Clinical implications of brain asymmetries.

No two human brains are alike, and with the rise of precision medicine in neurology, we are seeing an increased emphasis on understanding the individual variability in brain structure and function that renders every brain unique. Functional and structural brain asymmetries are a fundamental principle of brain organization, and recent research suggests substantial individual variability in these asymmetries that needs to be considered in clinical practice. In this Review, we provide an overview of brain asymmetries, variations in such asymmetries and their relevance in the clinical context. We review recent findings on brain asymmetries in neuropsychiatric and neurodevelopmental disorders, as well as in specific learning disabilities, with an emphasis on large-scale database studies and meta-analyses. We also highlight the relevance of asymmetries for disease symptom onset in neurodegenerative diseases and their implications for lateralized treatments, including brain stimulation. We conclude that alterations in brain asymmetry are not sufficiently specific to act as diagnostic biomarkers but can serve as meaningful symptom or treatment response biomarkers in certain contexts. On the basis of these insights, we provide several recommendations for neurological clinical practice.

Brain (Yakovlevian) torque direction is associated with volume asymmetry of the intracranial transverse sinuses: evidence from situs inversus totalis.

Previous research reported reversal of the prototypical brain torque in individuals with mirrored visceral topology (situs inversus totalis, SIT). Here, we investigate if typical asymmetry of the posterior intracranial venous system is also reversed in SIT and whether the direction and magnitude of this asymmetry is related to the direction and magnitude of the brain torque. Brain structural MRI images of 38 participants with SIT were compared with those of 38 matched control participants. Occipital and frontal petalia and bending were measured using a standardized procedure. In addition, representative sections of the left and right transverse sinuses were segmented, and their respective volumes determined. Participants with SIT showed general reversal of occipital and frontal petalia and occipital bending, as well as reversal of typical transverse sinus asymmetry. Transverse sinus volume was significantly correlated with several torque measures, such that the smaller transverse sinus was associated with a larger ipsilateral occipital petalia, contralateral occipital bending, and ipsilateral frontal bending. We propose an anatomical mechanism to explain occipital petalia and bending, and conclude that anatomical constraints imposed by the asymmetry of the posterior venous system provide and additional account to elucidate the formation of the human brain torque.

Brain functional segregation, handedness and cognition in situs inversus totalis: A replication study.

Situs inversus totalis (SIT) is a rare congenital anomaly in which the arrangement of the visceral organs is completely left-right mirrored. A previous study by our lab suggests that SIT (N = 15) correlated with more heterogeneous asymmetrical brain organization and increased left-handedness. In addition, visceral reversal correlated with poorer cognitive performance, especially when hemisphere organization was atypical. The current study sought to replicate these findings in a larger sample. We scanned 23 volunteers with SIT as well as an equal number of controls with usual organ arrangement, and used fMRI to determine their hemisphere dominance for two left hemisphere functions (language and manual praxis) and two right hemisphere functions (spatial attention and face recognition). Effects of SIT etiology were explored by pooling data from the original cohort with the replication sample. Our results reveal that each of those four cognitive functions demonstrated the expected population dominance in SIT, albeit they were less pronounced - but not significantly so - compared to controls. Unusual patterns of hemispheric crowding and mirror-reversal of functional brain organization was observed more often in SIT (48%) than in the controls (30%), but this difference also did not reach statistical significance. However, left-handedness was found to be significantly more common in SIT (26%) than in the overall population (10.6%). Finally, cognitive ability, as assessed by a neuropsychological test battery, was not associated with organ situs or hemisphere organization. Taken together, our data adds to the growing evidence that the determinants of visceral and neural asymmetries are largely independent from one another and that complete situs inversus does not co-occur with an obligatory transposition of the brain's functional architecture. There nevertheless might be instances in which (genetic) mechanisms could simultaneously cause complete visceral reversal and atypical brain laterality.

Laterality indices consensus initiative (LICI): A Delphi expert survey report on recommendations to record, assess, and report asymmetry in human behavioural and brain research.

Laterality indices (LIs) quantify the left-right asymmetry of brain and behavioural variables and provide a measure that is statistically convenient and seemingly easy to interpret. Substantial variability in how structural and functional asymmetries are recorded, calculated, and reported, however, suggest little agreement on the conditions required for its valid assessment. The present study aimed for consensus on general aspects in this context of laterality research, and more specifically within a particular method or technique (i.e., dichotic listening, visual half-field technique, performance asymmetries, preference bias reports, electrophysiological recording, functional MRI, structural MRI, and functional transcranial Doppler sonography). Experts in laterality research were invited to participate in an online Delphi survey to evaluate consensus and stimulate discussion. In Round 0, 106 experts generated 453 statements on what they considered good practice in their field of expertise. Statements were organised into a 295-statement survey that the experts then were asked, in Round 1, to independently assess for importance and support, which further reduced the survey to 241 statements that were presented again to the experts in Round 2. Based on the Round 2 input, we present a set of critically reviewed key recommendations to record, assess, and report laterality research for various methods.

Structural perisylvian asymmetry in naturally occurring atypical language dominance.

Functional and anatomical hemispheric asymmetries abound in the neural language system, yet the relationship between them remains elusive. One attractive proposal is that structural interhemispheric differences reflect or even drive functional language laterality. However, studies on structure-function couplings either find that left and right language dominant individuals display similar leftward structural asymmetry or yield inconsistent results. The current study aimed to replicate and extend prior work by comparing structural asymmetries between neurologically healthy left-handers with right hemispheric language dominance (N = 24) and typically lateralized left-handed controls (N = 39). Based on structural MRI data, anatomical measures of six 'language-related' perisylvian structures were derived, including the surface area of five gray matter regions with known language functions and the FDC (combined fiber density and fiber-bundle cross-sectional area) of the arcuate fasciculus. Only the surface area of the pars triangularis and the anterior insula differed significantly between participant groups, being on average leftward asymmetric in those with typical dominance, but right lateralized in volunteers with atypical language specialization. However, these findings did not survive multiple testing correction and the asymmetry of these structures demonstrated much inter-individual variability in either subgroup. By integrating our findings with those reported previously we conclude that while some perisylvian anatomical asymmetries may differ subtly between typical and atypical speech dominants at the group level, they serve as poor participant-specific predictors of hemispheric language specialization.

Neonatal brachial plexus palsy and hand representation in children and young adults.

AIM: To assess the impact of neonatal brachial plexus palsy (NBPP) on higher-order hand representation. METHOD: Eighty-two left-handed children and adolescents with and without right-sided NBPP were recruited. Thirty-one participants with NBPP (mean age [SD] 11y 4mo [4y 4mo]; age range 6y 2mo-21y 0mo; 15 females; C5-6, n=4, C5-7, n=12, C5-T1, n=11, C5-T1 with Horner sign, n=4) were assessed along with 30 controls (mean age 11y 5mo [4y 4mo]; age range 6y 7mo-21y 7mo; 14 females). Participants' estimated hand size and shape on measure of implicit and explicit hand representation was assessed. A linear mixed model (LMM) was used to investigate the effect of condition, sensorimotor impairment, and age. RESULTS: Individuals with NBPP showed a significant difference in implicit hand representation between affected and non-affected hands. LMM confirmed a significant influence of the severity of sensorimotor injury. Only the estimated implicit hand representation was associated with age, with a significant difference between 6- to 8-year-olds and 9- to 10-year-olds. INTERPRETATION: The effect of sensorimotor impairment on central hand representation in individuals with NBPP is specific due to its implicit component and is characterized by finger length underestimation in the affected hand compared to the characteristic underestimation in the unaffected hand. Neither NBPP nor age impacted the explicit hand estimate. This study confirms the importance of sensorimotor contribution to the development of implicit hand representation.

Fibre-specific laterality of white matter in left and right language dominant people.

Language is the most commonly described lateralised cognitive function, relying more on the left hemisphere compared to the right hemisphere in over 90% of the population. Most research examining the structure-function relationship of language lateralisation only included people showing a left language hemisphere dominance. In this work, we applied a state-of-the-art "fixel-based" analysis approach, allowing statistical analysis of white matter micro- and macrostructure on a fibre-specific level in a sample of participants with left and right language dominance (LLD and RLD). Both groups showed a similar extensive pattern of white matter lateralisation including a comparable leftwards lateralisation of the arcuate fasciculus, regardless of their functional language lateralisation. These results suggest that lateralisation of language functioning and the arcuate fasciculus are driven by independent biases. Finally, a significant group difference of lateralisation was detected in the forceps minor, with a leftwards lateralisation in LLD and rightwards lateralisation for the RLD group.

Hand size representation in healthy children and young adults.

Whereas we experience our body as a coherent volumetric object, the brain appears to maintain highly fragmented representations of individual body parts. Little is known about how body representations of hand size and shape are built and evolve during infancy and young adulthood. This study aimed to investigate the effect of hand side, handedness, and age on the development of central hand size representation. The observational study with comparison groups was conducted with 90 typically developing Belgian school children and young adults (48 male and 42 female; age range = 5.0-23.0 years; 49 left-handed and 41 right-handed). Participants estimated their hand size and shape using two different tasks. In the localization task, participants were verbally cued to judge the locations of 10 anatomical landmarks of an occluded hand. An implicit hand size map was constructed and compared with actual hand dimensions. In the template selection task, the explicit hand shape was measured with a depictive method. Hand shape indexes were calculated and compared for the actual, implicit, and explicit conditions. Participants were divided into four age groups (5-8 years, 9-10 years, 11-16 years, and 17-23 years). Implicit hand maps featured underestimation of finger length and overestimation of hand width, which is already present in the youngest children. Linear mixed modeling revealed no influence of hand side on finger length underestimation; nonetheless, a significant main effect of age (p = .001) was exposed. Sinistrals aged 11 to 16 years showed significantly less underestimation (p = .03) than dextrals of the same age. As for the hand shape, the implicit condition differed significantly with the actual and explicit conditions (p < .001). Again, the implicit shape index was subjected to handedness and age effects, with significant differences being found between sinistrals and dextrals in the age groups of 9 and 10 years (p = .029) and 11 to 16 years (p < .001). In conclusion, the implicit metric component of the hand representation in children and young adults is misperceived, featuring shortened fingers and broadened hands since a very young age. Crucially, the finger length underestimation increases with age and shows a different developmental trajectory for sinistrals and dextrals. In contrast, the explicit hand shape is approximately veridical and seems immune from age and handedness effects. This study confirms the dual character of somatoperception and establishes a point of reference for children and young adults.

Evaluating the performance of the visual half field paradigm as a screening tool to detect right hemispheric language dominance.

Language is among the most studied functional asymmetries, yet little is known about right hemispheric language dominance. Because of its low prevalence, including a big sample of individuals with this variant of brain organization implies testing large groups, which may not be feasible when using expensive techniques. One solution involves screening a large sample using a cost-efficient method and next inviting only those participants flagged as potentially right dominant for follow-up investigation. The behavioural visual half field paradigm has previously been validated and successfully applied in this manner. We report a large-scale visual half field screening performed in 315 left-handers to detect such individuals for subsequent MRI scanning. Of 38 cases selected as probably right language dominant based on a left visual half field advantage (>20 ms), 22 (58%) were confirmed by language fMRI to be rightward lateralized. This study also explored means to improve the predictive performance of the visual half field task. While we found its performance depended strongly on the chosen cut-off, overall, reaction time criteria resulted in higher true positive rates, while those based on accuracy led to superior positive predictive values. The most optimal strategy, however, may involve combining criteria considering both accuracy and reaction time.

Hemispheric dominance for visuospatial attention does not predict the direction of pseudoneglect.

Pseudoneglect refers to a tendency of neurologically healthy individuals to produce leftward perceptual biases during spatial tasks, which is traditionally measured using line bisection tasks. This behavioral asymmetry is often explained as a consequence of right hemispheric dominance for visuospatial attention. The present study directly tested this notion by comparing line bisection performance between left-handers with either right hemispheric dominance (RVSD, N = 40) or "atypical" left hemispheric dominance (LVSD, N = 23) for visuospatial attention as determined by fMRI. Although we expected a reversal of pseudoneglect in participants with LVSD, our results show that they equally often err to the left of the true center compared to RVSD controls (74% of LVSD participants and 80% of RVSD participants). However, the magnitude of misbisections was found to be slightly, but significantly, smaller in the LVSD subgroup.We conclude that hemispheric asymmetry for visuospatial attention is not the main determinant of pseudoneglect as is commonly thought, but rather only constitutes one of the multiple factors which (subtly) contributes to its direction and magnitude.

Mirrored brain organization: Statistical anomaly or reversal of hemispheric functional segregation bias?

Humans demonstrate a prototypical hemispheric functional segregation pattern, with language and praxis lateralizing to the left hemisphere and spatial attention, face recognition, and emotional prosody to the right hemisphere. In this study, we used fMRI to determine laterality for all five functions in each participant. Crucially, we recruited a sample of left-handers preselected for atypical (right) language dominance (n = 24), which allowed us to characterize hemispheric asymmetry of the other functions and compare their functional segregation pattern with that of left-handers showing typical language dominance (n = 39). Our results revealed that most participants with left language dominance display the prototypical pattern of functional hemispheric segregation (44%) or deviate from this pattern in only one function (35%). Similarly, the vast majority of right language dominant participants demonstrated a completely mirrored brain organization (50%) or a reversal for all but one cognitive function (32%). Participants deviating by more than one function from the standard segregation pattern showed poorer cognitive performance, in line with an oft-presumed biological advantage of hemispheric functional segregation.

Heterogeneous Response of Chemotherapy-Related Cognitive Decline in Patients with Breast Cancer: A Prospective Study.

OBJECTIVE: A significant proportion of adjuvant-treated breast cancer patients experience cognitive decline, challenging the person's ability to return to normal activities after treatment. However, not every patient experiences cognitive problems, and even in patients with impairments, determining clinically important cognitive decline remains challenging. Our objective was to explore differences in neuropsychological performance following adjuvant chemotherapy (CT) in patients with breast cancer. METHOD: We conducted a prospective observational study in an Oncology Breast Clinic and assessed neuropsychological performance before and after adjuvant CT and in non-CT-treated women with breast cancer and healthy controls (HCs). Standardised between-group differences and regression-based change scores were calculated. RESULTS: CT-treated patients (n = 66) performed significantly different from non-CT-treated patients (n = 39) and HCs (n = 56). There was a significant effect on verbal fluency (p = .0013). CT performed significantly worse than non-CT and HC [effect size (ES) = .89, p < .001 and ES = .61, p ≤ .001, respectively] and from HCs with regard to proactive interference (ES = .62, p ≤ .001). Regression-based scores revealed more severe cognitive decline in the CT-treated group [24.24% (16/66)] than in the non-CT-treated group [15.20% (6/39)] and HC group [7.14% (4/56)]. Patients who underwent CT and showed cognitive decline were less educated and older, with significantly lower baseline scores. CONCLUSIONS: CT-treated patients showed more vulnerability on cognitive control and monitoring than non-CT-treated breast cancer patients and HCs. Older patients with less education and lower baseline cognitive performance represent a group at risk for cognitive decline following CT. Identification of patients at risk for decline could improve targeted support and rehabilitation.

The right visual field advantage for word processing is stronger in older adults.

The human brain is functionally asymmetric. Producing and understanding language, for instance, engages the left hemisphere to a larger extent than the right in most people. Recent research showed that lateralization for auditory word processing increases with age. The present study extends these findings to the visual domain. We measured lateralization for visual word processing with the visual half field task in young (20-30 years) and older participants (70-80 years). The older cohort had a larger right visual field advantage in terms of reaction time (p = .016, dolder adults = 0.16, dyounger adults = 0.13) and accuracy (p = .053, dolder adults = 0.73, dyounger adults = 0.25). This difference was mainly driven by a weaker performance for words presented in the left visual field. Our findings suggest that hemisphere dominance for language increases with aging. Alternatively, the findings could be explained by delayed inter-hemispheric communication in older adults.

The genetics of situs inversus without primary ciliary dyskinesia.

Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.

Network diffusion modeling predicts neurodegeneration in traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a heterogeneous disease with multiple neurological deficits that evolve over time. It is also associated with an increased incidence of neurodegenerative diseases. Accordingly, clinicians need better tools to predict a patient's long-term prognosis. METHODS: Diffusion-weighted and anatomical MRI data were collected from 17 adolescents (mean age = 15y8mo) with moderate-to-severe TBI and 19 healthy controls. Using a network diffusion model (NDM), we examined the effect of progressive deafferentation and gray matter thinning in young TBI patients. Moreover, using a novel automated inference method, we identified several injury epicenters in order to determine the neural degenerative patterns in each TBI patient. RESULTS: We were able to identify the subject-specific patterns of degeneration in each patient. In particular, the hippocampus, temporal cortices, and striatum were frequently found to be the epicenters of degeneration across the TBI patients. Orthogonal transformation of the predicted degeneration, using principal component analysis, identified distinct spatial components in the temporal-hippocampal network and the cortico-striatal network, confirming the vulnerability of these networks to injury. The NDM model, best predictive of the degeneration, was significantly correlated with time since injury, indicating that NDM can potentially capture the pathological progression in the chronic phase of TBI. INTERPRETATION: These findings suggest that network spread may help explain patterns of distant gray matter thinning, which would be consistent with Wallerian degeneration of the white matter connections (i.e., "diaschisis") from diffuse axonal injuries and multifocal contusive injuries, and the neurodegenerative patterns of abnormal protein aggregation and transmission, which are hallmarks of brain changes in TBI. NDM approaches could provide highly subject-specific biomarkers relevant for disease monitoring and personalized therapies in TBI.

Early electrodiagnosis in the management of neonatal brachial plexus palsy: A systematic review.

Neonatal brachial plexus palsy (NBPP) is a prominent form of newborn morbidity with a potentially disabling persistence. Neurosurgical intervention is indicated in select NBPP patients. Early prognostic assessment would facilitate rational selection of those infants for surgery. We conducted a systematic literature review to determine the prognostic value of early electrodiagnosis (EDx) in NBPP. We included 16 observational studies with a total sample size of 747 children. Risk of bias and quality of evidence were rated. Wide variation was found in EDx techniques, outcome algorithms, and decisionmaking. Nevertheless, the most methodologically sound studies support the use of EDx, at standardized time-frames, as a key prognostic modality for complementing clinical judgment and neuroimaging. An accurate knowledge of the underlying anatomy of the nerve injury helps to counsel families and to guide reconstructive strategy.

Risk factors for neonatal brachial plexus palsy: a systematic review and meta-analysis.

AIM: To provide a comprehensive update on the most prevalent, significant risk factors for neonatal brachial plexus palsy (NBPP). METHOD: Cochrane CENTRAL, MEDLINE, Web of Science, Embase, and ClinicalTrials.gov were searched for relevant publications up to March 2019. Studies assessing risk factors of NBPP in relation to typically developing comparison individuals were included. Meta-analysis was performed for the five most significant risk factors, on the basis of the PRISMA statement and MOOSE guidelines. Pooled odds ratios (ORs), 95% confidence intervals (CIs), and across-study heterogeneity (I2 ) were reported. Reporting bias and quality of evidence was rated. In addition, we assessed the incidence of NBPP. RESULTS: Twenty-two observational studies with a total sample size of 29 419 037 live births were selected. Significant risk factors included shoulder dystocia (OR 115.27; 95% CI 81.35-163.35; I2 =92%), macrosomia (OR 9.75; 95% CI 8.29-11.46; I2 =70%), (gestational) diabetes (OR 5.33; 95% CI 3.77-7.55; I2 =59%), instrumental delivery (OR 3.8; 95% CI 2.77-5.23; I2 =77%), and breech delivery (OR 2.49; 95% CI 1.67-3.7; I2 =70%). Caesarean section appeared as a protective factor (OR 0.13; 95% CI 0.11-0.16; I2 =41%). The pooled overall incidence of NBPP was 1.74 per 1000 live births. It has decreased in recent years. INTERPRETATION: The incidence of NBPP is decreasing. Shoulder dystocia, macrosomia, maternal diabetes, instrumental delivery, and breech delivery are risk factors for NBPP. Caesarean section appears as a protective factor. WHAT THIS PAPER ADDS: The overall incidence of neonatal brachial plexus palsy is 1.74 per 1000 live births. The incidence has declined significantly. Shoulder dystocia, macrosomia, maternal diabetes, instrumental delivery, and breech delivery are the main risk factors. Prevention is difficult owing to unpredictability and often labour-related risk.