Anatomical and Functional Comparison of the Caudate Tail in Primates and the Tail of the Striatum in Rodents: Implications for Sensory Information Processing and Habitual Behavior.

The tail of the striatum (TS) is located at the caudal end in the striatum. Recent studies have advanced our knowledge of the anatomy and function of the TS but also raised questions about the differences between rodent and primate TS. In this review, we compare the anatomy and function of the TS in rodent and primate brains. The primate TS is expanded more caudally during brain development in comparison with the rodent TS. Additionally, five sensory inputs from the cortex and thalamus converge in the rodent TS, but this convergence is not observed in the primate TS. The primate TS, including the caudate tail and putamen tail, primarily receives inputs from the visual areas, implying a specialized function in processing visual inputs for action generation. This anatomical difference leads to further discussion of cellular circuit models to comprehend how the primate brain processes a wider range of complex visual stimuli to produce habitual behavior as compared with the rodent brain. Examining these differences and considering possible neural models may provide better understanding of the anatomy and function of the primate TS.

Shared genetic effects of emotion and subcortical volumes in healthy adults.

Ample studies have reported a strong association between emotion and subcortical volumes; still, the underlying mechanism regarding this relation remains unclear. Using a twin design, the current study aimed to explore the intrinsic association between emotion and subcortical volumes by examining their phenotypic, genetic, and environmental correlations. We used a group dataset of 960 individuals from the Human Connectome Project (234 monozygotic twins, 145 dizygotic twins, 581 not twins, males = 454, age = 22-37 years). We found that both emotion and subcortical volumes were heritable. Of the 17 emotional traits, 13 were significantly phenotypically correlated with the volumes of multiple subcortical regions. There was no environmental correlation between emotion and subcortical volumes; however, we found a genetic overlap between overall emotional traits and caudate volume. Taken together, our results showed that emotion and subcortical volumes were heritable and closely related. Although the caudate has been often studied with execution of movement, given that the caudate volume is genetically associated with diverse emotional domains, such as negative affect, psychological well-being, and social relationships, it may suggest that the caudate volume might also be an important factor when studying the brain basis of emotion.

Who initiates punishment, who joins punishment? Disentangling types of third-party punishers by neural traits.

The act of punishing unfair behavior by unaffected observers (i.e., third-party punishment) is a crucial factor in the functioning of human societies. In everyday life, we see different types of individuals who punish. While some individuals initiate costly punishment against an unfair person independently of what other observers do (independent punishers), others condition their punishment engagement on the presence of another person who punishes (conditional punishers). Still others do not want to partake in any sort of punishment (nonpunishers). Although these distinct behavioral types have a divergent impact on human society, the sources of heterogeneity are poorly understood. We present novel laboratory evidence on the existence of these three types. We use anatomical brain characteristics in combination with stated motives to characterize these types. Findings revealed that independent punishers have larger gray matter volume in the right temporo-parietal junction compared to conditional punishers and nonpunishers, an area involved in social cognition. Conditional punishers are characterized by larger gray matter volume in the right dorsolateral prefrontal cortex, a brain area known to be involved in behavioral control and strategic reasoning, compared to independent punishers and nonpunishers. Finally, both independent punishers and nonpunishers are characterized by larger gray matter volume in an area involved in the processing of social and monetary rewards, that is, the bilateral caudate. By using a neural trait approach, we were able to differentiate these three types clearly based on their neural signatures, allowing us to shed light on the underlying psychological mechanisms.

Anatomic Correlates and Surgical Experience with Goel Orbital Cortical Approach to Caudate Head Tumors.

OBJECTIVE: We analyzed cortical landmarks, trajectory of approach, and various fiber tracts in the vicinity of our earlier described approach through the orbital/basal surface of the frontal lobe to access tumors located in the region of the caudate nucleus. We also present a new lateral orbital trajectory to approach these tumors. METHODS: The orbital surfaces of 3 formalin fixed and frozen cadaveric brain specimens were dissected to decipher the white fibers in the region of the caudate nucleus. Safe trajectories to lesions of the head of the caudate nucleus were identified, and the anatomic landmarks of the approach were evaluated. Three patients with caudate head tumors were operated using this approach. RESULTS: The caudate head lies at an average distance of 34 mm from the tip of the frontal pole, 24 mm from the basal medial orbital surface of the frontal lobe, 35 mm from the basal lateral orbital surface, and 37 mm from the superior surface of the frontal lobe. Two avenues were identified to approach the caudate head: one by making a cortical incision in the lateral orbital gyrus (lateral orbital approach), and the second by making a corticectomy in the medial orbital gyrus (medial orbital approach) in line with the temporal pole. All 3 patients were operated successfully using this approach. CONCLUSIONS: Surgical approach to the caudate head through the orbital surface of the frontal lobe as described by us provides the shortest trajectory and safe surgical route to access tumors of the caudate nucleus.

Smaller Volume in Left-Lateralized Brain Structures Correlates with Greater Experience of Negative Non-target Emotions in Neurodegenerative Diseases.

Subjective emotional experience that is congruent with a given situation (i.e., target emotions) is critical for human survival (e.g., feeling disgusted in response to contaminated food motivates withdrawal behaviors). Neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease affect brain regions critical for cognitive and emotional functioning, resulting in increased experience of emotions incongruent with the situation (i.e., non-target emotions, such as feeling happy when seeing someone grieving). We examined neuroanatomical correlates of subjective experience of non-target emotions in 147 patients with neurodegenerative diseases and 26 healthy individuals. Participants watched three films intended to elicit particular target emotions and rated their experience of negative and positive target and non-target emotions after watching each film. We found that smaller volume in left hemisphere regions (e.g., caudate, putamen, and dorsal anterior insula) was associated with greater experience of negative non-target emotions. Follow-up analyses confirmed that these effects were left-lateralized. No correlates emerged for positive non-target emotions. These findings suggest that volume loss in left-hemisphere regions produces a more diffuse, incongruent experience of non-target emotions. These findings provide a potential neuroanatomical basis for understanding how subjective emotional experience is constructed in the brain and how this can be disrupted in neurodegenerative disease.

The topology of higher-order complexes associated with brain hubs in human connectomes.

Higher-order connectivity in complex systems described by simplexes of different orders provides a geometry for simplex-based dynamical variables and interactions. Simplicial complexes that constitute a functional geometry of the human connectome can be crucial for the brain complex dynamics. In this context, the best-connected brain areas, designated as hub nodes, play a central role in supporting integrated brain function. Here, we study the structure of simplicial complexes attached to eight global hubs in the female and male connectomes and identify the core networks among the affected brain regions. These eight hubs (Putamen, Caudate, Hippocampus and Thalamus-Proper in the left and right cerebral hemisphere) are the highest-ranking according to their topological dimension, defined as the number of simplexes of all orders in which the node participates. Furthermore, we analyse the weight-dependent heterogeneity of simplexes. We demonstrate changes in the structure of identified core networks and topological entropy when the threshold weight is gradually increased. These results highlight the role of higher-order interactions in human brain networks and provide additional evidence for (dis)similarity between the female and male connectomes.

The Caudate Nucleus: Its Connections, Surgical Implications, and Related Complications.

BACKGROUND: The caudate nucleus is a C-shaped structure that is located in the center of the brain and is divided into 3 parts: the head, body, and tail. METHODS: We detail the anatomic connections, relationships with other basal ganglia structures, and clinical implications of injury to the caudate nucleus. RESULTS: Anatomically, the most inferior transcapsular gray matter is the lentiform peduncle, which is the connection between the lentiform nucleus and caudate nucleus as well as the amygdala. The border between the tail and body of the caudate nucleus is the posterior insular point. The tail of the caudate nucleus is extraependymal in some parts and intraependymal in some parts of the roof of the temporal horn of the lateral ventricle. The tail of the caudate nucleus crosses the inferior limiting sulcus (temporal stem), and section of the tail during approaches to lesions involving the temporal stem may cause motor apraxia. The mean distance from the temporal limen point, which is the junction of the limen insula and inferior limiting sulcus, to the tail of the caudate nucleus in the temporal stem is 15.87 ± 3.10 mm. CONCLUSIONS: Understanding of the functional anatomy and connections of the distinct parts of the caudate nucleus is essential for deciding the extent of resection of lesions involving the caudate nucleus and the types of deficits that may be found postoperatively.

Role of T1 mapping to evaluate brain aging in a healthy population.

PURPOSE: To investigate the relationship between healthy brain aging and T1 relaxation time obtained by T1 mapping. MATERIALS AND METHODS: A total of 211 (102 males, 109 females; age range: 20-89 years; mean age: 54 years) healthy volunteers underwent T1 mapping between July 2018 and January 2019. Regions of interest (ROIs) were placed on T1 maps in different anatomical regions, including the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe white matter (WM). Additionally, linear and quadratic regression analyses of ROIs were performed. RESULTS: There were significant quadratic and negative linear correlations between T1 relaxation times in the thalamus, putamen, and age (p < .001). Although the nucleus accumbens did not show a significant relationship between T1 relaxation times and age by linear regression (p = .624), a statistically significant relationship was obtained by quadratic regression (p < .001). For the globus pallidus, head of the caudate nucleus, genu of the corpus callosum and frontal lobe WM the quadratic regression analysis showed a better relationship than the linear correlation analysis. CONCLUSION: Age-related changes in T1 relaxation time vary by location in GM and WM.

Separate Contribution of Striatum Volume and Pitch Discrimination to Individual Differences in Music Reward.

Individual differences in the level of pleasure induced by music have been associated with the response of the striatum and differences in functional connectivity between the striatum and the auditory cortex. In this study, we tested whether individual differences in music reward are related to the structure of the striatum and the ability to discriminate pitch. We acquired a 3-D magnetization-prepared rapid-acquisition gradient-echo image for 32 musicians and 26 nonmusicians who completed a music-reward questionnaire and a test of pitch discrimination. The analysis of both groups together showed that sensitivity to music reward correlated negatively with the volume of both the caudate and nucleus accumbens and correlated positively with pitch-discrimination abilities. Moreover, musicianship, pitch discrimination, and caudate volume significantly predicted individual differences in music reward. These results are consistent with the proposal that individual differences in music reward depend on the interplay between auditory abilities and the reward network.

Glutaminergic signaling in the caudate nucleus is required for behavioral sensitization to methylphenidate.

Methylphenidate (MPD) is a widely prescribed psychostimulant for the treatment of attention deficit hyperactivity disorder, and is growing in use as a recreational drug and academic enhancer. MPD acts on the reward/motive and motor circuits of the CNS to produce its effects on behavior. The caudate nucleus (CN) is known to be a part of these circuits, so a lesion study was designed to elucidate the role of the CN in response to acute and chronic MPD exposure. Five groups of n = 8 rats were used: control, sham CN lesions, non-specific electrolytic CN lesions, dopaminergic-specific (6-OHDA toxin) CN lesion, and glutaminergic-specific (ibotenic acid toxin) CN lesions. On experimental day (ED) 1, all groups received saline injections. On ED 2, surgeries took place, followed by a 5-day recovery period (ED 3-7). Groups then received six daily MPD 2.5 mg/kg injections (ED 9-14), then three days of washout with no injection (ED 15-17), followed by a re-challenge with the previous 2.5 mg/kg MPD dose (ED 18). Locomotive activity was recorded for 60 min after each injection by a computerized animal activity monitor. The electrolytic CN lesion group responded to the MPD acute and chronic exposures similarly to the control and sham groups, showing an increase in locomotive activity, i.e. sensitization. The dopaminergic-specific CN lesion group failed to respond to MPD exposure both acute and chronically. The glutaminergic-specific CN lesion group responded to MPD exposure acutely but failed to manifest chronic effects. This confirms the CN's dopaminergic system is necessary for MPD to manifest its acute and chronic effects on behavior, and demonstrates that the CN's glutaminergic system is necessary for the chronic effects of MPD such as sensitization. Thus, the dopaminergic and glutaminergic components of the CN play a significant role in differentially modulating the acute and chronic effects of MPD respectively.

Quantification of Microsurgical Anatomy in Three-Dimensional Model: Transfrontal Approach for Anterior Portion of the Thalamus.

The thalamus located in the deep site of cerebrum with the risk of internal capsule injury during operation. The purpose of this study was to compare the anatomy for exposure and injury using simulative surgical corridor of 3-dimensional model. The 3-dimensional anatomy model of thalamus in cerebrum was created based on magnetic resonance imaging performed for 15 patients with trigeminal neuralgia. The midpoint of line between anterior edge and top of thalamus was the target exposed. Axis connecting the target with the anterior edge and top of caudate head was used to outline the cylinder, respectively, simulating surgical corridors 1 and 2 of transfrontal approach. Cerebral tissues involved in the corridors were observed, measured, and compared. Incision of cortex was made on the anterior portion of inferior frontal gyrus through corridor 1 and middle frontal gyrus through corridor 2. Both of the 2 corridors passed the caudate nucleus, the anterior limb and genu of internal capsule, ultimately reached the upper anterior portion of thalamus. The volumes of white matter, caudate head, and thalamus in the corridor 1 were more than those in corridor 2. Conversely, the volumes of cortex, internal capsule in corridor 2 were more than those in corridor 1. In conclusion, surgical anatomy-specific volume is helpful to postulate the intraoperative injury of transfrontal approach exposing anterior portion of the thalamus. The detailed information in the quantification of microsurgical anatomy will be used to develop minimally invasive operation.

Shape-related characteristics of age-related differences in subcortical structures.

OBJECTIVES: With an increasing aging population, it is important to understand biological markers of aging. Subcortical volume is known to differ with age; additionally considering shape-related characteristics may provide a better index of age-related differences. Fractal dimensionality is more sensitive to age-related differences, but is borne out of mathematical principles, rather than neurobiological relevance. We considered four distinct measures of shape and how they relate to aging and fractal dimensionality: surface-to-volume ratio, sphericity, long-axis curvature, and surface texture. METHODS: Structural MRIs from a combined sample of over 600 healthy adults were used to measure age-related differences in the structure of the thalamus, putamen, caudate, and hippocampus. For each, volume and fractal dimensionality were calculated, as well as four distinct shape measures. These measures were examined for their utility in explaining age-related variability in brain structure. RESULTS: The four shape measures were able to account for 80%-90% of the variance in fractal dimensionality. Of the distinct shape measures, surface-to-volume ratio was the most sensitive biomarker. CONCLUSION: Though volume is often used to characterize inter-individual differences in subcortical structures, our results demonstrate that additional measures can be useful complements. Our results indicate that shape characteristics are useful biological markers of aging.

Different contributions of preparatory activity in the basal ganglia and cerebellum for self-timing.

The ability to flexibly adjust movement timing is important for everyday life. Although the basal ganglia and cerebellum have been implicated in monitoring of supra- and sub-second intervals, respectively, the underlying neuronal mechanism remains unclear. Here, we show that in monkeys trained to generate a self-initiated saccade at instructed timing following a visual cue, neurons in the caudate nucleus kept track of passage of time throughout the delay period, while those in the cerebellar dentate nucleus were recruited only during the last part of the delay period. Conversely, neuronal correlates of trial-by-trial variation of self-timing emerged earlier in the cerebellum than the striatum. Local inactivation of respective recording sites confirmed the difference in their relative contributions to supra- and sub-second intervals. These results suggest that the basal ganglia may measure elapsed time relative to the intended interval, while the cerebellum might be responsible for the fine adjustment of self-timing.

The neuromorphological caudate-putaminal clustering of neostriate interneurons: Kohonen self-organizing maps and supervised artificial neural networks with multivariate analysis.

AIMS: The objective of this study is to investigate the possibility of the neuromorphotopological clustering of neostriate interneurons (NSIN) and their consequent classification into caudate (CIN) and putaminal neuron type (PIN), according to the nuclear localization of the neurons. It tends to discover whether these two topological neuron types are morphologically different. MATERIAL AND METHODS: The binary images of adult human NSIN are used for the purposes of the analysis. The total of the 46 neuromorphological parameters is used. They can be divided into the following classes: neuron surface/size, shape, compartmental length, dendritic branching, neuromorphological organization and complexity. The clustering is performed by an algorithm which consists of the steps of predictor extraction, multivariate cluster analysis set and cluster identification. RESULTS: Unifactor analysis extracted as significant the following parameters: neurosoma/perikaryon size (AS), the size of a dendritic tree (ADT), the size of a dendritic field area (ADF), the size of an entire neuron field area (ANF), the size of a perineuronal space (APNS), the fractal dimension of a neuron (DN), the index of perikaryon asymmetry (MS), total dendritic length (L), standardized total dendritic length (Lst), standardized dendritic width (DWDTHst), dendritic centrifugal branching order (DCBO), branching polarization index (MDCBO), dendritic partial surface (DSP), the fractal dimension of a skeletonized neuron image (DS), the index of maximal complex density of a dendritic tree (NMAX) and standardized dendritic branching pattern complexity (CDF/ADFst). The cluster analysis set together with Kohonen self-organizing maps and backpropagation feed-forward artificial neural networks confirmed the classification on both unsupervised and supervised manner, respectively. As a final step, the cluster identification is performed by an assignment of each neuron to a particular cluster. CONCLUSION: NSIN can be classified neuromorphologically into CIN and PIN type. Differences are expected since the two nuclei have different functional roles in processing the information involved in volitional movement control.

Microsurgical anatomy of the central core of the brain.

OBJECTIVE The purpose of this study was to describe in detail the cortical and subcortical anatomy of the central core of the brain, defining its limits, with particular attention to the topography and relationships of the thalamus, basal ganglia, and related white matter pathways and vessels. METHODS The authors studied 19 cerebral hemispheres. The vascular systems of all of the specimens were injected with colored silicone, and the specimens were then frozen for at least 1 month to facilitate identification of individual fiber tracts. The dissections were performed in a stepwise manner, locating each gray matter nucleus and white matter pathway at different depths inside the central core. The course of fiber pathways was also noted in relation to the insular limiting sulci. RESULTS The insular surface is the most superficial aspect of the central core and is divided by a central sulcus into an anterior portion, usually containing 3 short gyri, and a posterior portion, with 2 long gyri. It is bounded by the anterior limiting sulcus, the superior limiting sulcus, and the inferior limiting sulcus. The extreme capsule is directly underneath the insular surface and is composed of short association fibers that extend toward all the opercula. The claustrum lies deep to the extreme capsule, and the external capsule is found medial to it. Three fiber pathways contribute to form both the extreme and external capsules, and they lie in a sequential anteroposterior disposition: the uncinate fascicle, the inferior fronto-occipital fascicle, and claustrocortical fibers. The putamen and the globus pallidus are between the external capsule, laterally, and the internal capsule, medially. The internal capsule is present medial to almost all insular limiting sulci and most of the insular surface, but not to their most anteroinferior portions. This anteroinferior portion of the central core has a more complex anatomy and is distinguished in this paper as the "anterior perforated substance region." The caudate nucleus and thalamus lie medial to the internal capsule, as the most medial structures of the central core. While the anterior half of the central core is related to the head of the caudate nucleus, the posterior half is related to the thalamus, and hence to each associated portion of the internal capsule between these structures and the insular surface. The central core stands on top of the brainstem. The brainstem and central core are connected by several white matter pathways and are not separated from each other by any natural division. The authors propose a subdivision of the central core into quadrants and describe each in detail. The functional importance of each structure is highlighted, and surgical approaches are suggested for each quadrant of the central core. CONCLUSIONS As a general rule, the internal capsule and its vascularization should be seen as a parasagittal barrier with great functional importance. This is of particular importance in choosing surgical approaches within this region.

Behavioural Differences and Neural Substrates of Altruistic and Spiteful Punishment.

Altruistic punishment following social norm violations promotes human cooperation. However, experimental evidence indicates that some forms of punishment are spiteful rather than altruistic. Using two types of punishment games and seven non-strategic games, we identified strong behavioural differences between altruistic and spiteful punishers. Altruistic punishers who rejected unfair offers in the ultimatum game and punished norm violators in the third-party punishment game behaved pro-socially in various non-strategic games. Spiteful punishers who rejected unfair offers in the ultimatum game but did not punish norm violators in the third-party punishment game behaved selfishly in non-strategic games. In addition, the left caudate nucleus was larger in spiteful punishers than in altruistic punishers. These findings are in contrast to the previous assumption that altruistic punishers derive pleasure from enforcement of fairness norms, and suggest that spiteful punishers derive pleasure from seeing the target experience negative consequences.

Immersive bilingualism reshapes the core of the brain.

Bilingualism has been shown to affect the structure of the brain, including cortical regions related to language. Less is known about subcortical structures, such as the basal ganglia, which underlie speech monitoring and language selection, processes that are crucial for bilinguals, as well as other linguistic functions, such as grammatical and phonological acquisition and processing. Simultaneous bilinguals have demonstrated significant reshaping of the basal ganglia and the thalamus compared to monolinguals. However, it is not clear whether these effects are due to learning of the second language (L2) at a very young age or simply due to continuous usage of two languages. Here, we show that bilingualism-induced subcortical effects are directly related to the amount of continuous L2 usage, or L2 immersion. We found significant subcortical reshaping in non-simultaneous (or sequential) bilinguals with extensive immersion in a bilingual environment, closely mirroring the recent findings in simultaneous bilinguals. Importantly, some of these effects were positively correlated to the amount of L2 immersion. Conversely, sequential bilinguals with comparable proficiency and age of acquisition (AoA) but limited immersion did not show similar effects. Our results provide structural evidence to suggestions that L2 acquisition continuously occurs in an immersive environment, and is expressed as dynamic reshaping of the core of the brain. These findings propose that second language learning in the brain is a dynamic procedure which depends on active and continuous L2 usage.

Heritability of the shape of subcortical brain structures in the general population.

The volumes of subcortical brain structures are highly heritable, but genetic underpinnings of their shape remain relatively obscure. Here we determine the relative contribution of genetic factors to individual variation in the shape of seven bilateral subcortical structures: the nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. In 3,686 unrelated individuals aged between 45 and 98 years, brain magnetic resonance imaging and genotyping was performed. The maximal heritability of shape varies from 32.7 to 53.3% across the subcortical structures. Genetic contributions to shape extend beyond influences on intracranial volume and the gross volume of the respective structure. The regional variance in heritability was related to the reliability of the measurements, but could not be accounted for by technical factors only. These findings could be replicated in an independent sample of 1,040 twins. Differences in genetic contributions within a single region reveal the value of refined brain maps to appreciate the genetic complexity of brain structures.

Distinct roles for primate caudate dopamine D1 and D2 receptors in visual discrimination learning revealed using shRNA knockdown.

The striatum plays important motor, associative and cognitive roles in brain functions. However, the rodent dorsolateral (the primate putamen) and dorsomedial (the primate caudate nucleus) striatum are not anatomically separated, making it difficult to distinguish their functions. By contrast, anatomical separation exists between the caudate nucleus and putamen in primates. Here, we successfully decreased dopamine D1 receptor (D1R) or D2R mRNA expression levels selectively in the marmoset caudate using shRNA knockdown techniques, as determined using positron emission tomography imaging with specific D1R and D2R ligands and postmortem in situ hybridization analysis. We then conducted a voxel-based correlation analysis between binding potential values of PET imaging and visual discrimination learning task performance in these genetically modified marmosets to find a critical role for the caudate D2R but no apparent role for the caudate D1R. This latter finding challenges the current understanding of the mechanisms underlying D1R activation in the caudate.

Microsurgical and Tractographic Anatomy of the Supplementary Motor Area Complex in Humans.

OBJECTIVE: To evaluate the microsurgical anatomy of the fiber tract connections of the supplementary motor area (SMA) and pre-SMA, and examine its potential functional role with reference to clinical trials in the literature. METHODS: Ten postmortem formalin-fixed human brains (20 sides) and 1 cadaveric head were prepared following Klingler's method. The fiber dissection was performed in a stepwise fashion, from lateral to medial and also from medial to lateral, under an operating microscope, with 3D images captured at each stage. Our findings were supported by in vivo magnetic resonance imaging tractography in 2 healthy subjects. RESULTS: The connections of the SMA complex, composed of the pre-SMA and the SMA proper, are composed of short "U" association fibers and the superior longitudinal fasciculus I, cingulum, claustrocortical fibers, callosal fibers, corticospinal tract, frontal aslant tract, and frontostriatal tract. The claustrocortical fibers may play an important role in the integration of motor, language, and limbic functions of the SMA complex. The frontostriatal tract connects the pre-SMA to the putamen and caudate nucleus, and also forms parts of both the internal capsule and the dorsal external capsule. CONCLUSIONS: The SMA complex has numerous connections throughout the cerebrum. An understanding of these connections is important for presurgical planning for lesions in the frontal lobe and helps explain symptoms related to SMA injury.