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Neuroscience and Biobehavioral Reviews 53 (2015) 131–138

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

jou rn al h om epage: www.elsev ier .com/ locate /neubiorev

hat startles tell us about control of posture and gait

orik Nonnekesa,∗, Mark G. Carpenterb, J. Timothy Inglisb, Jacques Duysensc,ivian Weerdesteyna,d

Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Rehabilitation, Nijmegen, The NetherlandsSchool of Kinesiology, University of British Columbia, Vancouver, BC, CanadaResearch Center for Movement Control and Neuroplasticity, Department of Kinesiology, KU Leuven, Leuven, BelgiumSint Maartenskliniek Research, Nijmegen, The Netherlands

r t i c l e i n f o

rticle history:eceived 8 September 2014eceived in revised form 12 March 2015ccepted 3 April 2015vailable online 13 April 2015

eywords:tartle

a b s t r a c t

Recently, there has been an increase in studies evaluating startle reflexes and StartReact, many in tasksinvolving postural control and gait. These studies have provided important new insights. First, sev-eral experiments indicate a superimposition of startle reflex activity on the postural response duringunexpected balance perturbations. Overlap in the expression of startle reflexes and postural responsesemphasizes 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. Orig-inally this work was concentrated on simple voluntary ballistic movements, but gait initiation, online

tartReactostural controlait

step adjustments and postural responses can be initiated earlier by a startling stimulus as well, indicat-ing advanced motor preparation of posture and gait. Third, recent experiments on StartReact using TMSand patients with corticospinal lesions suggest that this motor preparation involves a close interactionbetween cortical and subcortical structures. In this review, we provide a comprehensive overview onstartle reflexes, StartReact, and their interaction with posture and gait.

© 2015 Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312. Startle reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

2.1. Neural pathways and characteristics of the startle reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322.2. Modulation of startle reflex expression by posture and gait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322.3. Modulation of posture and gait by startle reflexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

3. StartReact effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333.1. Acceleration of reaction times by a startling stimulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333.2. Mechanisms underlying StartReact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333.3. Differences between startle reflexes and StartReact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353.4. StartReacts effects observed during gait initiation and online step adjustments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353.5. StartReact effects and postural responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

. Introduction fastest generalized motor reaction in humans and animals (Valls-

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

∗ Corresponding author.E-mail address: jorik.nonnekes@radboudumc.nl (J. Nonnekes).

ttp://dx.doi.org/10.1016/j.neubiorev.2015.04.002149-7634/© 2015 Elsevier Ltd. All rights reserved.

Sole et al., 2008). Startling stimuli also have the ability to acceleratemotor responses, a phenomenon termed StartReact (Carlsen et al.,2004b; Valls-Sole et al., 1999). Recently, there has been an increasein the number of studies evaluating startle reflexes and StartReact,

many in tasks involving postural control and gait. These studieshave helped to improve our understanding on the neural mecha-nisms underlying startle reflexes and StartReact, and also provided

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nsight into the neural control of posture and gait. Here, a compre-ensive review on startle reflexes, the StartReact effect, and their

nteraction with posture and gait is provided.

. Startle reflexes

.1. Neural pathways and characteristics of the startle reflex

A startle reflex is an involuntary motor reaction to unex-ected sensory input and consists of a generalized flexion responsehat follows a rostro-caudal progression (Brown et al., 1991a;hokroverty et al., 1992; Wilkins et al., 1986). Startle reflex activity

s most prominently seen in the sternocleidomastoid muscle. Sub-equently, the descending volley may activate more distal musclesn the trunk and upper and lower extremities. A pure generalizedtartle reflex is not always seen in both proximal and distal musclesBrown et al., 1991a). Startle reflex activity is thought to result fromhe activation of reticulospinal motor tracts in the pontomedullaryeticular formation (pmRF), which in the case of auditory startle,s triggered by direct synaptic activation from the cochlear nucleusKoch, 1999; Yeomans and Frankland, 1995). Importantly, neuronsf the pmRF are not modality specific, and therefore respond toifferent types of afferent information (Wu et al., 1988). For exam-le, startle reflexes can be elicited by acoustic stimuli (Brown et al.,991b), tactile stimuli (Gokin and Karpukhina, 1985), high inten-ity visual stimuli (Bradley et al., 1990), and by stimulation ofhe vestibular system via unexpected vertical drops of the bodyBisdorff et al., 1995; Gruner, 1989). Startling stimuli do not onlyesult in startle reflexes, but also in blink responses due to acti-ation of the orbicularis oculi muscle. Pathways underlying blinkesponses are thought to be different from startle reflexes, involv-ng neurons of the inferior colliculus and mesencephalic reticularormation (Hori et al., 1986).

Habituation and prepulse inhibition are important characteris-ics of startle reflexes. Habituation of startle reflexes is observedhen startling stimuli are given in repetition. Startle reflexesecrease in amplitude with repeated exposure, and eventually onlyhe blink response will remain (Brown et al., 1991b). Habitua-ion occurs most often after two to six presentations of a startlingtimulus, and is presumably the result of synaptic depression athe pmRF (Chokroverty et al., 1992). Prepulse inhibition is thenhibitory effect of a weak sensory signal given 30–500 ms prior tohe startling stimulus (Graham, 1975; Koch et al., 1993; Swerdlow,013). The neural pathways involved in prepulse inhibition likely

nclude the pedunculopontine nucleus (PPN) (Inglis and Winn,995; Koch, 1999), as studies in rats showed that PPN-lesionsbolish prepulse inhibition (Swerdlow and Geyer, 1993). For moreetailed information about prepulse inhibition and habituation oftartle reflexes, we refer to excellent reviews by Valls-Sole et al.2008) and Carlsen et al. (2011).

.2. Modulation of startle reflex expression by posture and gait

Studies that evaluated startle reflexes during gait and variousostures have shown that the expression of startle reflex activity

s modulated by afferent input. During gait, a phase dependentodulation of startle reflexes is observed, with more promi-

ent startle reflexes in the stance leg compared to the swingeg (Nieuwenhuijzen et al., 2000; Schepens and Delwaide, 1995).tartle reflexes in lower leg muscles are more prevalent whiletanding compared to sitting, whereas rates of occurrence of

eflex EMG activity in the sternocleidomastoid muscle do not dif-er between both postures (Brown et al., 1991a; Delwaide andchepens, 1995). Moreover, shorter latencies of reflex EMG activityn leg muscles are observed while standing (70–95 ms) compared

avioral Reviews 53 (2015) 131–138

to sitting (120 ms) (Brown et al., 1991a; Delwaide and Schepens,1995). Finally, a recent study found that more subtle changes inposture, such as weight-bearing asymmetry, also influence startlereflex expression in leg muscles (Nonnekes et al., 2013d). It hasbeen suggested by these authors that afferent loading informationplays a critical role in the observed modulation of startle reflexes.Such information is provided by Ib-afferents from Golgi tendonorgans and cutaneous mechanoreceptors in the foot soles (Dietzand Duysens, 2000; Duysens et al., 2000; Kavounoudias et al., 2001).Modulation of startle reflex activity by afferent loading informationlikely takes place at the spinal cord, as studies in cats indicated thatsymmetrical volleys from the pmRF are gated at premotoneurallevel by spinal interneuronal networks (Drew, 1991; Schepens andDrew, 2006).

2.3. Modulation of posture and gait by startle reflexes

Startle reflexes likely contribute to the large amplitude posturalresponses that are observed when balance is perturbed unexpect-edly or for the first time in a series of perturbations (Campbell et al.,2013; Siegmund et al., 2008). Amplitudes of postural responses tobalance perturbations are significantly larger during the first trialcompared to subsequent trials involving the same postural stimu-lus, a phenomenon known as first trial effect (Allum et al., 2011).First trial effects are observed in whole body postural responsesthat occur when standing balance is perturbed (Allum et al., 2011;Bloem et al., 1998; Chong et al., 1999; Keshner et al., 1987; OudeNijhuis et al., 2009, 2010; Tang et al., 2012), but also in posturalresponses in neck and trunk muscles that occur during seated per-turbations (Blouin et al., 2006, 2007). These first trial effects havebeen suggested to result from summation of startle reflex activ-ity on the basic postural response (Blouin et al., 2006; Campbellet al., 2013; Nanhoe-Mahabier et al., 2012; Siegmund et al., 2008).This hypothesis is supported by three observations. First, posturalresponses habituate after the first trial in a series of repeated per-turbations, just like habituation of startle reflexes (Campbell et al.,2013; Oude Nijhuis et al., 2010). Habituation of postural responsescould as such consist of the extinction of startle reflexes, leavingonly the postural response (Siegmund et al., 2008). Second, earlymasseter activity after first trial perturbations might be indica-tive of a startle-like component contributing to balance responses(Visser et al., 2010), as early activation of this muscle is indicativeof the presence of a startle reflex (Brown et al., 1991b). A thirdobservation in support of startle-like components contributing tobalance responses relates to coherence in EMG activity betweenbilateral neck muscles during rear-end perturbations (Blouin et al.,2006). An increased coherence in the 10–20 Hz bandwidth isobserved after startling auditory stimuli, and is thought to rep-resent increased reticulospinal activity (Grosse and Brown, 2003).During rear-end forward perturbations, an increased coherence inthe 10–20 Hz bandwidth was seen during the first trial (Blouinet al., 2006). During subsequent habituated trials the synchronybetween bilateral neck muscles decreased significantly, but reap-peared when a startling acoustic stimulus was superimposed onthe whiplash-like perturbation. Hence, these results also indicate asuperimposition of startle reflex activity on the postural responseduring first trial perturbations.

The above observations raise the question whether the summa-tion of startle reflex activity on the basic postural response resultsin functional benefits. The function of the startle reflex could liein 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 disadvantagesas well. The expression of startle reflexes following rear-end col-lisions has been suggested to contribute to increased forces andstrains in neck tissues, leading to whiplash injuries (Mang et al.,

Biobehavioral Reviews 53 (2015) 131–138 133

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012). In the same way, a startle reflex overlaid onto a normal pos-ural response may be detrimental to balance, if it interferes withhe planned amplitude, direction and inter-segmental coordinationetween limbs. Indeed, center of mass deviations are larger duringrst trial perturbations compared to habituated postural responsesOude Nijhuis et al., 2010). Hence, the generalized startle reflexesnduced by highly unexpected perturbations appear to reduce theet effect of appropriate corrective responses, which comes to theetriment of postural stability.

. StartReact effect

.1. Acceleration of reaction times by a startling stimulus

When a startling stimulus is presented in a reaction time taskogether with the imperative stimulus, reaction times are signif-cantly accelerated, a phenomenon known as StartReact (Carlsent al., 2012; Valls-Sole et al., 2008, 1999). In addition to an acceler-tion of reaction times, an increase in EMG amplitudes and muscleorce has also been reported for StartReact experiments (Anzakt al., 2011; Kumru et al., 2006; Queralt et al., 2008). The firsttartReact experiments involved the acceleration of voluntary armovements and voluntary rising onto the toes from a standing

osition (Valls-Sole et al., 1999, 1995). These studies showed that startling acoustic stimulus (SAS) accelerates movement laten-ies without changing the basic spatiotemporal pattern of musclectivation of the movement involved. Based on this observation,t was argued that SAS releases a pre-prepared motor program,ather than simply superimposing reflex activity on the intendedovement. To test this hypothesis, Carlsen et al. (2004b) evaluated

tartReact effects on a series of arm movements to targets of 20, 40nd 60 degrees. When a 20 degrees movement was prepared, a SASesulted in a 20 degrees movement with its associated EMG pattern.owever, when a 40 or 60 degrees movement was pre-planned,

he EMG pattern was in accordance with the 40 or 60 degreesovement, providing evidence for release of a pre-prepared motor

rogram by a startling stimulus. This notion is further supportedy the observation that a SAS, in the absence of the imperativetimulus, can elicit the planned movement, which is not observedhen a SAS is given in isolation prior to the experiment (Kumru

nd Valls-Sole, 2006; Valls-Sole, 2004).A second study by Carlsen et al. (2004a) evaluated the StartReact

ffect in a simple and choice reaction task. Since motor prepa-ation does not generally occur during a choice reaction task, itas hypothesized that StartReact would not be observed during

choice reaction task. Indeed, a SAS only accelerated latenciesuring the simple reaction task and not during the choice reac-ion task. Subsequent studies did report acceleration of reactionimes in some choice reaction tasks (Kumru and Valls-Sole, 2006;

acKinnon et al., 2007; Oude Nijhuis et al., 2007), but this camet the expense of response errors. These observations suggest thatubjects may prefer to pre-plan a movement sequence in advance,ven if that plan may be potentially incorrect. Hence, the observedtartReact effects during choice reaction tasks also indicate thatotor preparation is a prerequisite for the acceleration of reaction

imes by a SAS.

.2. Mechanisms underlying StartReact

Although there is general consensus that StartReact is due toelease of a pre-prepared motor program by a startling stimu-

us, the neural structures involved are still a matter of ongoingebate. Three hypotheses have been proposed to explain the mech-nism underlying StartReact. First, a SAS could act as an additionaltimulus on top of the imperative stimulus, thereby increasing

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

the energy of the sensory input, a process known as intersensoryfacilitation (Nickerson, 1973). Intersensory facilitation could sub-sequently result in an acceleration of sensorimotor coupling at thecortical level, resulting in accelerated release of motor programs,conveyed by the corticospinal tract (see Fig. 1A). However, it hasbeen reported that reaction time shortening during a StartReactexperiment is not dependent on the intensity of the stimulus, butrather on whether the stimulus is perceived as startling (Carlsenet al., 2007). Another argument against the intersensory facilitationhypothesis comes from the observation that a SAS can trigger therequested movement at similarly short latencies when applied inthe 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 directlyreleases a subcortically stored motor program (Carlsen et al.,2004b; Valls-Sole et al., 1999), which is conveyed by the reticu-lospinal tract (see Fig. 1B) (Rothwell, 2006). This hypothesis has

134 J. Nonnekes et al. / Neuroscience and Biobehavioral Reviews 53 (2015) 131–138

Fig. 2. (A) Schematic diagram of the neurologic disruption in patients with HSP. CST = corticospinal tract. RST = reticulospinal tract. In patients with HSP, the reticulospinaltract 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 notaffect the corticospinal tract to the upper extremities. (B) Mean onset latencies (SE) during the simple reaction time tasks involving voluntary ankle dorsiflexion (upperg trols. *a (2014

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raphs) and wrist flexion (lower graphs) in patients with HSP and age-matched con s significant SAS × group interaction. This figure is reprinted from Nonnekes et al.

een proposed as latencies of the fastest StartReact effects seemo be too fast to involve the motor cortex (Valls-Sole et al., 1999).

oreover, onsets of muscles involved in StartReact effects tend toave the same latency as those seen in a startle reflex, indicat-

ng conduction by the reticulospinal tract (Valls-Sole et al., 1999).ecent evidence supporting this notion has been developed fromtudies using two clinical patient models. In chronic stroke patients,t was first found that StartReact responses are intact for elbow flex-on and extension movements (Honeycutt and Perreault, 2012). Forlbow flexion, there were no differences in either onset latency ofuscle activation patterns between stroke patients and controls.uring elbow extension, a SAS exhibited inappropriate activity in

he flexors, but this diminished over time, leaving a normal mus-le activation pattern. Likely, inappropriate startle reflex activityas seen during the first elbow extension trials, which habituated

ver time (Honeycutt and Perreault, 2012). More recently, it haseen shown that StartReact effects on hand extension movementsre intact in most stroke patients as well (Honeycutt et al., 2014).hese results can be interpreted in favor of a SAS releasing a motorrogram from a subcortical level, but one has to acknowledge thattroke patients have remaining cortical connections, which leaveshe possibility that a SAS releases a cortically stored motor programonveyed by these residual corticospinal fibers (see below).

StartReact effects were also studied in patients with hereditarypastic paraplegia (HSP) (Fisher et al., 2013; Nonnekes et al., 2014c).SP is a disease characterized by retrograde axonal degeneration of

he corticospinal tract (Bonsch et al., 2003; Jorgensen et al., 2005;ardone and Tezzon, 2003; Pelosi et al., 1991; Polo et al., 1993;artucci et al., 2007), while leaving the reticulospinal tract unaf-ected (Nonnekes et al., 2013b, 2014c). Typically, HSP in its pureorm does not affect the corticospinal tract to the upper extrem-ties (Jorgensen et al., 2005; Pelosi et al., 1991; Polo et al., 1993;artucci et al., 2007) (see Fig. 2A). StartReact effects in patientsith pure HSP were compared to those in age-matched controls

sing a reaction task involving ankle dorsiflexion and a secondeaction task involving wrist flexion (Nonnekes et al., 2014c). Ankleorsiflexion reaction times were delayed in patients with HSP com-ared to controls, in line with delayed motor evoked potentials

indicates significant differences between trials with and without a SAS. + indicatesc) in agreement with the journal’s policy.

in tibialis anterior in response to supramaximal transcranial mag-netic stimulation (TMS). However, when the ankle dorsiflexion taskwas combined with a SAS, reaction times were accelerated in bothpatients with HSP and controls, but to a larger extent in patientswith HSP, resulting in completely normalized EMG and movementonset latencies (see Fig. 2B). When the reaction time task involvedvoluntary wrist flexion, no differences in onset latencies betweenpatients with HSP and controls were observed, irrespective of thepresence of a SAS. This observed pattern of results was interpretedby the authors in favor of a SAS releasing a subcortically storedmotor program, conveyed by the reticulospinal tract.

The third hypothesis on StartReact proposes that the SAS couldact as a subcortically mediated trigger for a cortically stored motorprogram (Alibiglou and MacKinnon, 2012; Carlsen et al., 2012), con-veyed by the corticospinal tract (see Fig. 1C). The latter hypothesisis supported by three recent studies that evaluated the effect of TMSon the StartReact effect (Alibiglou and MacKinnon, 2012; Marinovicet al., 2014; Stevenson et al., 2014). Alibiglou and MacKinnon (2012)showed that a single, suprathreshold pulse of TMS delivered overthe primary motor cortex delayed reaction times to a startling stim-ulus. These findings were replicated in a subsequent study thatdemonstrated longer delays in reaction times with shorter timebetween the TMS pulse and the startling stimulus (Stevenson et al.,2014). Finally, Marinovic et al. (2014) found that during preparationfor anticipatory movements, the net excitability of the corticospinalpathway is enhanced shortly after a loud acoustic stimulus is pre-sented.

Evidence for a cortical role in the StartReact effect is also pro-vided by a recent study that evaluated movement-related EEGpotentials during motor preparation. MacKinnon and colleaguesshowed that under preparatory conditions in which the timing ofonset of the imperative cue could be predicted in advance, the pre-sentation of a SAS could release a planned movement sequence asearly as 1.5 s prior to the expected cue (MacKinnon et al., 2013).

Importantly, the incidence of release significantly increased duringcortical motor preparation (as indicated by the Contingent Nega-tive Variation (CNV) in the movement-related EEG). For conditionsin which the timing of the imperative cue could not be predicted,

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AS-evoked reaction times of less than 100 ms were significantlyess common and movement-related EEG potentials were markedlyeduced compared to the condition in which the timing of themperative cue could be predicted. These findings therefore suggesthat motor preparation at the cortical level prior to an imperativetimulus sets a modulatory state for the early and unintentionalelease of the planned action.

Despite these seemingly contrasting hypotheses, however,nvolvement of the cortex in the StartReact effect and the sug-ested mechanism of a subcortical motor program being releasedy a SAS are not mutually exclusive. The delaying effect of TMSn SAS-induced acceleration of motor responses may be explainedy the fact that TMS over the motor cortex not only has inhibitingffects on the cortical neurons, but also on cells within the reticu-ar formation (Fisher et al., 2012). In addition, the observation thatortical motor preparation was associated with a greater proba-ility of advanced release of the prepared movement (MacKinnont al., 2013) neither excludes a subcortical pathway underlying thetartReact effect. The modulatory state for the release of plannedction may not be restricted to the motor cortex, as the incidencef SAS-induced startle reflexes also increases with greater motorreparedness (Carlsen and MacKinnon, 2010).

On the other hand, the completely normal SAS-induced reactionimes in people with cortical lesions or corticospinal degenera-ion do not seem to be compatible with a transcortical pathwayHoneycutt and Perreault, 2012; Honeycutt et al., 2014; Nonnekest al., 2014). Hence, the current body of evidence seems to favorhe hypothesis of the SAS releasing a prepared movement through

subcortical pathway. However, we suggest the cortex to play aritical role in the StartReact phenomenon by altering the state ofhe involved subcortical structures, which is in line with the modelecently proposed by Shemmell (2015). Future studies need to fur-her unravel the exact neural pathways involved in StartReact. ThemRF may be regarded as a candidate subcortical structure in thisespect, as it not only constitutes a key structure in the startle reflexircuitry, but has also been demonstrated in studies in monkeysnd cats to be involved in motor preparation (Buford and Davidson,004; Schepens and Drew, 2004).

.3. Differences between startle reflexes and StartReact

There are several observations that suggest that startle reflexesnd StartReact effects are at least partly dissociated. First, whilerepulse inhibition modifies startle reflexes, it does not appearo influence the StartReact effect (Valls-Sole et al., 2005). Second,tartle reflexes in the sternocleidomastoid muscle do not seemo be a requirement for StartReact effects. Although Carlsen et al.2007) reported an attenuation of StartReact effects when no reflexctivity was observed in the sternocleidomastoid muscle, severalther studies have not found a significant relationship betweeneflex activity in the sternocleidomastoid muscle and StartReact,oth for experiments involving simple reaction time tasks (Non-ekes et al., 2014c), and for tasks involving gait and posturalesponses (Campbell et al., 2013; MacKinnon et al., 2007; Nonnekest al., 2014c, 2013c; Reynolds and Day, 2007; Rogers et al., 2011).

final observation in support of dissociated processes betweentartle reflexes and StartReact comes from a study in patients witharkinson’s disease and severe freezing of gait (Thevathasan et al.,011). In these patients, StartReact effects and startle reflexes wereeported to be absent, but deep brain stimulation of the PPN selec-ively restored StartReact effects, while leaving the impairment intartle reflexes unchanged.

Interestingly, the StartReact effect has also been observedn response to lower-intensity stimuli not usually regarded astartling in nature, with the likelihood of early release of the pre-ared movement being related to the strength of the stimulus

avioral Reviews 53 (2015) 131–138 135

(Delval et al., 2012). StartReact paradigms typically apply acous-tic stimuli at ∼120 dB, which intensity is large enough not only torelease the prepared movement, but also to overcome the neuralthresholds in the startle circuitry at the pmRF, resulting in a startlereflex. In the study of Delval et al. (2012), however, an 80 dB acous-tic stimulus resulted in a fair proportion (29%) of trials with earlyrelease of the prepared motor response, and it also evoked a startlereflex in SCM in 18% of the trials (with 27% overlap between theseevents). These observations indicate that the preparatory motorstate dramatically reduced the neural thresholds of StartReact andstartle reflex circuitry (described as a progressive ‘releasing of thebrakes’) (MacKinnon et al., 2013). The relatively small proportionof trials with both early release of the prepared motor response anda startle reflex in SCM, however, suggest that the neural thresholdsof these circuits may differ to some extent. This notion further sup-ports the postulated dissociation between startle reflexes and theStartReact phenomenon.

3.4. StartReacts effects observed during gait initiation and onlinestep adjustments

Following the observation of startle-induced acceleration ofsimple reactive movements, several groups investigated whetherStartReact effects can also be induced during more complexmovements, such as gait under a variety of conditions involv-ing preplanning of movement. It was shown that StartReact wasalso applicable to two aspects of gait: gait initiation and onlinestep adjustments (MacKinnon et al., 2007; Queralt et al., 2008;Reynolds and Day, 2007). Gait initiation involves anticipatory pos-tural adjustments (APAs) that propel the body mass forward andlaterally to unload the swing leg (Massion, 1992). Interestingly,these APAs can be significantly accelerated by a startling stimu-lus (Delval et al., 2012; MacKinnon et al., 2007), which suggestspostural preparation before a step is made.

The application of StartReact has more recently been used tostudy gait initiation in patients with Parkinson’s disease (PD).Impairments during gait initiation are common in patients with PDand include reduced step length and small APAs (Burleigh-Jacobset al., 1997; Gantchev et al., 1996; Mille et al., 2007). In the moreadvanced stages, freezing of gait can emerge. Freezing of gait ischaracterized by sudden, relatively brief episodes of an inabilityto step or by extremely short steps (Nutt et al., 2011). StartRe-act experiments have been used to study whether deficient motorpreparation contributes to freezing of gait. Intact startle-inducedacceleration of APAs has been observed in PD-patients withoutfreezing of gait (Fernandez-Del-Olmo et al., 2012; Nonnekes et al.,2014b; Rogers et al., 2011), indicating preserved motor prepara-tion. Interestingly, reduced StartReact effects of APAs have beenreported in PD-patients with freezing of gait (Nonnekes et al.,2014b). Hence, in these patients, the APA to initiate a step may notbe properly prepared in advance. An alternative explanation forthe reduced StartReact effect in freezers may be that the reflexiverelease of motor responses is deficient due to subcortical structuresbeing less responsive to excitatory stimuli. Although not confirmedyet, the finding of reduced StartReact effects in freezers could berelevant to the mechanisms underlying freezing of gait. Subcorticalstructures, in particular the pmRF and PPN, are involved in the inte-gration of APAs with subsequent stepping movements (la Fougereet al., 2010; Musienko et al., 2008; Nutt et al., 2011; Schepens et al.,2008). Deficiencies in APA representation or release at the sub-cortical 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 duringonline step adjustments (Queralt et al., 2008; Reynolds and Day,2007). Reynolds and Day (2007) evaluated the effect of a SAS on

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tepping adjustments in the medial or lateral direction, responseshat are thought to be organized at subcortical level (Reynolds anday, 2012). Interestingly, startle-induced shortening of reaction

imes was observed, even though the direction of the adjustmentsas not known in advance. Queralt et al. (2008) studied step adjust-ents in the sagittal plane in response to a sudden obstacle while

articipants walked on a treadmill. In their study, obstacles wereeleased in specific moments of the step cycle, accompanied by aAS (40 ms after obstacle release) in 25% of the trials. Contact of theoot with the obstacle could be avoided by either lengthening orhortening of the ongoing stride, the likelihood of which dependedn the moment of obstacle release. Results showed that both short-ning and lengthening of the stride was accelerated in trials inhich a SAS was applied. Step adjustments in the same directionere also observed when the SAS was presented in the absence

f obstacle release, but at the same moment in the step cycle. Theatter observations suggest that during gait, motor preparation fornline gait adjustments takes place in advance.

We hypothesize that a startling stimulus releases a motor pro-ram for the online step adjustment, which is further modulatedt the level of the spinal cord, depending on the phase of the gait-ycle, yielding either shortening or lengthening of the stride. Thisypothesis is supported by studies in cats, which reported thatescending activity can be manipulated by spinal structures, pro-iding activation or suppression of motoneurons, depending onhe phase requirements (Drew, 1991). The observation that direc-ionally appropriate on-line step adjustments to sudden medial orateral target jumps were also susceptible to StartReact (Reynoldsnd Day, 2007), raises the intriguing question whether there maye a subcortical pathway for visual control of the lower extremity.he role of the collicular circuitry in the generation of arm reach-ng movements is well established and a link to leg movementsas been suggested (through projections to the cuneiform nucleus,hilipp and Hoffmann, 2014).

.5. StartReact effects and postural responses

The relationship between StartReact and postural responses haseen explored in two ways. First, it has been investigated whetherostural perturbations can induce StartReact effects. As outlined

n Section 2.3 of this review, there is evidence for superpositionf startle reflex activity on the postural response, in particular fol-owing the very first trial of an unexpected balance perturbation.he suggestion that a postural perturbation can act as a startlingtimulus was recently tested in two studies that applied a pos-ural perturbation to induce StartReact effects. Indeed, whole bodyalance perturbations were shown to elicit StartReact effects onrist extension movements (Campbell et al., 2013). Similarly, rapiderturbations of arm posture induced StartReact effects on elbowxtension movements as well (Ravichandran et al., 2013). Hence,hese observations provide further evidence for the startling naturef unexpected postural perturbations.

Second, studies have investigated whether motor preparationlso takes place for postural responses to external balance pertur-ations, yielding these responses susceptible to acceleration by aAS. In contrast to voluntary reactions in response to an imper-tive auditory or visual stimulus, automatic postural responseso not involve transcortical pathways (Jacobs and Horak, 2007;uant et al., 2004; Taube et al., 2006), but are likely encoded byssemblies of neurons in the pmRF (Stapley and Drew, 2009). How-ver, three parallel studies (Campbell, 2012; Campbell et al., 2012;onnekes et al., 2013c) demonstrated that these automatic pos-

ural responses can still be accelerated by a SAS. Campbell andolleagues evaluated the effect of auditory stimuli after repeatedued sideways perturbations. A nonstartling auditory tone wasble to evoke a postural response in the absence of a perturbation

avioral Reviews 53 (2015) 131–138

(Campbell et al., 2012), indicating the presence of a classically con-ditioned response. Interestingly, a SAS induced significantly earlieronsets of conditioned postural responses compared to the auditorytone, hinting toward advanced preparation of postural responses.A second argument for such preparation came from a study thatevaluated whether automatic postural responses to balance pertur-bations can be accelerated by a SAS (Nonnekes et al., 2013c). In thisstudy, postural responses to backward and forward perturbationswere induced by a balance platform that could translate in the for-ward or backward direction, respectively (Nonnekes et al., 2013a).In 25% of balance perturbations, a SAS was given at the start ofplatform translation. Postural responses to backward perturbationscould be significantly accelerated by a SAS, both when a backwardperturbation was expected, but also when perturbation directionwas not known in advance. In line with the study of Campbell et al.(2012), a SAS yielded postural responses at similar latencies in theabsence compared to those in the presence of a balance perturba-tion, and both these latencies similarly scaled with perturbationintensity. Interestingly, a SAS did not shorten postural responses toforward perturbations (Nonnekes et al., 2013c), this finding beingreplicated in a subsequent study by the same group (Nonnekeset al., 2014a). While the latter study demonstrated a directionalspecificity of StartReact effects on postural responses in the sagi-ttal plane, subsequent work has shown that postural responses canbe accelerated by a startling stimulus in the lateral direction as well(Campbell, 2012). Hence, backward and sideways perturbationsare susceptible to StartReact, while forward responses are not. Themechanism responsible for this directional specificity of StartReactin postural responses is not yet understood. It may be that posturalresponses in forward, backward and sideways directions involvedifferent neural circuits, with startle circuits selectively interactingwith postural responses to recover from backward and sidewaysperturbations (Nonnekes et al., 2013c).

4. Conclusion

Recent work on startle reflexes and StartReact has providedimportant new insights into the neural mechanisms underlyingstartle reflexes and StartReact, and have contributed to our under-standing of control of posture and gait. First, studies using patientswith corticospinal lesions support a mechanism for StartReactthat incorporates a motor program that is stored in subcorticalcenters and triggered by a startling stimulus. Experiments usingTMS suggest that the cortex plays a critical role in the StartRe-act phenomenon, possibly by altering the state of the involvedsubcortical structures. Second, it is recognized that the behaviorssusceptible to StartReact have expanded considerably, now alsoinvolving postural control and gait. Originally this work was con-centrated on simple voluntary movements, but in recent years ithas been shown that gait initiation, online step adjustments andpostural responses to backward and sideways perturbations canbe speeded up by a startling stimulus as well. This indicates thatadvanced motor preparation takes place for these elements of pos-tural control and gait. This preparation presumably involves a closeinteraction between cortical and subcortical structures. However,the exact neural pathways involved in advanced motor prepara-tion of posture and gait remain to be unraveled by future studies. Inlight of our understanding of the mechanisms involved in StartRe-act, these results support the growing body of evidence for thecortical and subcortical contributions to balance and gait (Adkinet al., 2006; Campbell et al., 2009; Jacobs and Horak, 2007; Marlinet al., 2014; Nonnekes et al., 2010; Quant et al., 2004; Reynolds

and Day, 2005). Third, several studies indicate a superimpositionof startle reflex activity on the postural response during first trialbalance perturbations. The summation of startle reflex activity onthe postural response can be detrimental for postural stability if it

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nterferes with the amplitude and direction of the balance correct-ng response. The growing number of studies in this area of researchas also raised several new questions on posture and gait control,

ncluding the mechanisms underlying the directional specificity ofAS-induced acceleration of postural responses and the suscepti-ility of visually-guided step adjustments to StartReact, which areuggested topics for further research.

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