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.

Variability in Hemispheric Functional Segregation Phenotypes: A Review and General Mechanistic Model.

Many functions of the human brain are organized asymmetrically and are subject to strong population biases. Some tasks, like speaking and making complex hand movements, exhibit left hemispheric dominance, whereas others, such as spatial processing and recognizing faces, favor the right hemisphere. While pattern of preference implies the existence of a stereotypical way of distributing functions between the hemispheres, an ever-increasing body of evidence indicates that not everyone follows this pattern of hemispheric functional segregation. On the contrary, the review conducted in this article shows that departures from the standard hemispheric division of labor are routinely observed and assume many distinct forms, each having a different prevalence rate. One of the key challenges in human neuroscience is to model this variability. By integrating well-established and recently emerged ideas about the mechanisms that underlie functional lateralization, the current article proposes a general mechanistic model that explains the observed distribution of segregation phenotypes and generates new testable hypotheses.

Early white matter connectivity and plasticity in post stroke aphasia recovery.

A disruption of white matter connectivity is negatively associated with language (recovery) in patients with aphasia after stroke, and behavioral gains have been shown to coincide with white matter neuroplasticity. However, most brain-behavior studies have been carried out in the chronic phase after stroke, with limited generalizability to earlier phases. Furthermore, few studies have investigated neuroplasticity patterns during spontaneous recovery (i.e., not related to a specific treatment) in the first months after stroke, hindering the investigation of potential early compensatory mechanisms. Finally, the majority of previous research has focused on damaged left hemisphere pathways, while neglecting the potential protective value of their right hemisphere counterparts for language recovery. To address these outstanding issues, we present a longitudinal study of thirty-two patients with aphasia (21 males and 11 females, M = 69.47 years, SD = 10.60 years) who were followed up for a period of 1 year with test moments in the acute (1-2 weeks), subacute (3-6 months) and chronic phase (9-12 months) after stroke. Constrained Spherical Deconvolution-based tractography was performed in the acute and subacute phase to measure Fiber Bundle Capacity (FBC), a quantitative connectivity measure that is valid in crossing fiber regions, in the bilateral dorsal arcuate fasciculus (AF) and the bilateral ventral inferior fronto-occipital fasciculus (IFOF). First, concurrent analyses revealed positive associations between the left AF and phonology, and between the bilateral IFOF and semantics in the acute - but not subacute - phase, supporting the dual-stream language model. Second, neuroplasticity analyses revealed a decrease in connection density of the bilateral AF - but not the IFOF - from the acute to the subacute phase, possibly reflecting post stroke white matter degeneration in areas adjacent to the lesion. Third, predictive analyses revealed no contribution of acute FBC measures to the prediction of later language outcomes over and above the initial language scores, suggesting no added value ofthe diffusion measures for languageprediction. Our study provides new insights on (changes in) connectivity of damaged and undamaged language pathways in patients with aphasia in the first months after stroke, as well as if/how such measures are related to language outcomes at different stages of recovery. Individual results are discussed in the light of current frameworks of language processing and aphasia recovery.

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.

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.

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.

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.

White matter asymmetries in human situs inversus totalis.

Diffusion weighted imaging (DWI) was used to investigate white matter asymmetries in participants with situs inversus totalis (SIT) and matched controls. Regardless of visceral condition, hemispheric differences were found for the arcuate fasciculus (ARC) and the superior longitudinal fasciculus (SLF), which are involved in language and visuospatial functioning, respectively. The ARC appears lateralized to the left hemisphere, analogous to the left lateralization of functional areas associated with language. The SLF, on the other hand, is lateralized to the right, corresponding with rightward lateralization of visuospatial functioning. Interestingly, SIT participants show a significantly lower number of streamlines in the Uncinate Fasciculus (UNC). In addition, UNC volume appears associated with measures of cognitive performance, a finding in line with previously reported performance differences between SIT participants and controls.

Laterality for recognizing written words and faces in the fusiform gyrus covaries with language dominance.

Recognizing words and faces engages highly specialized sites within the middle fusiform gyrus, known as the visual word form area (VWFA) and fusiform face area (FFA) respectively. The VWFA and FFA have clear but opposite population-level asymmetries, with the VWFA typically being lateralized to the left and the FFA to the right hemisphere. The present study investigates how language dominance may relate to these asymmetries. We hypothesize that individuals with left hemisphere dominance for word production (i.e., left language dominance, LLD) will have typical lateralization for word and face recognition in the fusiform gyrus, whereas participants with right language dominance (RLD) will demonstrate 'atypical' rightward laterality for words and leftward dominance for faces. To test this hypothesis, we recruited twenty-seven left-handers who had previously been identified as being LLD or RLD based on a visual half field task. Using fMRI, hemisphere dominance was determined for language (Broca's region) as well as for word and face recognition in the middle fusiform gyrus for each participant. The direction of asymmetry correlated significantly between language and recognizing words (ρ = .648, p < .001) as well as between language and face recognition (ρ = -.620, p = .001). Moreover, most LLD-participants were typically lateralized for faces and written words, while both functions tended to be reversed in individuals with RLD. However, segregation between language and face recognition was less clear in participants with RLD, as many of them lacked an obvious asymmetry for faces. Although our results thus suggest there is no one-on-one relationship between asymmetries for language, written word and face recognition, they also argue against a complete independence of their lateralization.

Anticipation of a mentally effortful task recruits Dorsolateral Prefrontal Cortex: An fNIRS validation study.

Preparing for a mentally demanding task calls upon cognitive and motivational resources. The underlying neural implementation of these mechanisms is receiving growing attention because of its implications for professional, social, and medical contexts. While several fMRI studies converge in assigning a crucial role to a cortico-subcortical network including Anterior Cigulate Cortex (ACC) and striatum, the involvement of Dorsolateral Prefrontal Cortex (DLPFC) during mental effort anticipation has yet to be replicated. This study was designed to target DLPFC contribution to anticipation of a difficult task using functional Near Infrared Spectroscopy (fNIRS), as a more cost-effective tool measuring cortical hemodynamics. We adapted a validated mental effort task, where participants performed easy and difficult mental calculation, and measured DLPFC activity during the anticipation phase. As hypothesized, DLPFC activity increased during anticipation of a hard task as compared to an easy task. Besides replicating previous fMRI work, these results establish fNIRS as an effective tool to investigate cortical contributions to anticipation of effortful behavior. This is especially useful if one requires testing large samples (e.g., to target individual differences), populations with contraindication for functional MRI (e.g., infants or patients with metal implants), or subjects in more naturalistic environments (e.g., work or sport).

The mis-wired language network in children with developmental language disorder: insights from DTI tractography.

This study aims to detect the neural substrate underlying the language impairment in children with developmental language disorder (DLD) using diffusion tensor imaging (DTI) tractography. Deterministic DTI tractography was performed in a group of right-handed children with DLD (N = 17; mean age 10;07 ± 2;01 years) and a typically developing control group matched for age, gender and handedness (N = 22; mean age 11;00 ± 1;11 years) to bilaterally identify the superior longitudinal fascicle, arcuate fascicle, anterior lateral segment and posterior lateral segment (also called dorsal language network) and the middle and inferior longitudinal fascicle, extreme capsule fiber system and uncinate fascicle (also called ventral language network). Language skills were assessed using an extensive, standardized test battery. Differences in language performance, white matter organization and structural lateralization of the language network were statistically analyzed. Children with DLD showed a higher overall volume and higher ADC values for the left-hemispheric language related WM tracts. In addition, in children with DLD, the majority (88%; 7/8) of the studied language related WM tracts did not show a significant left or right lateralization pattern. These structural alterations might underlie the language impairment in children with DLD.

Atypical brain functional segregation is more frequent in situs inversus totalis.

Most humans show typical brain functional specialization with language and praxis favoring left hemisphere lateralization and spatial attention and face recognition showing right hemisphere dominance. Lateralization of these cognitive functions was investigated using fMRI in participants with complete visceral reversal and matched control participants. While most participants revealed typical brain organization, atypical functional segregation was significantly more frequent in participants with visceral reversal. Interestingly, some left handers maintained typical functional segregation but showed complete reversal of all cognitive functions regardless of visceral organization. Cognitive performance, as measured with a neuropsychological test battery, was significantly predicted by the degree of atypical functional segregation of praxis and spatial attention. Increased deviation from typical functional segregation paired with lower cognitive performance. The findings suggest that typical functional segregation reflects an optimal evolutionary solution with deviations being associated with reduced cognitive performance.

Brain structural and functional asymmetry in human situs inversus totalis.

Magnetic resonance imaging was used to investigate brain structural and functional asymmetries in 15 participants with complete visceral reversal (situs inversus totalis, SIT). Language-related brain structural and functional lateralization of SIT participants, including peri-Sylvian gray and white matter asymmetries and hemispheric language dominance, was similar to those of 15 control participants individually matched for sex, age, education, and handedness. In contrast, the SIT cohort showed reversal of the brain (Yakovlevian) torque (occipital petalia and occipital bending) compared to the control group. Secondary findings suggested different asymmetry patterns between SIT participants with (n = 6) or without (n = 9) primary ciliary dyskinesia (PCD, also known as Kartagener syndrome) although the small sample sizes warrant cautious interpretation. In particular, reversed brain torque was mainly due to the subgroup with PCD-unrelated SIT and this group also included 55% left handers, a ratio close to a random allocation of handedness. We conclude that complete visceral reversal has no effect on the lateralization of brain structural and functional asymmetries associated with language, but seems to reverse the typical direction of the brain torque in particular in participants that have SIT unrelated to PCD. The observed differences in asymmetry patterns of SIT groups with and without PCD seem to suggest that symmetry breaking of visceral laterality, brain torque, and language dominance rely on different mechanisms.