International Journal of Pediatrics abuse including volatile substances, heroin, and opioids [78–80]. An exaggerated response may also be detected in infants with a severe bilateral intrauterine disturbance such as hydranencephaly [31]. Asymmetry of the response is usually a sign of local injury. Damage to a peripheral nerve or cervical cord or a fracture of the clavicle may inhibit the reﬂex on the aﬀected side. However, it should be noted that Dubowitz [14] demonstrated an asymmetrical response in normal infants. Their responses appeared to be related to the clenching of one ﬁst during the procedure, and he considered that this might be caused by inhibition of the response on one side due to contraction of the ﬁnger ﬂexors. Because Reiners et al. [81] found, in a prospective study, that none of 22 infants with a clavicular fracture exhibited an asymmetrical Moro response, the diagnostic value of the reﬂex for the detection of such fractures should not be overestimated. Retention of the reﬂex is common in children with MR without motor disturbance including Down’s syndrome and in children with CP of the athetoid type [10, 69]. It is also sometimes observed in children with a severe brain malformation or with CP of the spastic type [31, 69]. 3.3. Neural Mechanism 3.3.1. The Reﬂex Center. Katona [17] reported that the Moro reﬂex could be elicited in anencephalic newborns with a nervous system that had developed only to the rostral level of the pons. In a study involving analysis of the relationship between the morphological structures of the rudimentary brain and primitive reﬂexes in six anencephalic newborns, Hanabusa [39] found that the Moro reﬂex could be elicited only when the vestibular nuclei were preserved. This ﬁnding indicates that the reﬂex is principally mediated by the vestibular nuclei. Ro¨nnqvist et al. [82] reported that the average latency of the Moro reﬂex in 15 term neonates in the quiet awaking state detected with an optoelectronic device was 117.0 ms on the right arm and 129.2 ms on the left. These latencies are much longer than those of the spinal reﬂexes, clearly indicating that the reﬂex is mediated in the brain stem, not at the level of the spinal cord [83, 84]. Thus, the center of the Moro reﬂex seems to be in the lower region of the pons to the medulla. 3.3.2. Aﬀerent and Eﬀerent Pathways. The origin of aﬀerent pathways for the Moro reﬂex, whether it is primarily vestibular, proprioceptive, or exteroceptive, has been a main subject of discussion. The head drop, the most common way of eliciting the reﬂex, stimulates both the vestibular system and the proprioceptive receptors in the neck. Ro¨nnqvist [13] investigated the reﬂex by tilting the table without extension of the infants’ neck to eliminate the proprioceptive inputs from the cervical vertebrae and neck muscles. The response could be elicited in 225/250 trials (90%), and twenty-one of the 25 negative trials were made while the infants were sleep- ing or crying. Prechtl [12] also demonstrated that sudden raising or dropping of the infants, whose head, neck, and trunk were ﬁxed in a plaster cast, could elicit the response. 5 Bloomﬁeld et al. [85] reported an infant with CHARGE syndrome who exhibited a persistent complete absence of the Moro reﬂex with preservation of other primitive reﬂexes. Moro’s original method cannot yield a satisfactory response if the table is too stable to produce a change in position on striking and necessitates jolting movement of the table to elicit a response [10]. These ﬁndings support the view that this reﬂex is principally mediated by the vestibular system. In contrast to the grasp reﬂex, the Moro reﬂex has not been observed in a fetus, which is also in agreement with its vestibular origin, because fetuses are protected from acceleration or shaking in intrauterine life [68, 86]. On the other hand, Parmelee Jr. [11] found that vestibu- lar stimulation was not suﬃcient for a good Moro response when neck movement was prevented. Prechtl [12] described an infant with bilateral absence of the inner ears who had exhibited a normal Moro response to a head drop, which was reported by Karlsson in an address to a study group in Oxford. These observations suggest that the proprioceptive inputs from the neck also contribute to elicitation of the reﬂex. There are direct and indirect, via the cervical cord, ascending pathways that originate in the proprioceptive receptors in the neck and connect with vestibular nuclei. These pathways originally send signals to the brain stem to regulate the neck righting [57]. The signals generated by the head drop may travel via these routes to reach and activate the reﬂex mechanism in the brain stem. The head drop method is most eﬀective, because it produces a large number of ascending signals to the target through the two pathways and thereby induces a high level of neural excitation that acts on the reﬂex center. Although pinching of an infant’s epigastrium has been reported to be eﬀective for eliciting the reﬂex [65], a nociceptive stimulus is generally ineﬀective [10, 11]. Besides the primary somatosensory aﬀerents, there is a path taken by nociceptor axons that reaches the pontine reticular forma- tion, which has close interconnections with vestibular nuclei [87–89]. The nociceptive signals may travel via this pathway toward the reﬂex center in the brain stem. However, the level of neural excitation generated by nociceptive stimulation appears to be usually low, and the response can be elicited only when it infrequently exceeds the threshold of the reﬂex. The reﬂex center probably contains a number of inter- neurons, because of the relatively long latency. The routes of aﬀerent pathways can be multiple, and the eﬀerent pathways of the response seem to originate in the vestibulospinal and/or reticulospinal neurons, because the response can even be obtained in anencephalic newborns devoid of both corti- cospinal and rubrospinal neurons [17, 39]. Thus, the reﬂex movement is generated by the subcortical structures without cortical participation, which explains why focal cerebral injury does not cause distinct disturbance of the Moro reﬂex [31]. It is also noteworthy that no asymmetrical response is sometimes detected in neonates and young infants who later develop spastic hemiplegia. The primary motor cortex and nonprimary motor areas project a lot of neurons to diﬀerent motor centers in the brain stem including vestibulospinal and reticulospinal neurons. The brain stem also receives inputs from the basal ganglia and cerebellum. The Moro