Pterygoideus proprius muscle: stuck between the greater wing and lateral pterygoid plate.

The muscles of mastication derive from a common embryological source, and the presence of accessory muscles in the infratemporal fossa (ITF) is uncommon. Here, we present findings from postmortem dissection of the ITF revealing a unilaterally present muscle extending from the greater wing of the sphenoid to blend inferiorly with the medial and lateral pterygoid muscles before attaching to the lateral pterygoid plate. This muscle is most consistent with the pterygoideus proprius muscle initially described in 1858. Though the exact embryological origin and function of this muscle remain speculative, these topics are nonetheless worth investigating as it may provide insight regarding the ontogeny of muscles descending from the first pharyngeal arch. Additionally, presence of the pterygoideus proprius muscle may have clinical implications and impact surrounding structures such as the mandibular division of the trigeminal nerve, maxillary artery, pterygoid venous plexus, masticatory muscles, and temporomandibular joint (TMJ).

Cortical dysmorphology and reduced cortico-collicular projections in an animal model of autism spectrum disorder.

Autism spectrum disorder is a neurodevelopmental disability that includes sensory disturbances. Hearing is frequently affected and ranges from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid is associated with increased risk of autism spectrum disorder in humans and timed valproic acid exposure is a biologically relevant and validated animal model of autism spectrum disorder. Valproic acid-exposed rats have fewer neurons in their auditory brainstem and thalamus, fewer calbindin-positive neurons, reduced ascending projections to the midbrain and thalamus, elevated thresholds, and delayed auditory brainstem responses. Additionally, in the auditory cortex, valproic acid exposure results in abnormal responses, decreased phase-locking, elevated thresholds, and abnormal tonotopic maps. We therefore hypothesized that in utero, valproic acid exposure would result in fewer neurons in auditory cortex, neuronal dysmorphology, fewer calbindin-positive neurons, and reduced connectivity. We approached this hypothesis using morphometric analyses, immunohistochemistry, and retrograde tract tracing. We found thinner cortical layers but no changes in the density of neurons, smaller pyramidal and non-pyramidal neurons in several regions, fewer neurons immunoreactive for calbindin-positive, and fewer cortical neurons projecting to the inferior colliculus. These results support the widespread impact of the auditory system in autism spectrum disorder and valproic acid-exposed animals and emphasize the utility of simple, noninvasive auditory screening for autism spectrum disorder.

Abnormal auditory brainstem responses in an animal model of autism spectrum disorder.

Auditory dysfunction is a common feature of autism spectrum disorder (ASD) and ranges from deafness to hypersensitivity. The auditory brainstem response (ABR) permits study of the amplitude and latency of synchronized electrical activity along the ascending auditory pathway in response to clicks and pure tone stimuli. Indeed, numerous studies have shown that subjects with ASD have ABR abnormalities. In utero exposure to the antiepileptic drug valproic acid (VPA) is associated with human cases of ASD and is used as an animal model of ASD. Previous studies have shown that VPA-exposed animals have significantly fewer neurons in the auditory brainstem and thalamus, reduced ascending projections to the auditory midbrain and thalamus and increased neuronal activation in response to pure tone stimuli. Accordingly, we hypothesized that VPA-exposed animals would have abnormal ABRs throughout their lifespans. We approached this hypothesis in two cohorts. First, we examined ABRs from both ears on postnatal day 22 (P22). Then, we examined monaural ABRs in animals at P28, 60, 120, 180, 240, 300 and 360. Our results suggest that at P22, VPA-exposed animals have elevated thresholds and increased peak latencies. However, by P60 these differences largely normalize with differences appearing only near hearing threshold. Additionally, our analysis revealed that maturation of ABR waves occurred at different trajectories in control and VPA-exposed animals. These results, together with our previous work, suggest that VPA exposure not only impacts total neuron number and connectivity, but also auditory evoked responses. Finally, our longitudinal analysis suggests that delayed maturation of auditory brainstem circuits may impact ABRs throughout the lifespan of the animal.

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders-Denial is not an option.

Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aß1 - 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority.

Noradrenergic axons hitch hiking along the human abducens nerve.

The abducens nerve (AN; cranial nerve VI) exits the brainstem at the inferior pontine sulcus, pierces the dura of the posterior cranial fossa, passes through the cavernous sinus in close contact to the internal carotid artery (ICA) and traverses the superior orbital fissure to reach the orbit to innervate the lateral rectus muscle. At its exit from the brainstem, the AN includes only axons from lower motor neurons in the abducens nucleus. However, as the AN crosses the ICA it receives a number of branches from the internal carotid sympathetic plexus. The arrangement, neurochemical profile and function of these sympathetic axons running along the AN remain unresolved. Herein, we use gross dissection and microscopic study of hematoxylin and eosin-stained sections and sections with tyrosine hydroxylase immunolabeling. Our results suggest the AN receives multiple bundles of unmyelinated axons that use norepinephrine as a neurotransmitter consistent with postganglionic sympathetic axons.

Characterization of the superior olivary complex of chimpanzees (Pan troglodytes) in comparison to humans.

The superior olivary complex (SOC) is a collection of nuclei in the hindbrain of mammals with numerous roles in hearing, including localization of sound sources in the environment, encoding temporal and spectral elements of sound, and descending modulation of the cochlea. While there have been several investigations of the SOC in primates, there are discrepancies in the descriptions of nuclear borders and even the presence of certain cell groups among studies and species. Herein, we aimed to clarify some of these issues by characterizing the SOC from chimpanzees using Nissl staining, quantitative morphometry and immunohistochemistry. We found the medial superior olive (MSO) to be the largest of the SOC nuclei and the arrangement of its neurons and peri-MSO to be very similar to humans. Additionally, we found neurons in the medial nucleus of the trapezoid body (MNTB) to be immunopositive for the calcium binding protein calbindin. Further, most neurons in the MNTB, and some neurons in the lateral nucleus of the trapezoid body were associated with large, calretinin-immunoreactive calyx terminals. Together, these findings indicate the organization of the SOC of chimpanzees is organized very similar to the SOC in humans and suggests modifications to this region among species consistent with differences in head/body size, restricted hearing range and sensitivity to low frequency sounds.

A portal quadrad with triple hepatic arteries.

The arterial support of the liver is most commonly from the celiac trunk via the proper hepatic artery (PHA). The PHA divides into left and right branches: the right hepatic artery (RHA) supplies the right and caudate lobes while the left hepatic artery (LHA) supplies the left and quadrate lobes. Aberrant hepatic arteries are relatively common, and the most frequent contributors are the superior mesenteric artery and left gastric artery. Herein we present findings from postmortem dissection of an abdominal cavity that revealed a rare combination of reported variations. Specifically, this subject had three extrahepatic arteries - a replaced LHA (rLHA), a PHA, and a replaced RHA (rRHA). The rLHA originated from the left gastric and the rRHA originated from the superior mesenteric artery. Knowledge of these variations is important for surgical and radiological procedures to avoid complications during treatment and improve patient outcomes.

Untrapped: bilateral hypoplasia of the trapezius muscle.

Agenesis or congenital hypoplasia of skeletal muscles occurs infrequently but may occur with specific conditions such as Poland syndrome. The trapezius muscle can vary in the extent of its bony attachments or may have additional slips, however congenital absence or hypoplasia is extremely rare. There are only a few reports of partial or complete absence of the trapezius muscle. Two cases of bilateral absence of the trapezius were both in males and were accompanied by the absence of additional muscle in the pectoral girdle. Herein, we describe a case of a 56-year-old male cadaver with bilateral hypoplasia of the trapezius. The muscle was largely represented by atrophied muscle fibers with an abundance of fibrotic or fatty connective tissue. This subject had very minor hypoplasia of the left pectoralis major muscle, but the remaining muscles of the pectoral girdle were normal. The spinal accessory nerve terminated in the sternocleidomastoid muscle on both sides, failing to reach the trapezius. We interpret these findings to be consistent with a minor variant of Poland syndrome.

Fall Risk, Sleep Behavior, and Sleep-Related Movement Disorders in Young Urbanites Exposed to Air Pollution.

BACKGROUND: Quadruple aberrant hyperphosphorylated tau, amyloid-ß, α-synuclein, and TDP-43 pathology had been documented in 202/203 forensic autopsies in Metropolitan Mexico City ≤40-year-olds with high exposures to ultrafine particulate matter and engineered nanoparticles. Cognition deficits, gait, equilibrium abnormalities, and MRI frontal, temporal, caudate, and cerebellar atrophy are documented in young adults. OBJECTIVE: This study aimed to identify an association between falls, probable Rapid Eye Movement Sleep Behavior Disorder (pRBD), restless leg syndrome (RLS), and insomnia in 2,466 Mexican, college-educated volunteers (32.5±12.4 years). METHODS: The anonymous, online study applied the pRBD and RLS Single-Questions and self-reported night-time sleep duration, excessive daytime sleepiness, insomnia, and falls. RESULTS: Fall risk was strongly associated with pRBD and RLS. Subjects who fell at least once in the last year have an OR = 1.8137 [1.5352, 2.1426] of answering yes to pRBD and/or RLS questions, documented in 29% and 24% of volunteers, respectively. Subjects fell mostly outdoors (12:01 pm to 6:00 pm), 43% complained of early wake up hours, and 35% complained of sleep onset insomnia (EOI). EOI individuals have an OR of 2.5971 [2.1408, 3.1506] of answering yes to the RLS question. CONCLUSION: There is a robust association between falls, pRBD, and RLS, strongly suggesting misfolded proteinopathies involving critical brainstem arousal and motor hubs might play a crucial role. Nanoparticles are likely a significant risk for falls, sleep disorders, insomnia, and neurodegenerative lethal diseases, thus characterizing air particulate pollutants' chemical composition, emission sources, and cumulative exposure concentrations are strongly recommended.

Leveling up: a long-range olivary projection to the medial geniculate without collaterals to the central nucleus of the inferior colliculus in rats.

The medial nucleus of the trapezoid body (MNTB) is one of the monaural cell groups situated within the superior olivary complex (SOC), a constellation of brainstem nuclei with numerous roles in hearing. Principal MNTB neurons are glycinergic and express the calcium-binding protein, calbindin (CB). The MNTB receives its main glutamatergic, excitatory input from the contralateral cochlear nucleus via the calyx of Held and converts this into glycinergic inhibition directed toward nuclei in the SOC and the ventral and intermediate nuclei of the lateral lemniscus (VNLL and INLL). Through this inhibition, the MNTB plays essential roles in localization of sound sources and encoding spectral and temporal features of sound. In rats, very few MNTB neurons project to the inferior colliculus. However, our recent study of SOC projections to the auditory thalamus revealed a substantial number of retrogradely labeled MNTB neurons. This observation led us to examine whether the rat MNTB provides a long-range projection to the medial geniculate body (MGB). We examined this possible projection using retrograde and anterograde tract tracing and immunohistochemistry for CB and the glycine receptor. Our results demonstrate a significant projection to the MGB from the ipsilateral MNTB that does not involve a collateral projection to the inferior colliculus.

Abnormal vestibular brainstem structure and function in an animal model of autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes several key neuropathological changes and behavioral impairments. In utero exposure to the anti-epileptic valproic acid (VPA) increases risk of an ASD diagnosis in human subjects and timed in utero exposure to VPA is a clinically relevant animal model of ASD. Many human subjects with ASD have cerebellar hypoplasia, fewer Purkinje cells, difficulties with balance, ophthalmic dysfunction and abnormal responses to vestibular stimulation and such vestibular difficulties are likely under reported in ASD. We have recently shown that animals exposed to VPA in utero have fewer neurons in their auditory brainstem, reduced axonal projections to the auditory midbrain and thalamus, reduced expression of the calcium binding protein calbindin (CB) in the brainstem and cerebellum, smaller and occasionally ectopic cerebellar Purkinje cells and ataxia on several motor tasks. Based on these findings, we hypothesized that in utero VPA exposure similarly impacts structure and function of the vestibular brainstem. We investigated this hypothesis using quantitative morphometric analyses, immunohistochemistry for CB, a battery of vestibular challenges, recording of vestibular-evoked myogenic potentials and spontaneous eye movements. Our results indicate that VPA exposure results in fewer neurons in the vestibular nuclei, fewer CB-positive puncta, difficulty on certain motor tasks, longer latency VEMPs and significantly more horizontal eye movements. These findings indicate that the vestibular nuclei are impacted by in utero VPA exposure and provide a basis for further study of vestibular circuits in human cases of ASD.

A case report of an accessory flexor digitorum profundus indicis contributing the first lumbrical.

Variations of the musculature within the upper extremity have been widely documented, with clinical implications ranging from motor dysfunction to compressive neuropathies. Herein, we described an aberrant muscle that originated from the anterior proximal forearm, formed a tendon that coursed through the carpal tunnel, and converged with the flexor digitorum profundus muscle to contribute to the first lumbrical. Additionally, the second lumbrical consisted of two heads, originating from the index and middle finger tendons of flexor digitorum profundus. Documentation and recognition of such anatomic variants is important, as this anatomic pattern may contribute to anterior interosseous or median nerve compression, incoordination, complications during surgery, and other clinical manifestations.

Learning in Stereo: The Relationship Between Spatial Ability and 3D Digital Anatomy Models.

Three-dimensional (3D) digital anatomical models show potential to demonstrate complex anatomical relationships; however, the literature is inconsistent as to whether they are effective in improving the anatomy performance, particularly for students with low spatial visualization ability (Vz). This study investigated the educational effectiveness of a 3D stereoscopic model of the pelvis, and the relationship between learning with 3D models and Vz. It was hypothesized that participants learning with a 3D pelvis model would outperform participants learning with a two-dimensional (2D) visualization or cadaveric specimen on a spatial anatomy test, particularly when comparing those with low Vz. Participants (n = 64) were stratified into three experimental groups, who each attended a learning session with either a 3D stereoscopic model (n = 21), 2D visualization (n = 21), or cadaveric specimen (n = 22) of the pelvis. Medical and pre-medical student participants completed a multiple-choice pre-test and post-test during their respective learning session, and a long-term retention (LTR) test 2 months later. Results showed no difference in anatomy test improvement or LTR performance between the experimental groups. A simple linear regression analysis showed that within the 3D group, participants with high Vz tended to retain more than those with low Vz on the LTR test (R2  = 0.31, P = 0.01). The low Vz participants may be cognitively overloaded by the complex spatial cues from the 3D stereoscopic model. Results of this study should inform resource selection and curriculum design for health professional students, with attention to the impact of Vz on learning.

Central Auditory and Vestibular Dysfunction Are Key Features of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, poor social skills, and difficulties with communication. Beyond these core signs and symptoms, the majority of subjects with ASD have some degree of auditory and vestibular dysfunction. Dysfunction in these sensory modalities is significant as normal cognitive development depends on an accurate representation of our environment. The hearing difficulties in ASD range from deafness to hypersensitivity and subjects with ASD have abnormal sound-evoked brainstem reflexes and brainstem auditory evoked potentials. Vestibular dysfunction in ASD includes postural instability, gait dysfunction, and impaired gaze. Untreated vestibular dysfunction in children can lead to delayed milestones such as sitting and walking and poor motor coordination later in life. Histopathological studies have revealed that subjects with ASD have significantly fewer neurons in the auditory hindbrain and surviving neurons are smaller and dysmorphic. These findings are consistent with auditory dysfunction. Further, the cerebellum was one of the first brain structures implicated in ASD and studies have revealed loss of Purkinje cells and the presence of ectopic neurons. Together, these studies suggest that normal auditory and vestibular function play major roles in the development of language and social abilities, and dysfunction in these systems may contribute to the core symptoms of ASD. Further, auditory and vestibular dysfunction in children may be overlooked or attributed to other neurodevelopmental disorders. Herein we review the literature on auditory and vestibular dysfunction in ASD. Based on these results we developed a brainstem model of central auditory and vestibular dysfunction in ASD and propose that simple, non-invasive but quantitative testing of hearing and vestibular function be added to newborn screening protocols.

The Untouchable Ventral Nucleus of the Trapezoid Body: Preservation of a Nucleus in an Animal Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by repetitive behaviors, poor social skills, and difficulties with communication and hearing. The hearing deficits in ASD range from deafness to extreme sensitivity to routine environmental sounds. Previous research from our lab has shown drastic hypoplasia in the superior olivary complex (SOC) in both human cases of ASD and in an animal model of autism. However, in our study of the human SOC, we failed to find any changes in the total number of neurons in the ventral nucleus of the trapezoid body (VNTB) or any changes in cell body size or shape. Similarly, in animals prenatally exposed to the antiepileptic valproic acid (VPA), we failed to find any changes in the total number, size or shape of VNTB neurons. Based on these findings, we hypothesized that the neurotransmitter profiles, ascending and descending axonal projections of the VNTB are also preserved in these neurodevelopmental conditions. We investigated this hypothesis using a combination of immunohistochemistry and retrograde tract tracing. We found no difference between control and VPA-exposed animals in the number of VNTB neurons immunoreactive for choline acetyltransferase (ChAT). Additionally, we investigated the ascending projections from the VNTB to both the central nucleus of the inferior colliculus (CNIC) and medial geniculate (MG) and descending projections to the cochlea. Our results indicate no significant differences in the ascending and descending projections from the VNTB between control and VPA-exposed animals despite drastic changes in these projections from surrounding nuclei. These findings provide evidence that certain neuronal populations and circuits may be protected against the effects of neurodevelopmental disorders.

Brainstem Quadruple Aberrant Hyperphosphorylated Tau, Beta-Amyloid, Alpha-Synuclein and TDP-43 Pathology, Stress and Sleep Behavior Disorders.

Quadruple aberrant hyperphosphorylated tau (p-τ), amyloid-ß peptide, alpha-synuclein and TDP-43 brainstem and supratentorial pathology are documented in forensic ≤40y autopsies in Metropolitan Mexico City (MMC), and p-τ is the major aberrant protein. Post-traumatic stress disorder (PTSD) is associated with an elevated risk of subsequent dementia, and rapid eye movement sleep behavior disorder (RBD) is documented in PD, AD, Lewy body dementia and ALS. This study aimed to identify an association between PTSD and potential pRBD in Mexico. An anonymous online survey of 4502 urban college-educated adults, 29.3 ± 10.3 years; MMC, n = 1865; non-MMC, n = 2637, measured PTSD symptoms using the Impact of Event Scale-Revised (IES-R) and pRBD symptoms using the RBD Single-Question. Over 50% of the participants had IES-R scores ≥33 indicating probable PTSD. pRBD was identified in 22.6% of the participants across Mexico and 32.7% in MMC residents with PTSD. MMC subjects with PTSD had an OR 2.6218 [2.5348, 2.7117] of answering yes to the pRBD. PTSD and pRBD were more common in women. This study showed an association between PTSD and pRBD, strengthening the possibility of a connection with misfolded proteinopathies in young urbanites. We need to confirm the RBD diagnosis using an overnight polysomnogram. Mexican women are at high risk for stress and sleep disorders.

Distribution of Glutamatergic and Glycinergic Inputs onto Human Auditory Coincidence Detector Neurons.

Localization of sound sources in the environment requires neurons that extract interaural timing differences (ITD) in low-frequency hearing animals from fast and precisely timed converging inputs from both ears. In mammals, this is accomplished by neurons in the medial superior olive (MSO). MSO neurons receive converging excitatory input from both the ipsilateral and contralateral cochlear nuclei and glycinergic, inhibitory input by way of interneurons in the medial and lateral nuclei of the trapezoid body (MNTB and LNTB, respectively). Key features of the ITD circuit are MSO neurons with symmetric dendrites that segregate inputs from the ipsilateral and contralateral ears and preferential distribution of glycinergic inputs on MSO cell bodies. This circuit for ITD is well characterized in gerbils, a mammal with a prominent MSO and a low-frequency hearing range similar to humans. However, the organization of this circuit in the human MSO has not been characterized. This is further complicated by limited understanding of the human LNTB. Nonetheless, we hypothesized that the ITD circuit characterized in laboratory animals is similarly arranged in the human MSO. Herein, we utilized neuron reconstructions and immunohistochemistry to investigate the distribution of glutamatergic and glycinergic inputs onto human MSO neurons. Our results indicate that human MSO neurons have simple, symmetric dendrites and that glycinergic inputs outnumber glutamatergic inputs on MSO cell bodies and proximal dendrites. Together these results suggest that the human MSO utilizes similar circuitry to other mammals with excellent low-frequency hearing.

Neonatal exposure to monosodium glutamate results in impaired auditory brainstem structure and function.

Excitotoxic injury during the neonatal period has been shown to result in neurodegenerative changes in several different brain regions. Exposure to monosodium glutamate (MSG) during the first two postnatal weeks results in glutamate neurotoxicity in the cochlea and has been shown to result in damage to cochlear hair cells and fewer neurons in the spiral ganglion. Further, we have shown that such exposure results in fewer neurons in the cochlear nucleus and superior olivary complex and abnormal expression of the calcium binding proteins calbindin and calretinin. Based on these findings, we hypothesized that neonatal MSG exposure would result in loss of neurons at more rostral levels in the auditory brainstem, and this exposure would result in abnormal brainstem auditory evoked potentials. We identified a significantly lower density of neurons in the spiral ganglion, heterogenous loss of neurons in the globular bushy cell-trapezoid body circuit, and fewer neurons in the nuclei of the lateral lemniscus and central nucleus of the inferior colliculus. The most severe loss of neurons was found in the inferior colliculus. Click-evoked auditory brainstem responses revealed significantly higher thresholds and longer latency responses, but these did not deteriorate with age. These results, together with our previous findings, indicate that neonatal exposure to MSG results in fewer neurons throughout the entire auditory brainstem and results in abnormal auditory brainstem responses.

A rare variation of the glossopharyngeal nerve.

The glossopharyngeal nerve (CN IX) provides innervation to the parotid gland, carotid body/sinus, mucosa of the middle ear, tongue and oropharynx and the stylopharyngeus muscle. The vagus nerve provides innervation to the remaining skeletal muscle of the pharynx. CN IX contributes to the pharyngeal plexus and normally provides innervation to the mucosa of the oropharynx. Herein, we describe a previously undescribed variation of CN IX. CN IX was observed to enter the pharyngeal wall but instead of forming terminal branches in the tonsillar fossa, CN IX descended along the posterior wall between the mucosa and pharyngeal constrictors to the esophagus. This unusual branch of CN IX gave rise to numerous branches along the pharynx but did not intermingle with laryngeal branches from the vagus nerve. From this dissection, we developed innervation maps of the pharynx and propose a central miswiring mechanism for this unusual variation.