Brain-behavior Relationships Research Articles

Invited Symposium 4: Innovations in Infant, Toddler, and Young Child Neuropsychological Models of Care

Abstract & Learning Objectives:The neuropsychology of babies, toddlers, and young children is a rapidly evolving frontier within our discipline. While there is an inaccurate perception among referral sources that neuropsychological services are not useful before school-age, pediatric neuropsychologists are especially well-suited to identify delay or dysfunction in the years before school entry (Baron and Anderson, 2012). Patterns of neurodevelopmental strengths and weaknesses can be detected very early on in development and used to make inferences about brain-behavior relationships integral for guiding treatment across a number of medical and neurodevelopmental diagnoses. As such, there is a need to foster ongoing clinical interest and expertise and promote the utility of neuropsychological services within this age range. The INS BabIes, ToddlerS, and Young children (BITSY) SIG was recently developed to bring together scientists and clinicians from across the world who conduct research and provide neuropsychological services within this age range to foster collaboration and learning. A priority of the BITSY SIG is not only to promote awareness of the novel needs of this age range, but to consider historical and ongoing disparities in service access, representation in research, and neuropsychological practice. For this inaugural BITSY SIG symposium, four members of the SIG will discuss innovations in infant, toddler, and young child neuropsychological models of care. This topic was developed in direct response to survey results from the first BITSY SIG meeting held during INS 2022, indicating the need for the development and refinement of clinical approaches that incorporate diverse perspectives as well as training opportunities in models of care for very young children. As such, speakers will cover innovations in neuropsychological service models from the prenatal period to formative early years that are inclusive of diverse neurological and neurodevelopmental populations commonly served by neuropsychologists including spina bifida, prematurity, hypoxic-ischemic encephalopathy (HIE), congenital heart disease (CHD), autism (ASD) and attention-deficit/hyperactivity disorder (ADHD). The first talk will highlight the unique role of the neuropsychologist in prenatal and infant consultation, whereas the second talk will focus on the state of the field with regard to the utility of neuroimaging in neonatal populations and the integration of this tool in neuropsychological care. The third talk will discuss early screening and assessment models in a diverse range of conditions within an interdisciplinary setting. The final talk will illustrate a novel neuropsychological intervention designed with and for the empowerment of caregivers for young children impacted by neurological and neurodevelopmental conditions. The unifying theme across the talks is how unplanned discoveries and acute observations of children and families during the critical early years have led to these inclusive care models that prioritize family preferences, values, and culture. Upon conclusion of this course, learners will be able to: 1.Summarize several novel models of neuropsychological care for infants, toddlers, and young children.2.Recognize ways in which neuropsychologists work within interdisciplinary teams to serve infants, toddlers, and young children and their families.3.Apply these models of care to your conceptualization of the scope of neuropsychological services available for infants, toddlers, and young children.

Symposium 01: Neuropsychological Outcomes Following Pediatric Stroke: Research Trends and Advances

Summary Abstract:Stroke is an important cause of acquired brain injury in youth and a significant source of childhood disability. Up to 80% of survivors suffer long-term neurological deficits, including impairments across a range of neuropsychological domains. An improved understanding of neuropsychological outcomes is key to optimizing clinical care, improving evaluation of prognosis, and developing effective rehabilitation and intervention strategies. The proposed symposium will begin with a literature review on neuropsychological outcomes following pediatric stroke. Next, four studies will be presented, each posing distinct and complementary research questions regarding predictors of outcomes. The roles of both clinical (e.g., lesion size, motor impairment, inflammatory response) and environmental factors (e.g., socioeconomic status, family functioning) will be explored regarding cognitive, social-emotional, and behavioral outcomes. The symposium will end with a Q&A period.Attendees will leave with an in-depth understanding of recent trends and scientific advances in research on neuropsychological outcomes in pediatric stroke, which should inform clinical practice and research directions. The first presentation examines predictors of neuropsychological outcomes following pediatric stroke. Findings have often conflicted, and more research is needed to disentangle the effects of predictors on specific domains. Explored predictors include: age at stroke; stroke subtype (hemorrhagic vs. ischemic); lesion location; lesion size; time since stroke; neurologic severity; seizure disorder; and socioeconomic status. This study examines the impact of these predictors on distinct neuropsychological domains. The next presentation addresses associations between neuropsychological outcomes and motor functioning following pediatric stroke. The development of cognitive and motor skills is interrelated and they share common neural substrates. In other populations, motor functioning predicts intellectual ability, and brain connectivity underlies this association. This study investigates associations between motor functioning and global neuropsychological outcomes in children with stroke and explores clinical features associated with motor impairments. The third presentation explores mental health outcomes. Neuropsychological deficits can hinder academic advancement and social-emotional development and may place youth at increased risk for psychological concerns. An increased focus on mental health is warranted given that psychosocial and behavioral issues are often the most concerning problems for parents and teachers. This study uses a qualitative paradigm to shed light on lived experience of youth with stroke with a focus on mental health, relationships, and social competence. The fourth presentation consists of a systematic review exploring the association between inflammatory response and neuropsychological outcome. Stroke induces an inflammation in the central and peripheral nervous systems, and high levels of inflammatory markers following stroke have been associated with poorer cognitive outcomes. This study reviews the state of research on this topic with a focus on pro-inflammatory cytokines and c-reactive protein. The symposium topics covered lie at the heart of the INS mission to study brain-behavior relationships using a multidisciplinary lens, with an emphasis on sharing and applying scientific knowledge. The symposium seeks to inform professionals working with youth with stroke about cutting-edge research, clinically applicable and novel insights, and ideas for future research directions. In this way, our symposium contributes to evidence-based care and the advancement of research.

6 Feasibility and Perceived Benefit of an Interdisciplinary Rehabilitation Approach within a Tertiary Pediatric Hematology/Oncology Setting

Objective:Medulloblastoma is the most common pediatric malignant brain tumor. Approximately 29% of medulloblastoma patients experience postoperative posterior fossa syndrome (PFS) characterized by impairments in speech, motor, and mood. An interdisciplinary rehabilitation approach is associated with greater rehabilitation gains than a single discipline approach for brain injury patients with significant rehabilitation needs. However, literature regarding the feasibility and utility of this approach within a tertiary care pediatric hematology/oncology setting is lacking. The Acute Neurological Injury (ANI) service was developed to coordinate care for neurologically complex hematology/oncology patients receiving active cancer treatment, including those with PFS. ANI care coordination includes bimonthly interdisciplinary team meetings, interdisciplinary goal implementation for each patient, parent psychoeducation about applicable brain-behavior relationships (including PFS) at treatment initiation, neuropsychological assessment at transition times throughout treatment, cognitive remediation, and coordinated end of treatment transition planning. We gathered caregiver perspective on this approach within a tertiary care pediatric hematology/oncology setting.Participants and Methods:Parents of children and young adults (ages 4-20) with PFS after medulloblastoma resection who received coordinated care as part of the ANI program (n=20) were interviewed at least 4 months following completion of cancer treatment. 75% experienced postoperative mutism while the remainder experienced significantly decreased speech without mutism. All received cranial-spinal irradiation and focal boosts to tumor sites followed by chemotherapy per multi-institutional treatment protocol. Caregivers were interviewed regarding perceived feasibility and utility of ANI program components including parent psychoeducation, neuropsychological assessment, cognitive remediation, and interdisciplinary team coordination/goal setting, as well as parental supports. Yes/no responses were gathered as well as responses regarding the perceived utility of aspects of the interdisciplinary ANI program approach via a five-point Likert scale.Results:Surveys were completed by 66% of families contacted. Mean age at first contact with neuropsychology as part of the ANI program was 9.45 years (SD=4.4 years). Mean time between end of treatment and parent interview was 3.20 years (SD=2.01 years). Most parents reported that initial psychoeducation about PFS helped to decrease their concerns (81%) and increased their understanding of their child’s functioning in the context of PFS (88%). They reported benefit from neuropsychological assessment reports prior to initiating adjuvant treatment (92%), at end of treatment (90%), and one year following initiation of cancer treatment (100%), though they perceived less benefit from assessments intended to inform provider interventions during treatment (81% and 66%). Reports were shared most often with schools (75%), behavioral therapists (50%), physicians (50%), and rehabilitation specialists (25%). Parents indicated that the interdisciplinary ANI program approach was helpful (94%) and the coordinated interdisciplinary goal was beneficial (92%). Most parents favored the weekly frequency of cognitive remediation sessions (83%). Much interest was voiced in establishing a formal mentoring program to offer peer support by parents whose children have previously experienced PFS to those acutely managing a new PFS diagnosis (95%). Of note, all participants indicated that they would be willing to serve in a peer mentor role (100%).Conclusions:The interdisciplinary ANI program approach is feasible with perceived benefits to families managing new PFS and medulloblastoma diagnoses and receiving active cancer treatment.

15 Socioeconomic Status in Association to Memory-Related Brain Activation in Middle-Aged Adults

Objective:Socioeconomic status (SES) has been recognized as an important factor in psychological research within the last few decades. Past literature recognizes that having lower SES can have a negative impact on many aspects of one’s health, especially in diseases related to brain aging. A recent avenue for research regarding SES and the brain-behavior relationship suggests that socioeconomic status can act as a moderator for brain activation during task performance. The hypothesis for this project was that there will be a negative correlational relationship between brain activity and SES when controlling for participants’ age, sex, and performance on the episodic memory tasks, but a positive correlation between task performance and SES was expected.Participants and Methods:With 100 middle-aged healthy adults from the Reference Ability Neural Network (RANN) study (53 male and 47 female, age M=48.0 +/- 7.55 years), three episodic memory fMRI tasks were performed and studied in relation to SES and age. The tasks were Logical Memory, Word Order, and Pair Associates tasks that involved episodic memory for story details, order of words presented, and pairing of words, respectively. We quantified memory performance with average accuracy from performance of the three tasks. We used the FSL software to preprocess and perform voxel-wise group analysis. All brain activation analyses were corrected for multiple comparison using cluster thresholds in FSL.Results:Correlation between SES and memory performance was found to be marginally significant (R=.188, p=.061). All tasks had areas of positively correlated activation for age. The Logical Memory task had multiple areas of brain activation that were positively correlated with age, particularly at the lateral occipital cortex, lingual gyrus, and the occipital fusiform gyrus, all areas that underlie visual processing. There were no areas of correlated brain activation for SES, sex, and task performance for the Pair Associates and Logical Memory tasks. Brain activation for the Word order task in the left precuneous cortex and the right middle frontal gyrus, left lateral occipital cortex, left occipital fusiform gyrus, and parts of the lingual gyrus was positively correlated with memory performance when controlled for age, sex, and SES.Conclusions:The hypothesis was not entirely supported by the results of this study, but the marginal effect between SES and memory performance can suggest that SES may affect memory performance within middle-aged adults. While we did not find a brain association with SES in this age group, we observed regions that underlie task performance. Further research can be done on possible moderating effects of Socioeconomic Status on memory and executive function with structural neuroimaging to further investigate the effects of SES on cognition.

Decreased DTI-ALPS and choroid plexus enlargement in fibromyalgia: a preliminary multimodal MRI study.

The glymphatic system is a fluid exchange pathway that clears waste products that is crucial for the maintenance of brain homeostasis. However, the exact role it plays in the emergence of fibromyalgia (FM) is still not fully understood. Here, we explored the changes in non-invasive MRI proxy probably related to the glymphatic function in FM patients, and explored brain-behavior relationships. A total of 40 participants, consisting of 20 individuals with FM and 20 healthy controls (HCs), were included in the study. The participants underwent structural T1-weighted MRI, diffusion tensor imaging (DTI), and clinical assessment. The data was obtained from an open access dataset. The study compared non-invasive MRI indices, including choroid plexus (CP) volume and DTI analysis along the perivascular space (ALPS), between the FM and HC groups. Furthermore, correlation analysis was conducted to determine the correlation between clinical parameters and both CP volume and DTI-ALPS index. Patients with FM had significantly higher CP volume and a lower DTI-ALPS index than HCs adjusting for age and intracranial volume. Higher CP volume was associated with lower DTI-ALPS index, and longer disease duration. Our findings demonstrate aberrant glymphatic function in FM, and that dysfunction in the brain glymphatic system may play a role in the neural mechanisms underlying FM.

Dissociation of Centrally and Peripherally Induced Transcranial Magnetic Stimulation Effects in Nonhuman Primates.

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent centrally induced neural mechanisms and peripherally induced sensory costimulation effects remain debated. Understanding how TMS stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging because of the limited spatiotemporal resolution of available noninvasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in a male and a female nonhuman primate (rhesus macaque) to study TMS mesoscale responses. We demonstrate that early TMS-evoked potentials show a sigmoidal dose-response curve with stimulation intensity. We further show that stimulation responses are spatially specific. We use several control conditions to dissociate centrally induced neural responses from auditory and somatosensory coactivation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications.SIGNIFICANCE STATEMENT Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method to stimulate the human brain. To advance its utility for clinical applications, a clear understanding of its underlying physiological mechanisms is crucial. Here, we perform invasive electrophysiological recordings in the nonhuman primate brain during TMS, achieving a spatiotemporal precision not available in human EEG experiments. We find that evoked potentials are dose dependent and spatially specific, and can be separated from peripheral stimulation effects. This means that TMS-evoked responses can indicate a direct physiological stimulation response. Our work has important implications for the interpretation of human TMS-EEG recordings and biomarker development.

Psilocybin-induced changes in cerebral blood flow are associated with acute and baseline inter-individual differences

Research into the use of psilocybin for the treatment of psychiatric disorders is a growing field. Nevertheless, robust brain–behavior relationships linking psilocybin-induced brain changes to subjective drug-induced effects have not been established. Furthermore, it is unclear if the acute neural effects are dependent on individual heterogeneity in baseline characteristics. To address this, we assessed the effects of three oral doses of psilocybin vs. placebo on cerebral blood flow (CBF) using arterial spin labeling in healthy participants (N = 70; n = 31, 0.16 mg/kg; n = 10, 0.2 mg/kg; n = 29, 0.215 mg/kg). First, we quantified psilocybin-induced changes in relative and absolute CBF. Second, in an exploratory analysis, we assessed whether individual baseline characteristics and subjective psychedelic experience are associated with changes in CBF. Psychological and neurobiological baseline characteristics correlated with the psilocybin-induced reduction in relative CBF and the psilocybin-induced subjective experience. Furthermore, the psilocybin-induced subjective experience was associated with acute changes in relative and absolute CBF. The results demonstrated that inter-individual heterogeneity in the neural response to psilocybin is associated with baseline characteristics and shed light on the mechanisms underlying the psychedelic-induced altered state. Overall, these findings help guide the search for biomarkers, paving the way for a personalized medicine approach within the framework of psychedelic-assisted therapy.

Concurrent TMS/fMRI reveals individual DLPFC dose-response pattern

BackgroundTMS is a valuable tool in both research and clinical settings, playing a crucial role in understanding brain-behavior relationships and providing treatment for various neurological and psychiatric conditions. Importantly, TMS over left DLPFC is an FDA approved treatment for MDD. Despite its potential, response variability to TMS remains a challenge, with stimulation parameters, particularly the stimulation intensity, being a primary contributor to these differences. ObjectiveThe objective of this study was to establish dose-response relationships of TMS stimulation in DLPFC by means of concurrent TMS/fMRI. MethodsHere, we stimulated 15 subjects at different stimulation intensities of 80, 90, 100 and 110 % relative to the motor threshold during concurrent TMS/fMRI. The experiment comprised two sessions: one session to collect anatomical data in order to perform neuronavigation and one session dedicated to dose-response mapping. We calculated GLMs for each intensity level and each subject, as well as at a group-level per intensity. ResultsOn a group level, we show that the strongest BOLD-response was at 100 % stimulation. However, investigating individual dose response-relationships showed differences in response patterns across the group: subjects that responded to subthreshold stimulation, subjects that required above threshold stimulation in order to show a significant BOLD-response and atypical responders. ConclusionsWe observed qualitative inter-subject variability in terms of dose-response relationship to TMS over left DLPFC, which hints towards the motor threshold not being directly transferable to the excitability of the DLPFC. Concurrent TMS/fMRI might have the potential to improve response rates to rTMS applications. As such, it may be valuable in the future to consider implementing this approach prior to clinical TMS or validating more cost-effective methods to determine dose and target with respect to changes in clinical symptoms.

Neural basis of speech and grammar symptoms in non-fluent variant primary progressive aphasia spectrum.

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative syndrome primarily defined by the presence of apraxia of speech (AoS) and/or expressive agrammatism. In addition, many patients exhibit dysarthria and/or receptive agrammatism. This leads to substantial phenotypic variation within the speech-language domain across individuals and time, in terms of both the specific combination of symptoms as well as their severity. How to resolve such phenotypic heterogeneity in nfvPPA is a matter of debate. 'Splitting' views propose separate clinical entities: 'primary progressive apraxia of speech' when AoS occurs in the absence of expressive agrammatism, 'progressive agrammatic aphasia' (PAA) in the opposite case, and 'AOS + PAA' when mixed motor speech and language symptoms are clearly present. While therapeutic interventions typically vary depending on the predominant symptom (e.g. AoS versus expressive agrammatism), the existence of behavioural, anatomical and pathological overlap across these phenotypes argues against drawing such clear-cut boundaries. In the current study, we contribute to this debate by mapping behaviour to brain in a large, prospective cohort of well characterized patients with nfvPPA (n = 104). We sought to advance scientific understanding of nfvPPA and the neural basis of speech-language by uncovering where in the brain the degree of MRI-based atrophy is associated with inter-patient variability in the presence and severity of AoS, dysarthria, expressive agrammatism or receptive agrammatism. Our cross-sectional examination of brain-behaviour relationships revealed three main observations. First, we found that the neural correlates of AoS and expressive agrammatism in nfvPPA lie side by side in the left posterior inferior frontal lobe, explaining their behavioural dissociation/association in previous reports. Second, we identified a 'left-right' and 'ventral-dorsal' neuroanatomical distinction between AoS versus dysarthria, highlighting (i) that dysarthria, but not AoS, is significantly influenced by tissue loss in right-hemisphere motor-speech regions; and (ii) that, within the left hemisphere, dysarthria and AoS map onto dorsally versus ventrally located motor-speech regions, respectively. Third, we confirmed that, within the large-scale grammar network, left frontal tissue loss is preferentially involved in expressive agrammatism and left temporal tissue loss in receptive agrammatism. Our findings thus contribute to define the function and location of the epicentres within the large-scale neural networks vulnerable to neurodegenerative changes in nfvPPA. We propose that nfvPPA be redefined as an umbrella term subsuming a spectrum of speech and/or language phenotypes that are closely linked by the underlying neuroanatomy and neuropathology.

Tract- and gray matter- based spatial statistics show white matter and gray matter microstructural differences in autistic males.

Autism spectrum disorder (ASD) is a neurodevelopmental condition commonly studied in the context of early childhood. As ASD is a life-long condition, understanding the characteristics of brain microstructure from adolescence into adulthood and associations to clinical features is critical for improving outcomes across the lifespan. In the current work, we utilized Tract Based Spatial Statistics (TBSS) and Gray Matter Based Spatial Statistics (GBSS) to examine the white matter (WM) and gray matter (GM) microstructure in neurotypical (NT) and autistic males. Multi-shell diffusion MRI was acquired from 78 autistic and 81 NT males (12-to-46-years) and fit to the DTI and NODDI diffusion models. TBSS and GBSS were performed to analyze WM and GM microstructure, respectively. General linear models were used to investigate group and age-related group differences. Within the ASD group, relationships between WM and GM microstructure and measures of autistic symptoms were investigated. All dMRI measures were significantly associated with age across WM and GM. Significant group differences were observed across WM and GM. No significant age-by-group interactions were detected. Within the ASD group, positive relationships with WM microstructure were observed with ADOS-2 Calibrated Severity Scores. Using TBSS and GBSS our findings provide new insights into group differences of WM and GM microstructure in autistic males from adolescence into adulthood. Detection of microstructural differences across the lifespan as well as their relationship to the level of autistic symptoms will deepen to our understanding of brain-behavior relationships of ASD and may aid in the improvement of intervention options for autistic adults.

Cathodal high-definition transcranial direct current stimulation (HD-tDCS) of the left ventral prefrontal cortex (vPFC) interferes with conscious error correction

Precise motor timing requires the ability to flexibly adapt one’s own movements with respect to changes in the environment. Previous studies suggest that the correction of perceived as compared to non-perceived timing errors involves at least partially distinct brain networks. The dorsolateral prefrontal cortex (dPFC) has been linked to the correction of perceived timing errors and evidence for a contribution of the ventrolateral PFC (vPFC) specifically to the correction of non-perceived errors exists. The present study aimed at clarifying the functional contribution of the left vPFC for the correction of timing errors by adopting high-definition transcranial direct current stimulation (HD-tDCS). Twenty-one young healthy volunteers synchronized their right index finger taps with respect to an isochronous auditory pacing signal. Perceivable and non-perceivable step-changes of the metronome were interspersed, and error correction was analyzed by means of the phase-correction response (PCR). In subsequent sessions anodal and cathodal HD-tDCS was applied to the left vPFC to establish a brain-behavior relationship. Sham stimulation served as control condition. Synchronization accuracy as well as error correction were determined immediately prior to and after HD-tDCS. The analysis suggests a detrimental effect of cathodal HD-tDCS distinctively on error correction in trials with perceived timing errors. The data support the significance of the left vPFC for error correction in the temporal domain but contradicts the view of a role in the correction of non-perceived errors.

Explicit face memory abilities are positively related to the non-intentional encoding of faces: Behavioral and ERP evidence

Individual differences in face memory abilities have been shown to be related to individual differences in brain activity. The present study investigated brain-behavior relationships for the N250 component in event-related brain potentials, which is taken as a neural sign of face familiarity. We used a task in which a designated, typical target face and several (high- and low-distinctive) nontarget faces had to be distinguished during multiple presentations across a session. Separately, face memory/recognition abilities were measured with easy versus difficult tasks. We replicated an increase of the N250 amplitude to the target face across the session and observed a similar increase for the non-target faces, indicating the build-up of memory representations also for these faces. On the interindividual level, larger across-session N250 amplitude increases to low-distinctive non-target faces were related to faster face recognition as measured in an easy task. These findings indicate that non-intentional encoding of non-target faces into memory is associated with the swift recognition of explicitly learned faces; that is, there is shared variance of incidental and intentional face memory.

A Shared Multivariate Brain-Behavior Relationship in a Transdiagnostic Sample of Adolescents

BackgroundInternalizing and externalizing psychopathology typically present in early childhood and can have negative implications on general functioning and quality of life. Prior work has linked increased psychopathology symptoms with altered brain structure. Multivariate analysis such as partial least squares correlation can help identify patterns of covariation between brain regions and psychopathology symptoms. This study examined the relationship between gray matter volume (GMV) and psychopathology symptoms in adolescents with various psychiatric diagnoses. MethodsStructural magnetic resonance imaging data were collected from 490 participants with various internalizing and externalizing diagnoses (197 female/293 male; age = 14.68 ± 2.35 years; IQ = 104.05 ± 13.11). Cortical and subcortical volumes were parcellated using the Desikan-Killiany atlas. Partial least squares correlation was used to identify multivariate linear relationships between GMV and the Strength and Difficulties Questionnaire difficulties domains (emotional, peer, conduct, and hyperactivity issues). Resampling approaches were used to determine significance (permutation test), stability (bootstrap resampling), and reproducibility (split-half resampling) of identified relationships. ResultsWe found a significant, stable, and largely reproducible dimension that linked lower Strength and Difficulties Questionnaire scores (less impairment) across all difficulties domains with greater widespread GMV (singular value = 1.17, accounts for 87.1% of the covariance; p < .001). This dimension emphasized the relationship between lower conduct problems and greater GMV in frontotemporal regions. ConclusionsOur results indicate that the most significant and stable brain-behavior relationship in a transdiagnostic sample is a domain-general relationship, linking lower psychopathology symptom scores to greater global GMV. This finding suggests that a shared brain-behavior relationship may be present across adolescents with and without clinically significant psychopathology symptoms.

Sex differences of the triple network model in children with autism: A resting-state fMRI investigation of effective connectivity.

Autism spectrum disorder (ASD) has a pronounced male predominance, but the underlying neurobiological basis of this sex bias remains unclear. Gender incoherence (GI) theory suggests that ASD is more neurally androgynous than same-sex controls. Given its central role, altered structures and functions, and sex-dependent network differences in ASD, the triple network model, including the central executive network (CEN), default mode network (DMN), and salience network (SN), has emerged as a candidate for characterizing this sex difference. Here, we measured the sex-related effective connectivity (EC) differences within and between these three networks in 72 children with ASD (36 females, 8-14 years) and 72 typically developing controls (TCs) (36 females, 8-14 years) from 5 sites of the Autism Brain Imaging Data Exchange repositories using a 2 × 2 analysis of covariance factorial design. We also assessed brain-behavior relationships and the effects of age on EC. We found significant diagnosis-by-sex interactions on EC: females with ASD had significantly higher EC than their male counterparts within the DMN and between the SN and CEN. The interaction pattern supported the GI theory by showing that the higher EC observed in females with ASD reflected a shift towards the higher level of EC displayed in male TCs (neural masculinization), and the lower EC seen in males with ASD reflected a shift towards the lower level of EC displayed in female TCs (neural feminization). We also found significant brain-behavior correlations and significant effects of age on EC.

Properties of white matter tract diffusivity in children with developmental dyslexia and comorbid attention deficit/hyperactivity disorder

BackgroundDevelopmental dyslexia (DD) and attention deficit/hyperactivity disorder (ADHD) are highly comorbid neurodevelopmental disorders. Individuals with DD or ADHD have both been shown to have deficits in white matter tracts associated with reading and attentional control networks. However, white matter diffusivity in individuals comorbid with both DD and ADHD (DD + ADHD) has not been specifically explored.MethodsParticipants were 3rd and 4th graders (age range = 7 to 11 years; SD = 0.69) from three diagnostic groups ((DD (n = 40), DD + ADHD (n = 22), and typical developing (TD) (n = 20)). Behavioral measures of reading and attention alongside measures of white matter diffusivity were collected for all participants.ResultsDD + ADHD and TD groups differed in mean fractional anisotropy (FA) for the left and right Superior Longitudinal Fasciculus (SLF)-Parietal Terminations and SLF-Temporal Terminations. Mean FA for the DD group across these SLF tracts fell between the lower DD + ADHD and higher TD averages. No differences in mean diffusivity nor significant brain-behavior relations were found.ConclusionsFindings suggest that WM diffusivity in the SLF increases along a continuum across DD + ADHD, DD, and TD.

Anhedonia and Delay Discounting: Differing Patterns of Brain-Behavior Relationships in Healthy Control Participants Versus Individuals With Posttraumatic Stress Disorder

BackgroundAnhedonia may contribute to individual differences in delay discounting (DD). In prior work, we found that higher anhedonia was associated with shallower DD in healthy control (HC) participants but steeper DD in individuals with posttraumatic stress disorder (PTSD). In this study, we aimed to directly compare the relationship between anhedonia and DD across groups and to identify functional brain correlates of this interaction. MethodsParticipants (HC group: n = 23, DSM-5 PTSD group: n = 23) completed a questionnaire assessing anhedonia (Snaith-Hamilton Pleasure Scale [SHAPS]), task-based functional magnetic resonance imaging of decision making including DD, and resting-state functional magnetic resonance imaging. Task-based activity and resting-state functional connectivity were evaluated in reward-related regions that have also been implicated in PTSD (nucleus accumbens [NAcc], right anterior insula). ResultsHigher SHAPS scores were associated with steeper DD in PTSD, but there was no relationship between DD and SHAPS in the HC group. There was a significant group-by-SHAPS interaction for NAcc activity, t31 = 2.92, p = .007: Greater NAcc activity when immediate rewards were chosen was associated with higher SHAPS in the PTSD group but lower SHAPS in the HC group. In resting-state functional connectivity, there was a group-by-SHAPS interaction between the NAcc seed and right parietal and frontal pole clusters. ConclusionsThese results extend prior findings that anhedonia is associated with steeper DD in PTSD and demonstrate that this behavioral finding occurs in the context of NAcc hyperactivity to immediate rewards and hyperconnectivity in anhedonic individuals with PTSD.

Multivariate analytical approaches for investigating brain-behavior relationships.

Many studies of brain-behavior relationships rely on univariate approaches where each variable of interest is tested independently, which does not allow for the simultaneous investigation of multiple correlated variables. Alternatively, multivariate approaches allow for examining relationships between psychopathology and neural substrates simultaneously. There are multiple multivariate methods to choose from that each have assumptions which can affect the results; however, many studies employ one method without a clear justification for its selection. Additionally, there are few studies illustrating how differences between methods manifest in examining brain-behavior relationships. The purpose of this study was to exemplify how the choice of multivariate approach can change brain-behavior interpretations. We used data from 9,027 9- to 10-year-old children from the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) to examine brain-behavior relationships with three commonly used multivariate approaches: canonical correlation analysis (CCA), partial least squares correlation (PLSC), and partial least squares regression (PLSR). We examined the associations between psychopathology dimensions including general psychopathology, attention-deficit/hyperactivity symptoms, conduct problems, and internalizing symptoms with regional brain volumes. The results of CCA, PLSC, and PLSR showed both consistencies and differences in the relationship between psychopathology symptoms and brain structure. The leading significant component yielded by each method demonstrated similar patterns of associations between regional brain volumes and psychopathology symptoms. However, the additional significant components yielded by each method demonstrated differential brain-behavior patterns that were not consistent across methods. Here we show that CCA, PLSC, and PLSR yield slightly different interpretations regarding the relationship between child psychopathology and brain volume. In demonstrating the divergence between these approaches, we exemplify the importance of carefully considering the method's underlying assumptions when choosing a multivariate approach to delineate brain-behavior relationships.

Methodologies for task-fMRI based prognostic biomarkers in response to aphasia treatment

With the diversity in aphasia coupled with diminished gains at the chronic phase, it is imperative to deliver effective rehabilitation plans. Treatment outcomes have therefore been predicted using lesion-to-symptom mapping, but this method lacks holistic functional information about the language-network. This study, therefore, aims to develop whole-brain task-fMRI multivariate analysis to neurobiologically inspect lesion impacts on the language-network and predict behavioral outcomes in persons with aphasia (PWA) undergoing language therapy. In 14 chronic PWA, semantic fluency task-fMRI and behavioral measures were collected to develop prediction methodologies for post-treatment outcomes. Then, a recently developed imaging-based multivariate method to predict behavior (i.e., LESYMAP) was optimized to intake whole-brain task-fMRI data, and systematically tested for reliability with mass univariate methods. We also accounted for lesion size in both methods. Results showed that both mass univariate and multivariate methods identified unique biomarkers for semantic fluency improvements from baseline to 2-weeks post-treatment. Additionally, both methods demonstrated reliable spatial overlap in task-specific areas including the right middle frontal gyrus when identifying biomarkers of language discourse. Thus whole-brain task-fMRI multivariate analysis has the potential to identify functionally meaningful prognostic biomarkers even for relatively small sample sizes. In sum, our task-fMRI based multivariate approach holistically estimates post-treatment response for both word and sentence production and may serve as a complementary tool to mass univariate analysis in developing brain-behavior relationships for improved personalization of aphasia rehabilitation regimens.

A topography-based predictive framework for naturalistic viewing fMRI

Functional magnetic resonance imaging (fMRI) during naturalistic viewing (NV) provides exciting opportunities for studying brain functions in more ecologically valid settings. Understanding individual differences in brain functions during NV and their behavioural relevance has recently become an important goal. However, methods specifically designed for this purpose remain limited. Here, we propose a topography-based predictive framework (TOPF) to fill this methodological gap. TOPF identifies individual-specific evoked activity topographies in a data-driven manner and examines their behavioural relevance using a machine learning-based predictive framework. We validate TOPF on both NV and task-based fMRI data from multiple conditions. Our results show that TOPF effectively and stably captures individual differences in evoked brain activity and successfully predicts phenotypes across cognition, emotion and personality on unseen subjects from their activity topographies. Moreover, TOPF compares favourably with functional connectivity-based approaches in prediction performance, with the identified predictive brain regions being neurobiologically interpretable. Crucially, we highlight the importance of examining individual evoked brain activity topographies in advancing our understanding of the brain-behaviour relationship. We believe that the TOPF approach provides a simple but powerful tool for understanding brain-behaviour relationships on an individual level with a strong potential for clinical applications.

Using modular connectome-based predictive modeling to reveal brain-behavior relationships of individual differences in working memory.

Working memory plays a crucial role in our daily lives, and brain imaging has been used to predict working memory performance. Here, we present an improved connectome-based predictive modeling approach for building a predictive model of individual working memory performance from whole-brain functional connectivity. The model was built using n-back task-based fMRI and resting-state fMRI data from the Human Connectome Project. Compared to prior models, our model was more interpretable, demonstrated a closer connection to the known anatomical and functional network. The model also demonstrates strong generalization on nine other cognitive behaviors from the HCP database and can well predict the working memory performance of healthy individuals in external datasets. By comparing the differences in prediction effects of different brain networks and anatomical feature analysis on n-back tasks, we found the essential role of some networks in differentiating between high and low working memory loads conditions.