 2006; Queralt et al., 2008). The first StartReact experiments involved the acceleration of voluntary arm movements and voluntary rising onto the toes from a standing position (Valls-Sole et al., 1999, 1995). These studies showed that a startling acoustic stimulus (SAS) accelerates movement latencies without changing the basic spatiotemporal pattern of muscle activation of the movement involved. Based on this observation, it was argued that SAS releases a pre-prepared motor program, rather than simply superimposing reflex activity on the intended movement. To test this hypothesis, Carlsen et al. (2004b) evaluated StartReact effects on a series of arm movements to targets of 20, 40 and 60 degrees. When a 20 degrees movement was prepared, a SAS resulted in a 20 degrees movement with its associated EMG pattern. However, when a 40 or 60 degrees movement was pre-planned, the EMG pattern was in accordance with the 40 or 60 degrees movement, providing evidence for release of a pre-prepared motor program by a startling stimulus. This notion is further supported by the observation that a SAS, in the absence of the imperative stimulus, can elicit the planned movement, which is not observed when a SAS is given in isolation prior to the experiment (Kumru and Valls-Sole, 2006; Valls-Sole, 2004). A second study by Carlsen et al. (2004a) evaluated the StartReact effect in a simple and choice reaction task. Since motor preparation does not generally occur during a choice reaction task, it was hypothesized that StartReact would not be observed during a choice reaction task. Indeed, a SAS only accelerated latencies during the simple reaction task and not during the choice reaction task. Subsequent studies did report acceleration of reaction times in some choice reaction tasks (Kumru and Valls-Sole, 2006; MacKinnon et al., 2007; Oude Nijhuis et al., 2007), but this came at the expense of response errors. These observations suggest that subjects may prefer to pre-plan a movement sequence in advance, even if that plan may be potentially incorrect. Hence, the observed StartReact effects during choice reaction tasks also indicate that motor preparation is a prerequisite for the acceleration of reaction times by a SAS. 3.2. Mechanisms underlying StartReact Although there is general consensus that StartReact is due to release of a pre-prepared motor program by a startling stimulus, the neural structures involved are still a matter of ongoing debate. Three hypotheses have been proposed to explain the mechanism underlying StartReact. First, a SAS could act as an additional stimulus on top of the imperative stimulus, thereby increasing

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Fig. 1. Potential mechanisms underlying StartReact (in part modified from Alibiglou and MacKinnon, 2012).

the energy of the sensory input, a process known as intersensory facilitation (Nickerson, 1973). Intersensory facilitation could subsequently result in an acceleration of sensorimotor coupling at the cortical level, resulting in accelerated release of motor programs, conveyed by the corticospinal tract (see Fig. 1A). However, it has been reported that reaction time shortening during a StartReact experiment is not dependent on the intensity of the stimulus, but rather on whether the stimulus is perceived as startling (Carlsen et al., 2007). Another argument against the intersensory facilitation hypothesis comes from the observation that a SAS can trigger the requested movement at similarly short latencies when applied in the absence of the imperative signal (Kumru and Valls-Sole, 2006; Nonnekes et al., 2013c; Queralt et al., 2008; Valls-Sole, 2004). The second hypothesis on StartReact proposes that a SAS directly releases a subcortically stored motor program (Carlsen et al., 2004b; Valls-Sole et al., 1999), which is conveyed by the reticulospinal tract (see Fig. 1B) (Rothwell, 2006). This hypothesis has

Please cite this article in press as: Nonnekes, J., et al., What startles tell us about control of posture and gait. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.04.002

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been proposed as latencies of the fastest StartReact effects seem to be too fast to involve the motor cortex (Valls-Sole et al., 1999). Moreover, onsets of muscles involved in StartReact effects tend to have the same latency as those seen in a startle reflex, indicating conduction by the reticulospinal tract (Valls-Sole et al., 1999). Recent evidence supporting this notion has been developed from studies using two clinical patient models. In chronic stroke patients, it was first found that StartReact responses are intact for elbow flexion and extension movements (Honeycutt and Perreault, 2012). For elbow flexion, there were no differences in either onset latency of muscle activation patterns between stroke patients and controls. During elbow extension, a SAS exhibited inappropriate activity in the flexors, but this diminished over time, leaving a normal muscle activation pattern. Likely, inappropriate startle reflex activity was seen during the first elbow extension trials, which habituated over time (Honeycutt and Perreault, 2012). More recently, it has been shown that StartReact effects on hand extension movements are intact in most stroke patients as well (Honeycutt et al., 2014). These results can be interpreted in favor of a SAS releasing a motor program from a subcortical level, but one has to acknowledge that stroke patients have remaining cortical connections, which leaves the possibility that a SAS releases a cortically stored motor program conveyed by these residual corticospinal fibers (see below). StartReact effects were also studied in patients with hereditary spastic paraplegia (HSP) (Fisher et al., 2013; Nonnekes et al., 2014c). HSP is a disease characterized by retrograde axonal degeneration of the corticospinal tract (Bonsch et al., 2003; Jorgensen et al., 2005; Nardone and Tezzon, 2003; Pelosi et al., 1991; Polo et al., 1993; Sartucci et al., 2007), while leaving the reticulospinal tract unaffected (Nonnekes et al., 2013b, 2014c). Typically, HSP in its pure form does not affect the corticospinal tract to the upper extremities (Jorgensen et al., 2005; Pelosi et al., 1991; Polo et al., 1993; Sartucci et al., 2007) (see Fig. 2A). StartReact effects in patients with pure HSP were compared to those in age-matched controls using a reaction task involving ankle dorsiflexion and a second reaction task involving wrist flexion (Nonnekes et al., 2014c). Ankle dorsiflexion reaction times were delayed in patients with HSP compared to controls, in line with delayed motor evoked potentials in tibialis anterior in response to supramaximal transcranial magnetic stimulation (TMS). However, when the ankle dorsiflexion task was combined with a SAS, reaction times were accelerated in both patients with HSP and controls, but to a larger extent in patients with HSP, resulting in completely normalized EMG and movement onset latencies (see Fig. 2B). When the reaction time task involved voluntary wrist flexion, no differences in onset latencies between patients with HSP and controls were observed, irrespective of the presence of a SAS. This observed pattern of results was interpreted by the authors in favor of a SAS releasing a subcortically stored motor program, conveyed by the reticulospinal tract. The third hypothesis on StartReact proposes that the SAS could act as a subcortically mediated trigger for a cortically stored motor program (Alibiglou and MacKinnon, 2012; Carlsen et al., 2012), conveyed by the corticospinal tract (see Fig. 1C). The latter hypothesis is supported by three recent studies that evaluated the effect of TMS on the StartReact effect (Alibiglou and MacKinnon, 2012; Marinovic et al., 2014; Stevenson et al., 2014). Alibiglou and MacKinnon (2012) showed that a single, suprathreshold pulse of TMS delivered over the primary motor cortex delayed reaction times to a startling stimulus. These findings were replicated in a subsequent study that demonstrated longer delays in reaction times with shorter time between the TMS pulse and the startling stimulus (Stevenson et al., 2014). Finally, Marinovic et al. (2014) found that during preparation for anticipatory movements, the net excitability of the corticospinal pathway is enhanced shortly after a loud acoustic stimulus is presented.

Evidence for a cortical role in the StartReact effect is also provided by a recent study that evaluated movement-related EEG potentials during motor preparation. MacKinnon and colleagues showed that under preparatory conditions in which the timing of onset of the imperative cue could be predicted in advance, the presentation of a SAS could release a planned movement sequence as early as 1.5 s prior to the expected cue (MacKinnon et al., 2013). Importantly, the incidence of release significantly increased during cortical motor preparation (as indicated by the Contingent Negative Variation (CNV) in the movement-related EEG). For conditions in which the timing of the imperative cue could not be predicted, SAS-evoked reaction times of less than 100 ms were significantly less common and movement-related EEG potentials were markedly reduced compared to the condition in which the timing of the imperative cue could be predicted. These findings therefore suggest that motor preparation at the cortical level prior to an imperative stimulus sets a modulatory state for the early and unintentional release of the planned action. Despite these seemingly contrasting hypotheses, however, involvement of the cortex in the StartReact effect and the suggested mechanism of a subcortical motor program being released by a SAS are not mutually exclusive. The delaying effect of TMS on SAS-induced acceleration of motor responses may be explained by the fact that TMS over the motor cortex not only has inhibiting effects on the cortical neurons, but also on cells within the reticular formation (Fisher et al., 2012). In addition, the observation that cortical motor preparation was associated with a greater probability of advanced release of the prepared movement (MacKinnon et al., 2013) neither excludes a subcortical pathway underlying the StartReact effect. The modulatory state for the release of planned action may not be restricted to the motor cortex, as the incidence of SAS-induced startle reflexes also increases with greater motor preparedness (Carlsen and MacKinnon, 2010). Q4 On the other hand, the completely normal SAS-induced reaction times in people with cortical lesions or corticospinal degeneration do not seem to be compatible with a transcortical pathway (Honeycutt and Perreault, 2012; Honeycutt et al., 2014; Nonnekes et al., 2014). Hence, the current body of evidence seems to favor the hypothesis of the SAS releasing a prepared movement through a subcortical pathway. However, we suggest the cortex to play a critical role in the StartReact phenomenon by altering the state of the involved subcortical structures, which is in line with the model recently proposed by Shemmell (2015). Future studies need to further unravel the exact neural pathways involved in StartReact. The pmRF may be regarded as a candidate subcortical structure in this respect, as it not only constitutes a key structure in the startle reflex circuitry, but has also been demonstrated in studies in monkeys and cats to be involved in motor preparation (Buford and Davidson, 2004; Schepens and Drew, 2004). 3.3. Differences between startle reflexes and StartReact There are several observations that suggest that startle reflexes and StartReact effects are at least partly dissociated. First, while prepulse inhibition modifies startle reflexes, it does not appear to influence the StartReact effect (Valls-Sole et al., 2005). Second, startle reflexes in the sternocleidomastoid muscle do not seem to be a requirement for StartReact effects. Although Carlsen et al. (2007) reported an attenuation of StartReact effects when no reflex activity was observed in the sternocleidomastoid muscle, several other studies have not found a significant relationship between reflex activity in the sternocleidomastoid muscle and StartReact, both for experiments involving simple reaction time tasks (Nonnekes et al., 2014c), and for tasks involving gait and postural responses (Campbell et al., 2013; MacKinnon et al., 2007; Nonnekes et al., 2014c, 2013c; Reynolds and Day, 2007; Rogers et al., 2011).

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Fig. 2. (A) Schematic diagram of the neurologic disruption in patients with HSP. CST = corticospinal tract. RST = reticulospinal tract. In patients with HSP, the reticulospinal tract is intact, but there is retrograde axonal degeneration of the corticospinal tract (schematically represented by the dotted line). Typically, HSP in its pure form does not affect the corticospinal tract to the upper extremities. (B) Mean onset latencies (SE) during the simple reaction time tasks involving voluntary ankle dorsiflexion (upper graphs) and wrist flexion (lower graphs) in patients with HSP and age-matched controls. * indicates significant differences between trials with and without a SAS. + indicates a s significant SAS × group interaction. This figure is reprinted from Nonnekes et al. (2014c) in agreement with the journal’s policy. 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407

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A final observation in support of dissociated processes between startle reflexes and StartReact comes from a study in patients with Parkinson’s disease and severe freezing of gait (Thevathasan et al., 2011). In these patients, StartReact effects and startle reflexes were reported to be absent, but deep brain stimulation of the PPN selectively restored StartReact effects, while leaving the impairment in startle reflexes unchanged. Interestingly, the StartReact effect has also been observed in response to lower-intensity stimuli not usually regarded as startling in nature, with the likelihood of early release of the prepared movement being related to the strength of the stimulus (Delval et al., 2012). StartReact paradigms typically apply acoustic stimuli at ∼120 dB, which intensity is large enough not only to release the prepared movement, but also to overcome the neural thresholds in the startle circuitry at the pmRF, resulting in a startle reflex. In the study of Delval et al. (2012), however, an 80 dB acoustic stimulus resulted in a fair proportion (29%) of trials with early release of the prepared motor response, and it also evoked a startle reflex in SCM in 18% of the trials (with 27% overlap between these events). These observations indicate that the preparatory motor state dramatically reduced the neural thresholds of StartReact and startle reflex circuitry (described as a progressive ‘releasing of the brakes’) (MacKinnon et al., 2013). The relatively small proportion of trials with both early release of the prepared motor response and a startle reflex in SCM, however, suggest that the neural thresholds of these circuits may differ to some extent. This notion further supports the postulated dissociation between startle reflexes and the StartReact phenomenon. 3.4. StartReacts effects observed during gait initiation and online step adjustments Following the observation of startle-induced acceleration of simple reactive movements, several groups investigated whether StartReact effects can also be induced during more complex movements, such as gait under a variety of conditions involving preplanning of movement. It was shown that StartReact was also applicable to two aspects of gait: gait initiation and online step adjustments (MacKinnon et al., 2007; Queralt et al., 2008;

Reynolds and Day, 2007). Gait initiation involves anticipatory postural adjustments (APAs) that propel the body mass forward and laterally to unload the swing leg (Massion, 1992). Interestingly, these APAs can be significantly accelerated by a startling stimulus (Delval et al., 2012; MacKinnon et al., 2007), which suggests postural preparation before a step is made. The application of StartReact has more recently been used to study gait initiation in patients with Parkinson’s disease (PD). Impairments during gait initiation are common in patients with PD and include reduced step length and small APAs (Burleigh-Jacobs et al., 1997; Gantchev et al., 1996; Mille et al., 2007). In the more advanced stages, freezing of gait can emerge. Freezing of gait is characterized by sudden, relatively brief episodes of an inability to step or by extremely short steps (Nutt et al., 2011). StartReact experiments have been used to study whether deficient motor preparation contributes to freezing of gait. Intact startle-induced acceleration of APAs has been observed in PD-patients without freezing of gait (Fernandez-Del-Olmo et al., 2012; Nonnekes et al., 2014b; Rogers et al., 2011), indicating preserved motor preparation. Interestingly, reduced StartReact effects of APAs have been reported in PD-patients with freezing of gait (Nonnekes et al., 2014b). Hence, in these patients, the APA to initiate a step may not be properly prepared in advance. An alternative explanation for the reduced StartReact effect in freezers may be that the reflexive release of motor responses is deficient due to subcortical structures being less responsive to excitatory stimuli. Although not confirmed yet, the finding of reduced StartReact effects in freezers could be relevant to the mechanisms underlying freezing of gait. Subcortical structures, in particular the pmRF and PPN, are involved in the integration of APAs with subsequent stepping movements (la Fougere et al., 2010; Musienko et al., 2008; Nutt et al., 2011; Schepens et al., 2008). Deficiencies in APA representation or release at the subcortical level could hamper the integration with subsequent steps, finally leading to the freezing of gait. However, future studies are needed to investigate this hypothesis. As mentioned above, StartReact effects are also observed during online step adjustments (Queralt et al., 2008; Reynolds and Day, 2007). Reynolds and Day (2007) evaluated the effect of a SAS on stepping adjustments in the medial or lateral direction, responses

Please cite this article in press as: Nonnekes, J., et al., What startles tell us about control of posture and gait. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.04.002

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that are thought to be organized at subcortical level (Reynolds and Day, 2012). Interestingly, startle-induced shortening of reaction times was observed, even though the direction of the adjustments was not known in advance. Queralt et al. (2008) studied step adjustments in the sagittal plane in response to a sudden obstacle while participants walked on a treadmill. In their study, obstacles were released in specific moments of the step cycle, accompanied by a SAS (40 ms after obstacle release) in 25% of the trials. Contact of the foot with the obstacle could be avoided by either lengthening or shortening of the ongoing stride, the likelihood of which depended on the moment of obstacle release. Results showed that both shortening and lengthening of the stride was accelerated in trials in which a SAS was applied. Step adjustments in the same direction were also observed when the SAS was presented in the absence of obstacle release, but at the same moment in the step cycle. The latter observations suggest that during gait, motor preparation for online gait adjustments takes place in advance. We hypothesize that a startling stimulus releases a motor program for the online step adjustment, which is further modulated at the level of the spinal cord, depending on the phase of the gaitcycle, yielding either shortening or lengthening of the stride. This hypothesis is supported by studies in cats, which reported that descending activity can be manipulated by spinal structures, providing activation or suppression of motoneurons, depending on the phase requirements (Drew, 1991a). The observation that directionally appropriate on-line step adjustments to sudden medial or lateral target jumps were also susceptible to StartReact (Reynolds and Day, 2007), raises the intriguing question whether there may be a subcortical pathway for visual control of the lower extremity. The role of the collicular circuitry in the generation of arm reaching movements is well established and a link to leg movements has been suggested (through projections to the cuneiform nucleus, Philipp and Hoffmann, 2014).

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conditioned response. Interestingly, a SAS induced significantly earlier onsets of conditioned postural responses compared to the auditory tone, hinting toward advanced preparation of postural responses. A second argument for such preparation came from a study that evaluated whether automatic postural responses to balance perturbations can be accelerated by a SAS (Nonnekes et al., 2013c). In this study, postural responses to backward and forward perturbations were induced by a balance platform that could translate in the forward or backward direction, respectively (Nonnekes et al., 2013a). In 25% of balance perturbations, a SAS was given at the start of platform translation. Postural responses to backward perturbations could be significantly accelerated by a SAS, both when a backward perturbation was expected, but also when perturbation direction was not known in advance. In line with the study of Campbell et al. (2012), a SAS yielded postural responses at similar latencies in the absence compared to those in the presence of a balance perturbation, and both these latencies similarly scaled with perturbation intensity. Interestingly, a SAS did not shorten postural responses to forward perturbations (Nonnekes et al., 2013c), this finding being replicated in a subsequent study by the same group (Nonnekes et al., 2014a). While the latter study demonstrated a directional specificity of StartReact effects on postural responses in the sagittal plane, subsequent work has shown that postural responses can be accelerated by a startling stimulus in the lateral direction as well (Campbell, 2012). Hence, backward and sideways perturbations are susceptible to StartReact, while forward responses are not. The mechanism responsible for this directional specificity of StartReact in postural responses is not yet understood. It may be that postural responses in forward, backward and sideways directions involve different neural circuits, with startle circuits selectively interacting with postural responses to recover from backward and sideways perturbations (Nonnekes et al., 2013c).

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The relationship between StartReact and postural responses has been explored in two ways. First, it has been investigated whether postural perturbations can induce StartReact effects. As outlined in Section 2.3 of this review, there is evidence for superposition of startle reflex activity on the postural response, in particular following the very first trial of an unexpected balance perturbation. The suggestion that a postural perturbation can act as a startling stimulus was recently tested in two studies that applied a postural perturbation to induce StartReact effects. Indeed, whole body balance perturbations were shown to elicit StartReact effects on wrist extension movements (Campbell et al., 2013). Similarly, rapid perturbations of arm posture induced StartReact effects on elbow extension movements as well (Ravichandran et al., 2013). Hence, these observations provide further evidence for the startling nature of unexpected postural perturbations. Second, studies have investigated whether motor preparation also takes place for postural responses to external balance perturbations, yielding these responses susceptible to acceleration by a SAS. In contrast to voluntary reactions in response to an imperative auditory or visual stimulus, automatic postural responses do not involve transcortical pathways (Jacobs and Horak, 2007; Quant et al., 2004; Taube et al., 2006), but are likely encoded by assemblies of neurons in the pmRF (Stapley and Drew, 2009). However, three parallel studies (Campbell, 2012; Campbell et al., 2012; Nonnekes et al., 2013c) demonstrated that these automatic postural responses can still be accelerated by a SAS. Campbell and colleagues evaluated the effect of auditory stimuli after repeated cued sideways perturbations. A nonstartling auditory tone was able to evoke a postural response in the absence of a perturbation (Campbell et al., 2012), indicating the presence of a classically

Recent work on startle reflexes and StartReact has provided important new insights into the neural mechanisms underlying startle reflexes and StartReact, and have contributed to our understanding of control of posture and gait. First, studies using patients with corticospinal lesions support a mechanism for StartReact that incorporates a motor program that is stored in subcortical centers and triggered by a startling stimulus. Experiments using TMS suggest that the cortex plays a critical role in the StartReact phenomenon, possibly by altering the state of the involved subcortical structures. Second, it is recognized that the behaviors susceptible to StartReact have expanded considerably, now also involving postural control and gait. Originally this work was concentrated on simple voluntary movements, but in recent years it has been shown that gait initiation, online step adjustments and postural responses to backward and sideways perturbations can be speeded up by a startling stimulus as well. This indicates that advanced motor preparation takes place for these elements of postural control and gait. This preparation presumably involves a close interaction between cortical and subcortical structures. However, the exact neural pathways involved in advanced motor preparation of posture and gait remain to be unraveled by future studies. In light of our understanding of the mechanisms involved in StartReact, these results support the growing body of evidence for the cortical and subcortical contributions to balance and gait (Adkin et al., 2006; Campbell et al., 2009; Jacobs and Horak, 2007; Marlin et al., 2014; Nonnekes et al., 2010; Quant et al., 2004; Reynolds and Day, 2005). Third, several studies indicate a superimposition of startle reflex activity on the postural response during first trial balance perturbations. The summation of startle reflex activity on

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the postural response can be detrimental for postural stability if it interferes with the amplitude and direction of the balance correcting response. The growing number of studies in this area of research has also raised several new questions on posture and gait control, including the mechanisms underlying the directional specificity of SAS-induced acceleration of postural responses and the susceptibility of visually-guided step adjustments to StartReact, which are suggested topics for further research. Uncited references Cruccu and Hallett (2006), Nonnekes et al. (2014d). References Adkin, A.L., Quant, S., Maki, B.E., McIlroy, W.E., 2006. Cortical responses associated with predictable and unpredictable compensatory balance reactions. Exp. Brain Res. 172, 85–93. Alibiglou, L., MacKinnon, C.D., 2012. The early release of planned movement by acoustic startle can be delayed by transcranial magnetic stimulation over the motor cortex. J. Physiol. 590, 919–936. Allum, J.H., Tang, K.S., Carpenter, M.G., Oude Nijhuis, L.B., Bloem, B.R., 2011. Review of first trial responses in balance control: influence of vestibular loss and Parkinson’s disease. Hum. Mov. Sci. 30, 279–295. Anzak, A., Tan, H.L., Pogosyan, A., Brown, P., 2011. Doing better than your best: loud auditory stimulation yields improvements in maximal voluntary force. Exp. Brain Res. 208, 237–243. Bisdorff, A.R., Bronstein, A.M., Gresty, M.A., Wolsley, C.J., Davies, A., Young, A., 1995. EMG-responses to sudden onset free fall. Acta Otolaryngol. Suppl. 520 (Pt 2), 347–349. Bloem, B.R., Beckley, D.J., van Hilten, B.J., Roos, R.A., 1998. Clinimetrics of postural instability in Parkinson’s disease. J. Neurol. 245, 669–673. Blouin, J.S., Inglis, J.T., Siegmund, G.P., 2006. Startle responses elicited by whiplash perturbations. J. Physiol. 573, 857–867. Blouin, J.S., Siegmund, G.P., Inglis, J.T., 2007. Interaction between acoustic startle and habituated neck postural responses in seated subjects. J. Appl. Physiol. 102, 1574–1586. Bonsch, D., Schwindt, A., Navratil, P., Palm, D., Neumann, C., Klimpe, S., Schickel, J., Hazan, J., Weiller, C., Deufel, T., Liepert, J., 2003. Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene. J. Neurol. Neurosurg. Psychiatry 74, 1109–1112. Bradley, M.M., Cuthbert, B.N., Lang, P.J., 1990. Startle reflex modification: emotion or attention? Psychophysiology 27, 513–522. Brown, P., Day, B.L., Rothwell, J.C., Thompson, P.D., Marsden, C.D., 1991a. The effect of posture on the normal and pathological auditory startle reflex. J. Neurol. Neurosurg. Psychiatry 54, 892–897. Brown, P., Rothwell, J.C., Thompson, P.D., Britton, T.C., Day, B.L., Marsden, C.D., 1991b. New observations on the normal auditory startle reflex in man. Brain 114 (Pt 4), 1891–1902. Buford, J.A., Davidson, A.G., 2004. Movement-related and preparatory activity in the reticulospinal system of the monkey. Exp. Brain Res. 159, 284–300. Burleigh-Jacobs, A., Horak, F.B., Nutt, J.G., Obeso, J.A., 1997. Step initiation in Parkinson’s disease: influence of levodopa and external sensory triggers. Mov. Disord. 12, 206–215. Campbell, A.D., Dakin, C.J., Carpenter, M.G., 2009. Postural responses explored through classical conditioning. Neuroscience 164, 986–997. Campbell, A.D., Chua, R., Inglis, J.T., Carpenter, M.G., 2012. Startle induces early initiation of classically conditioned postural responses. J. Neurophysiol. 108, 2946–2956. Campbell, A.D., Squair, J.W., Chua, R., Inglis, J.T., Carpenter, M.G., 2013. First trial and StartReact effects induced by balance perturbations to upright stance. J. Neurophysiol. 110, 2236–2245. Campbell, A.D., 2012. Insight into Human Dynamic Balance Control: Postural Response Initiation Explored Through Classical Conditioning and Startle. University of British Columbia, Columbia, Thesis. Carlsen, A.N., Chua, R., Inglis, J.T., Sanderson, D.J., Franks, I.M., 2004a. Can prepared responses be stored subcortically? Exp. Brain Res. 159, 301–309. Carlsen, A.N., Chua, R., Inglis, J.T., Sanderson, D.J., Franks, I.M., 2004b. Prepared movements are elicited early by startle. J. Mot. Behav. 36, 253–264. Carlsen, A.N., Dakin, C.J., Chua, R., Franks, I.M., 2007. Startle produces early response latencies that are distinct from stimulus intensity effects. Exp. Brain Res. 176, 199–205. Carlsen, A.N., Maslovat, D., Lam, M.Y., Chua, R., Franks, I.M., 2011. Considerations for the use of a startling acoustic stimulus in studies of motor preparation in humans. Neurosci. Biobehav. Rev. 35, 366–376. Carlsen, A.N., Maslovat, D., Franks, I.M., 2012. Preparation for voluntary movement in healthy and clinical populations: evidence from startle. Clin. Neurophysiol. 123, 21–33. Chokroverty, S., Walczak, T., Hening, W., 1992. Human startle reflex—technique and criteria for abnormal response. Electroencephalogr. Clin. Neurophysiol. 85, 236–242.

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Please cite this article in press as: Nonnekes, J., et al., What startles tell us about control of posture and gait. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.04.002

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What startles tell us about control of posture and gait.

Recently, there has been an increase in studies evaluating startle reflexes and StartReact, many in tasks involving postural control and gait. These s...
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