Exploring structural brain changes in children with neonatal brachial plexus palsy: a voxel-based morphometry analysis

Dzerassa  V.  Kadieva; Кадиева Дзерасса Викторовна; Federico Gallo; Галло Федерико; Maxim  A.  Ulanov; Уланов Максим Александрович; Anna  N.  Shestakova; Шестакова Анна Николаевна; Victoria  V.  Moiseeva; Моисеева Виктория Владимировна; Alina  M.  Hodorovskaya; Ходоровская Алина Михайловна; Olga  E.  Agronovich; Агранович Ольга Евгеньевна

doi:10.23868/gc568311

Изучение структурных атипий головного мозга у детей с акушерским параличом плечевого сплетения: воксель-базированная морфометрия

Авторы: Кадиева Д.В.¹, Галло Ф.¹, Уланов М.А.¹, Шестакова А.Н.¹, Моисеева В.В.¹, Ходоровская А.М.², Агранович О.Е.²
Учреждения:
1. Национальный исследовательский университет «Высшая школа экономики»
2. Национальный медицинский исследовательский центр детской травматологии и ортопедии имени Г.И. Турнера
Выпуск: Том 18, № 4 (2023)
Страницы: 331-339
Раздел: Оригинальные исследования
Статья получена: 12.08.2023
Статья одобрена: 24.10.2023
Статья опубликована: 15.12.2023
URL: https://genescells.ru/2313-1829/article/view/568311
DOI: https://doi.org/10.23868/gc568311
ID: 568311

Цитировать

Полный текст

Открытый доступ
Доступ закрыт

Доступ предоставлен
Доступ закрыт

Доступ платный или только для подписчиков

Аннотация
Полный текст
Об авторах
Список литературы
Дополнительные файлы
Статистика

Аннотация

Обоснование. Акушерский паралич плечевого сплетения — заболевание новорождённых, обычно возникающее в результате разрыва нерва во время трудных вагинальных родов, приводящее к параличу одной из верхних конечностей. Несмотря на то, что современные методы лечения могут гарантировать почти полную реиннервацию конечности, у некоторых пациентов все ещё наблюдается плохая двигательная функция. Одной из причин этого несоответствия может быть чередование в мозге, возникающее в результате ограниченного использования конечности с рождения.

Цель исследования — сравнить объёмы серого вещества у детей с акушерским параличом и здоровых.

Методы. Используя метод воксельной морфометрии в SPM12 (Statistical Parametric Mapping) в MATLAB R2019b, мы проанализировали 46 структурных МРТ 24 детей с акушерским параличом (средний возраст — 10,20 года), из них 12 девочек, и 22 здоровых детей контрольной группы соответствующего возраста (средний возраст — 9,63 года), из них 10 девочек.

Результаты. Мы обнаружили объёмные различия между пациентами и здоровыми участниками, которые выдержали поправку на множественную проверку гипотез (FWE, p <0,005). Результаты показали, что у детей с акушерским параличом были значительно меньшие объёмы левого миндалевидного тела, гиппокампа и правой энторинальной области.

Заключение. Принимая во внимание предыдущие исследования этих областей мозга, мы можем предположить, что комплекс миндалевидное тело–гиппокамп–энторинальная кора может играть значительную роль в моторном поведении.

Ключевые слова

моторные нарушения, объём серого вещества, акушерский паралич плечевого сплетения

Полный текст

INTRODUCTION

Obstetric brachial plexus palsy (OBPP) is an injury-related disease in newborns, usually originating from nerve tearing during a difficult vaginal delivery, leading to paralysis of one of the upper limbs [1]. The prevalence of OBPP ranges from 1.6 to 5.1 per 1000 births [2, 3]. Prognosis is generally favorable, with almost half of patients spontaneously recovering upper limb motor functioning. However, in 20–30% of children, severe OBPP can cause persistent hand dysfunction, skeletal deformity, cosmetic deformity, and limitations in activities of daily living, such as feeding, grooming, and dressing [4, 5]. Treatment is based on clinical severity and may include physical therapy, microsurgical nerve reconstruction, shoulder reconstruction, and tendon transfers [6].

Variations in clinical outcomes of OBPP across individuals may arise from alterations in the brain structure and function that results from a restricted use of the upper limb since birth [7–9]. Previous investigations demonstrate that despite muscle reinnervation, some patients show long-term motor deficits and developmental apraxia [9–11]. These suggest that following injury, neuroplastic changes result in unique adaptations in sensory and motor cerebral circuits early in development. While most studies focus on the treatment and repair of peripheral nerves, few have investigated the cerebral sequelae of OBPP. To develop successful rehabilitation strategies, it is crucial to understand the structural and functional differences in the brain of patients with lifelong OBPP when compared to healthy and recovered individuals.

In the present study, we investigate brain changes in children with OBPP. We aimed to explore gray matter volumetric differences between patients and healthy children. While cortical changes in OBPP has been previously reported [9, 12], this is the first report of deep brain structural alterations in OBPP.

METHODS

Participants

Forty-six age-matched children participated in this study: 24 patients (2–17 years old, mean age — 10.20, of whom 12 females), and 22 healthy controls (2–17 years old, mean age — 9.63, of whom 10 females). All healthy participants were right-handed. The hand dominance in the clinical group varied depending on the side of the palsy. Patients with OBPP were recruited and assessed at the Turner National Medical Research Center for Children’s Orthopedics and Trauma Surgery (Saint Petersburg, Russia). Patients from different parts of the country were assessed before reconstructive surgery. Participants in the control group were recruited and assessed at the National Research Institute of Emergency Children’s Surgery and Traumatology (Moscow, Russia). The study protocol was approved by the local ethics committee of the National Research University Higher School of Economics (N 19–3 dated 09 December 2019). Written informed consent was obtained from the participants’ guardians.

Only healthy participants without a history of neuropsychological or orthopedic disease were included in the control group. All patients with OBPP group reported signs and symptoms related to the disease, including upper limb contractures, flaccid palsy, and muscle hypoplasia or aplasia. Patients with any residual brain structural anomalies, such as hydrocephalus, were excluded.

Magnetic resonance imaging data collection

T1-weighted 3D images were collected using two Philips Ingenia Elition X 3.0T magnetic resonance scanners in both study sites. The following parameters were set for magnetic resonance imaging (MRI) data acquisition: voxel size — 1.0×1.0×1.0 mm³, repetition time — 8.5 ms, echo time — 3.7 ms, 180 slices, slice thickness — 1 mm, acquisition matrix — 256×256, field of view — 256×256 mm, and flip angle — 8°.

Magnetic resonance imaging data preprocessing

Images were visually inspected for movement artifacts and other abnormalities. Images were uniformly aligned to the anterior commissure–posterior commissure line. Images were then spatially normalized and segmented into gray matter (GM), white matter, and cerebrospinal fluid using SPM12 (Statistical Parametric Mapping, https://www.fil.ion.ucl.ac.uk/spm/) in MATLAB R2019b. Total intracranial volumes (TIV) were also automatically acquired. The normalized maps were modulated with the resulting Jacobian determinant maps to preserve GM volumes of native space and smoothed with an 8-mm FWHM Gaussian kernel. Voxel-based morphometry in CAT12 (Computational Anatomy Toolbox, https://neuro-jena.github.io/cat/) within SPM12 was used to compare whole-brain GM density in patients and controls. Maximum tissue probability labels derived from the Neuromorphometrics Atlas (http://www.neuromorphometrics.com/) were used to identify brain regions which showed significant volumetric differences between groups.

Statistical analysis

Voxel-based morphometry analysis was performed in CAT12 using a generalized linear model. The smoothed GM images of both groups were tested by a voxel-based two-sample t-test. TIV, age, and sex were set as covariates to account for differences in individual brain size.

RESULTS

Gray matter volumes comparison, controlled for TIV, age, gender and corrected for multiple comparisons, revealed significant differences between patients with OBPP and healthy controls in several regions. Patients showed significantly lower GM volume than controls in clusters whose peaks were located in the left amygdala and hippocampus (p <0.0001 family wise error (FWE)-corrected cluster level), right entorhinal area (p <0.002 FWE-corrected cluster level), and right hippocampus (p <0.002 FWE-corrected cluster level). The results are shown in Table 1 and Fig. 1. No regions showed greater GM volume in the OBPP group compared to controls. We did not observe differences in GM volume in the motor cortex between the groups.

Table 1. Cluster level and peak level voxel-based morphometry differences

Таблица 1. Статистически значимые результаты воксель-базированной морфометрии на уровне кластеров и пиковом уровне

Region	Cluster level		Peak level
Region	p_FWE–corr	K_c	p_FWE–corr	mm mm mm
Left hippocampus	0.0001	1899	0.0001	–24 –7 –22
Right entorhinal area	0.002	185	0.004	27 1 –15
Left amygdala	0.002	192	0.007	–24 0 –21
Right hippocampus	0.002	174	0.01	23 –10 –19

Fig. 1. Regional differences in gray matter volume between children with OBPP and healthy controls groups based on voxel-based morphometry analyses: a — left amygdala and hippocampus; b — right entorhinal area; c — right hippocampus.

Рис. 1. Области, демонстрирующие значительные различия в объёме серого вещества между пациентами и здоровыми участниками на основе воксельной морфометрии: a — левая миндалина и гиппокамп; b — правая энторинальная область; c — правый гиппокамп.

DISCUSSION

In this explorative study, we compared the brain structures of young patients with OBPP and age-matched healthy controls. Our findings corroborate previous work suggesting that neonatal injury to a peripheral nerve can lead to the reorganization in the brain [9, 13]. We found volumetric differences between patients and healthy controls using a stringent procedure to control the family-wise error rate. Below, we discuss our results by individual brain region.

Amygdala

The amygdala is most known for its role in emotions, reward processing, context-appropriate social behaviors, and modulation of memory [14–16]. However, the role of the amygdala in goal-directed movement is supported by its projections to the premotor and primary motor cortices [17, 18]. Notably, reduced volumes in the amygdala have been reported in patients with neurodegenerative motor diseases, such as Huntington’s disease and amyotrophic lateral sclerosis [19, 20]. Further investigations of the motor contributions of the amygdala are required to further characterize alterations beyond GM volumes.

Hippocampus

Aligned with its well-established role in memory [21, 22], the hippocampus has a documented motor function, especially during motor sequence learning [23–25]. In addition, the hippocampus has been implicated in theta wave generation during spatial navigation, which improves motor performance [26]. Hippocampal projections to the sensorimotor cortex have been shown to be activated during repetitive and learned-paced movements [27]. This finding suggests that the hippocampus may contribute to volitional finger movements, even in the absence of motor learning. Taken together, our results on reduced hippocampal volume in a motor disease highlights the potential role of the hippocampus in voluntary movement.

Entorhinal area

A recent study by de Brouwer et al. [28] reported that higher entorhinal cortex volumes were associated with better during error and reinforcement motor learning. In support of this, our results revealed higher entorhinal cortical volumes in healthy children compared to those with OBPP.

Moreover, the entorhinal cortex has strong connections with the hippocampus and amygdala. Projections between the entorhinal cortex and hippocampus play a role in spatial navigation and memory in humans and animals [29–32]. Projections from the amygdala to both hippocampus and entorhinal cortex govern reward-driven modulation of memory processes [33]. Moreover, both structures have functional connections with medial prefrontal cortex (mPFC) and anterior cingulate cortex, which support synaptic plasticity-mediated memory consolidation [34]. Our results suggest that volumetric differences due to neonatal injury have manifold functional consequences, which include sensorimotor function, as well as higher-order cognitive functions, such as learning and episodic memory.

Motor cortex

We found no changes in GM volume in the primary motor cortex in OBPP. This result is consistent with previous studies that reported no differences in motor cortical volumes between patients with OBPP and controls [35, 36]. From healthy adult studies, acquisition and execution of motor skills is supported by distributed neural networks that include the premotor cortex, parieto-occipital area, subcortical structures, cerebellum, and hippocampus [37–42]. Moreover, the roles of the primary motor cortex and other motor structures during motor learning and execution are unequal, depending on the stage and type of motor skill [43]. Finally, developmental studies show that the peak of plastic changes in the sensorimotor cortical areas occurs early in the first year of life [44]. This suggests that further acquisition of motor skills later in development recruits other motor areas. Therefore, we propose that OBPP children might rely on compensatory strategies in motor learning and functioning in systems beyond the primary cortex that develop later in development. These structures and networks govern motor programming, sensorimotor transformation, and spatial navigation. These circuits might support motor adaptations used by OBPP children to overcome their motor deficits.

Altogether, our present study provides a basis for a fascinating novel involvement of deep brain structures, such as the amygdala, hippocampus, and entorhinal area, in motor-related behavior. Our next step will be to conduct a surface-based analysis comparing the cortical properties in the brains of patients with OBPP and healthy controls.

CONCLUSION

One third of children with obstetric brachial plexus palsy never recover their motor abilities even after complete restoration of limb innervation. Current literature focus on peripheral nerve rehabilitation. Less attention has been given to central nervous system changes due to limb disuse and its negative effects in successful recovery. We compared structural brain changes in children with obstetric brachial plexus and healthy controls to understand how this restrictions in movement can affect the cerebral organization. We found the obstetric brachial plexus, gray matter volumes were reduced in the left amygdala, bilateral hippocampus, and right entorhinal cortex. We hypothesize that these subcortical regions might play a significant role in motor function. However, further investigations on the anatomical and functional changes in these deep brain structures are warranted to support their role in motor circuits and motor disease.

ADDITIONAL INFORMATION

Funding source. This work is an output of a research project supported by the grant N 20-68-47038.

Competing interests. The authors declare that they have no competing interests.

Authors' contribution. D.V. Kadieva — data collection and processing, analysis, preparation of the text of the article; F. Gallo — editing of the article, literature review; M.A. Ulanov — editing of the article, literature review; A.N. Shestakova and A.M. Hodorovkaya — MRI collection; O.E. Agranovich — surgical treatment of the patient, assistance with collecting MRI data; V.V. Moiseeva — editing of the article.All authors confirm that their authorship meets the international ICMJE criteria (all authors have made a significant contribution to the development of the concept, research and preparation of the article, read and approved the final version before publication).

ДОПОЛНИТЕЛЬНО

Источник финансирования. Научное исследование проведено при поддержке гранта № 20-68-47038.

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи.

Вклад авторов. Д.В. Кадиева — сбор и обработка данных, анализ, подготовка текста статьи; Ф. Галло — редактирование статьи, обзор литературы; М.А. Уланов — редактирование статьи, обзор литературы; А.Н. Шестакова и А.М. Ходоровская — сбор данных МРТ; О.Е. Агранович — хирургическое лечение пациента, помощь с сборе данных МРТ; В.В. Моисеева — редактирование статьи. Все авторы подтверждают соответствие своего авторства международным критериям ICMJE (все авторы внесли существенный вклад в разработку концепции, проведение исследования и подготовку статьи, прочли и одобрили финальную версию перед публикацией).