Joshua Sensenbaugh, B.S.- Wright State University, School of Professional Psychology, Psy.D. Program (Doctoral Student)
Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term for a group of neurocognitive and behavioral difficulties that are brought upon by prenatal alcohol exposure (1). Studies have estimated that the prevalence of FASD within the U.S. ranges from 1 to 5% of children (2-3). The clinical features of FASD often include: prenatal growth deficiency, minor facial anomalies, problems with various organ systems, neurocognitive deficits, and self-regulation/adaptive functioning difficulties (4-5). The most identifiable features of FASD are the sentinel facial features (i.e., thin upper lip, smooth philtrum, and small palpebral fissures) (6-8). Although the minor facial anomalies can make the identification of FASD easier, there are subsets of disorders that fall under FASD that do not require the facial features to make a diagnosis (1, 6). Thus, a thorough neuropsychological assessment, as part of an interdisciplinary team effort, is required to determine if a diagnosis of FASD fits for a suspected individual (6, 9).
The effects of alcohol exposure during pregnancy may have a direct teratogenic impact on the brain of the developing fetus, ultimately leading to neurocognitive impairments. Some of the brain areas directly impacted in the fetus include the frontal lobes, corpus callosum, basal ganglia, amygdala, hippocampus, hypothalamus, and cerebellum (10-11). Because not all children exposed to alcohol consumption during pregnancy may be affected to the same degree, the pattern, quantity, and timing of the alcohol consumption as well as different socio-emotional risk factors are important determinants of the degree of impairment (4). The various neuropsychological deficits that result from alcohol exposure during pregnancy exist on a continuum from subtle impairments to more severe deficits (12). Many studies have attempted to develop a neuropsychological profile for FASD because of the difficulties screening and diagnosing the individuals who exist on the FASD spectrum without the sentinel facial features (1, 6-8). In addition, developing a neuropsychological profile for FASD can help reduce the likelihood of individuals being misdiagnosed for other disorders like attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD) (13).
Despite some features that overlap with other disorders, researchers have developed a distinct neuropsychological profile for FASD consisting of: global intellectual deficits, executive-functioning deficits, memory impairment, difficulties with learning, deficits in visual-spatial abilities and processing speed, and language/motor delays (5, 7, 8, 12). Children with FASD often exhibit global intellectual deficits, and some may meet the criteria for a diagnosis of an intellectual disability (14). In addition to intellectual difficulties, individuals with FASD often exhibit problems with achievement and learning, specifically problems related to mathematical abilities (15). Some of the difficulties in math achievement may be directly related to deficits in visual-spatial abilities (16). Further examining deficits in visual-spatial abilities, individuals with FASD may have difficulties with visual memory, visual-motor integration, spatial memory, and visual perceptual skills (17). Memory impairment in FASD is generally verbal and visual spatial memory particularly concerning encoding and retrieving information (5, 18-19). Problems with language and communication typically are common and highly variable in individuals with FASD, but they often have difficulties with pragmatics as well as understanding and using abstract or figurative language (20-21). Lastly, motor delays and deficits in motor skills and coordination are expected during childhood which persist into adulthood presenting as problems with overall balance and motor clumsiness (22-23).
As the neurocognitive impairments in FASD appear to be wide-ranging, deficits in executive-functioning skills are particularly significant and can explain some of the behavioral and social impairments in individuals with FASD (12). Since the frontal lobes of the brain are responsible for executive-functioning skills, many studies have examined the effects of prenatal alcohol exposure on frontal lobe areas finding damage and cell loss in areas, such as the left ventral frontal lobe, orbitofrontal lobe, and medial prefrontal cortex (10-11). The executive-functioning difficulties that have been discovered in FASD include: problem-solving/planning, response inhibition, attentional vigilance, working memory, fluency, and set-shifting (7, 24-25). An important point to consider is that these deficits in executive-functioning tend to be global and are not dependent on the level of IQ or the severity of the disorder (26). In addition, many of these deficits in executive-functioning can become more pronounced as an individual with FASD ages unless some form of intervention is provided (27). While efforts are continued to spread awareness of the effects of drinking alcohol during pregnancy, it’s imperative to continue efforts of further researching neuropsychological features of FASD in order to improve assessment, diagnosis, and targeting interventions.
Abstract (taken directly from ncbi.nlm.nih.gov): This grand rounds manuscript reviews important considerations in developing case conceptualizations for individuals with a history of prenatal alcohol exposure. This case study provides an introduction to fetal alcohol spectrum disorders, diagnostic issues, a detailed description of the individual's history, presenting symptoms, neuropsychological test results, and an integrated summary. We describe a 9-year old girl diagnosed with a fetal alcohol spectrum disorder (FASD): Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE). This patient is a composite of a prototypical child who participated as part of a research project at the Center for Behavioral Teratology who was subsequently seen at an outpatient child psychiatry facility.
Glass, L., & Mattson, S. N. (2017). Fetal Alcohol Spectrum Disorders: A case study. Journal of Pediatric Neuropsychology, 3(2), 114–135. http://doi.org/10.1007/s40817-016-0027-7
Fetal Alcohol Spectrum Disorders (FASD)- Presented by SAMHSA
FASD: Screening, Assessment, and Diagnosis- Presented by Carol Weitzman, MD FAAP from American Academy of Pediatrics (AAP)
FASD Intervention and Treatment- Presented by Dr. Claire Coles from NOFAS
Cook, J. L., Green, C. R., Lilley, C. M., Anderson, S. M., Baldwin, M. E., Chudley, A. E., & ... Rosales, T. (2016). Fetal alcohol spectrum disorder: A guideline for diagnosis across the lifespan. Canadian Medical Association Journal, 188(3), 191-197. doi:10.1503/cmaj.141593
Davis, K., Desrocher, M., & Moore, T. (2011). Fetal Alcohol Spectrum Disorder: A review of neurodevelopmental findings and interventions. Journal of Developmental and Physical Disabilities, 23(2), 143-167. doi:10.1007/s10882-010-9204-2
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Contributor: Daniella Ladowski, M.Sc., University of Western Ontario (Doctoral Candidate)
Amyotrophic Lateral Sclerosis (ALS), also referred to as motor neuron disease, is a progressive disease affecting both upper and lower motor neurons. According to the El Escorial criteria  and its revisions [2-5], diagnosis is largely based on clinical and electrophysiological evidence of motor neuron dysfunction to the exclusion of other motor disorders. However, ALS may be conceptualized as a collection of disorders with numerous phenotypic variants, each with its own implications for prognosis and treatment [6-7]. One such variant is ALS with comorbid frontotemporal dementia (FTD).
One third to one half of individuals with ALS exhibit cognitive impairment in at least one domain, and approximately 15% meet criteria for FTD [8-9]. It is unlikely that ALS with FTD represents a discrete diagnostic category; rather, cognitive and behavioural symptoms that are characteristic of FTD appear to fall on a continuum in ALS . Among individuals with ALS, common cognitive symptoms include executive dysfunction (e.g., impaired verbal fluency, complex attention, cognitive flexibility) and to a lesser degree, language and memory impairment [10-12]. Behavioural abnormalities may also be prominent, including apathy, irritability, disinhibition, and impaired social cognition [12-14]. Based on the observation that individuals without dementia may exhibit clinically meaningful cognitive and behavioural changes, Strong and colleagues  proposed a classification system for frontotemporal syndromes in ALS, which characterizes syndromes that meet criteria for a dementia diagnosis [ALS-FTD and ALS-comorbid dementia (non-FTD)] as well as those that do not meet full criteria but represent significant impairments (ALS-behavioural impairment and ALS-cognitive impairment).
In addition to cognitive and behavioural symptomatology, ALS and FTD share common neuropathological features. In neuroimaging studies, cognitively-impaired individuals with ALS exhibit patterns of atrophy and hypometabolism/hypoperfusion in frontotemporal regions that are comparable to those observed in FTD [13,16-18]. Even in the absence of overt dementia, large-scale abnormalities in cortical thickness and functional connectivity have been detected in ALS [19-20]. In terms of pathogenesis, some genetic mutations and other biomarkers have been implicated in both ALS and FTD . For example, in 2006, Neumann and colleagues  discovered that TAR DNA-binding protein 43 (TDP-43) was the major disease protein in both ALS and FTD. In 2011, mutations of the C9ORF72 gene were shown to explain familial cases of co-occurring ALS and FTD linked to chromosome 9 [22-23]. These and other discoveries are further evidence of the disease continuum that accounts for ALS and FTD concordance.
Detection of cognitive impairment in individuals with ALS is essential for treatment planning. Individuals with ALS-FTD demonstrate lower rates of compliance with nutritional and respiratory interventions compared to individuals with ALS alone . Since these interventions are administered in advanced stages of the disease to prolong survival, noncompliance likely contributes to the shorter survival times observed among individuals with ALS-FTD compared to ALS alone [24-25]. Among individuals without FTD, executive impairment may also predict shorter survival in ALS, whereas more subtle or non-executive impairments are not thought to affect survival [25-26]. Greater cognitive impairment in ALS has also been linked to increased caregiver burden . Finally, capacity in healthcare decision-making is an important consideration in ALS, especially as it relates to end-of-life decisions. Given that cognitive symptoms often precede motor symptoms in ALS-FTD , it may be prudent to establish advance directives at the earliest signs of cognitive decline before decision-making becomes affected and speech/motor disturbances hinder communication. In light of these challenges, early neuropsychological assessment should be undertaken in order to best prepare patients, caregivers, and clinicians for the road ahead.
Beeldman, E., Raaphorst, J., Klein Twennaar, M., Govaarts, R., Pijnenburg, Y. A. L., de Haan, R. J., … Schmand, B. A. (2018). The cognitive profile of behavioural variant FTD and its similarities with ALS: A systematic review and meta-analysis. Journal of Neurology, Neurosurgery & Psychiatry. Advance online publication. http://doi.org/10.1136/jnnp-2017-317459
Abstract: Approximately 30% of patients with amyotrophic lateral sclerosis (ALS) have cognitive impairment and 8%–14% fulfil the criteria for behavioural variant frontotemporal dementia (bv-FTD). The cognitive profiles of ALS and bv-FTD have been reported to be comparable, but this has never been systematically investigated. We aimed to determine the cognitive profile of bv-FTD and examine its similarities with that of ALS, to provide evidence for the existence of a cognitive disease continuum encompassing bv-FTD and ALS. We therefore systematically reviewed neuropsychological studies on bv-FTD patients and healthy volunteers. Neuropsychological tests were divided in 10 cognitive domains and effect sizes were calculated for all domains and compared with the cognitive profile of ALS by means of a visual comparison and a Pearson’s r correlation coefficient. We included 120 studies, totalling 2425 bv-FTD patients and 2798 healthy controls. All cognitive domains showed substantial effect sizes, indicating cognitive impairment in bv-FTD patients compared to healthy controls. The cognitive domains with the largest effect sizes were social cognition, verbal memory and fluency (1.77–1.53). The cognitive profiles of bv-FTD and ALS (10 cognitive domains, 1287 patients) showed similarities on visual comparison and a moderate correlation 0.58 (p=0.13). When social cognition, verbal memory, fluency, executive functions, language and visuoperception were considered, i.e. the cognitive profile of ALS, Pearson’s r was 0.73 (p=0.09), which raised to 0.92 (p=0.03), when language was excluded in this systematic analysis of patients with a non-language subtype of FTD. The cognitive profile of bv-FTD consists of deficits in social cognition, verbal memory, fluency and executive functions and shows similarities with the cognitive profile of ALS. These findings support a cognitive continuum encompassing ALS and bv-FTD.
(Lecture) Pathology and current molecular classification of ALS/FTD
Presenter: Dr. Tibor Hortobagyi, Department of Neuropathology, University of Debrecen, Hungary
Dr. Hortobagyi provides a summary of neuropathological findings in ALS from the first candidate disease proteins and genetic mutations to the current state of knowledge, noting common biomarkers of ALS and FTD. This video begins with a general discussion of the importance of neuropathological investigation for the classification of neurodegenerative disorders.
(Seminar) Caregiver education program for ALS-FTD
Presenter: Dr. Susan Walsh, ALS Association of Greater Philadelphia, USA
This is the first part of a three-part educational seminar for caregivers of individuals with ALS and FTD. In this segment, Dr. Walsh provides background information on ALS and FTD. The second and third segments (also available on Youtube) describe practical strategies with respect to behaviour management and problem solving.
(Handout) ALS & Cognitive Changes
Publisher: ALS Society of Canada
This handout provides basic information on cognitive and behavioural changes in ALS. In the past, individuals with ALS and their caregivers have reported feeling under-informed about cognitive changes , so a handout such as this one can be helpful in starting important conversations about what to expect.
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26.Mioshi, E., Caga, J., Lillo, P., Hsieh, S., Ramsey, E., Devenney, E., … Kiernan, M. C. (2014). Neuropsychiatric changes precede classic motor symptoms in ALS and do not affect survival. Neurology, 82(2), 149–154. http://doi.org/10.1212/WNL.0000000000000023
27.Lillo, P., Mioshi, E., & Hodges, J. R. (2012). Caregiver burden in amyotrophic lateral sclerosis is more dependent on patients’ behavioral changes than physical disability: A comparative study. BMC Neurology, 12. http://doi.org/10.1186/1471-2377-12-156
28.Wicks, P., & Frost, J. (2008). ALS patients request more information about cognitive symptoms. European Journal of Neurology, 15(5), 497–500. http://doi.org/10.1111/j.1468-1331.2008.02107.x
Contributor: Yosefa Allegra Ehrlich, M.Phil., Ph.D. Candidate in Clinical Psychology, Queens College, City University of New York (CUNY)
The use of biomarkers in diagnosing Alzheimer’s disease (AD) in vivo is gaining popularity. Biomarkers refer to measureable characteristics that indicate the presence of biologic and/or pathologic processes (1). This shift is based on an expanding body of research indicating that in vivo methods validly estimate post-mortem AD pathologic changes that characterize the disease (2–5). The goals of incorporating biomarkers into the diagnosis include: clarifying the multifaceted etiology/pathophysiology (5), standardizing research terms (4,6), identifying individuals in preclinical phases (6,7), improving diagnostic accuracy (8), and developing more precise interventions (9).
Over the past decade, the National Institute on Aging and Alzheimer’s Association (NIAA-AA) and the International Working Group (IWG) have continually proposed new criteria for the diagnosis of AD. There are points of overlap as well as divergence between their suggested frameworks. In a position paper still under review (5), the NIAA-AA propose a definition of AD based on evidence of three biological markers of pathologic processes: (a) b-amyloid plaques, (b) phosphorylated tau (P-tau), (c) markers of neuronal injury (e.g., elevated CSF total tau (T-tau)) and cerebral hypometabolism and atrophy (10). Presence of b-amyloid deposition alone (with normal tau and no neurodegeneration) is considered Alzheimer’s pathologic change. A diagnosis of AD indicates evidence of both b-amyloid and P-tau. Neuronal injury is understood to emerge as a consequence of b-amyloid and tau and is not specific to AD pathology (11); accordingly, those markers are conceptualized to emerge in the later stages of the disease continuum and are not essential for a diagnosis. Importantly, these diagnostic states exist independently of clinical symptoms. The authors recognize that cognitive impairment generally corresponds with increased presence of biomarkers and suggest that clinical changes should be measured along six stages of increasing impairment with the first stage beginning with positive evidence of biomarkers. This framework reflects an effort to disentangle the presence of AD neuropathology (disease process) from the clinical syndrome (signs/symptoms).
The IWG-2 criteria for AD (9,3,2,12,13) also require in vivo evidence of pathology ((a)decreased CSF b-amyloid and increased CSF P- and T-tau, (b) increased amyloid PET, (c) AD autosomal mutation) for an AD diagnosis. Similar to the NIA-AA, the IWG-2 agrees that biomarkers can be detectable in pre-clinical (asymptomatic) states and calls for a continuum-based understanding of disease course. However, the groups’ definitions diverge regarding clinical phenotypic expression. The IWG-2 criteria call for evidence of cognitive disturbance, primarily episodic memory impairment, in issuing a diagnosis. In the preclinical stage, patients with MCI and positive biomarkers receive a diagnosis of MCI due to AD or, interchangeably, prodromal AD (3,12,13). A diagnosis of typical AD is only distinguished by the degree of cognitive impairment (2). By including the cognitive criterion in the diagnosis, the authors are conceptualizing AD as both biological and syndromic (clinico-pathological).
While the definition of an AD diagnosis remains unresolved, the utility and validity of biomarkers measured via imaging and CSF markers have been well demonstrated (14). Fibrillary b-amyloid deposition associated with AD can be validly and reliably measured in vivo via increased amyloid PET binding and low CSF Ab42 (15). Pathologic tau deposition in AD can be assessed through newly developed PET ligands that show elevated cortical tau binding as well as elevated P-tau CSF markers (15,16). Neuronal injury is measured via cortical atrophy (on MRI) and/or hypometabolism (on FDG PET) generally in medial temporal, medial parietal, and lateral temporal-parietal cortices (17).
Limitations of incorporating biomarkers in AD diagnoses apply in both research and clinical settings. Despite increased validity, none of the in vivo biomarker tools are as sensitive as histology (18). The lack of consensus among researchers on diagnostic criteria limits standardization and generalizability of findings. There are also no clear numeric cut-offs by which to categorize biomarker levels; while some have proposed continuous measurements (5), this complicates researchstandardization as well as clinical translation. The primary clinical concern surrounds poor specificity and sensitivity of biomarkers to clinical symptoms associated with AD (19). Between 30 to 40% of individuals with no cognitive impairment (asymptomatic) show biological abnormalities in vivo and on autopsy (20,21), while 10 to 30% of individuals with clinical signs of AD-related dementia have clean autopsies (22). This has led to the proposal of including additional factors (e.g., vascular) as biomarkers (23) to increase prognostic reliability. Further clinical challenges include prohibitive costs, limited accessibility, inconsistent regulatory approval, and uncertain insurance reimbursement (12). Finally, as in many areas of research, more population-based studies are needed to validate the utility of biomarkers in diverse ethnic groups (24).
Highlighted Abstract: Fluid and imaging biomarkers for Alzheimer's disease: Where we stand and where to head to.
There is increasing evidence that a number of potentially informative biomarkers for Alzheimer disease (AD) can improve the accuracy of diagnosing this form of dementia, especially when used as a panel of diagnostic assays and interpreted in the context of neuroimaging and clinical data. Moreover, by combining the power of CSF biomarkers with neuroimaging techniques to visualize Aβ deposits (or neurodegenerative lesions), it might be possible to better identify individuals at greatest risk for developing MCI and converting to AD. The objective of this article was to review recent progress in selected imaging and chemical biomarkers for prediction, early diagnosis and progression of AD. We present our view point of a scenario that places CSF and imaging markers on the verge of general utility based on accuracy levels that already match (or even surpass) current clinical precision.
Henriques, A. D., Benedet, A. L., Camargos, E. F., Rosa-Neto, P., & Nóbrega, O. T. (2018). Fluid and imaging biomarkers for Alzheimer’s disease: Where we stand and where to head to. Experimental Gerontology, (January), 1–9. http://doi.org/10.1016/j.exger.2018.01.002
Other Media and Resources:
Webinar- Hear Clifford Jack, MD present his conceptualization of biomarker stages
Webinar- Learn about the development and uses of the AlzBiomarker database
Webinar- Biomarkers, cognition, and cognitive reserve in AD
Bondi, M.W., Edmonds, E.C., Salmon, D.P., 2017. Alzheimer’s Disease: Past, Present, and Future. J. Int. Neuropsychol. Soc. 23, 818–831.
Frisoni, G. B., Boccardi, M., Barkhof, F., Blennow, K., Cappa, S., Chiotis, K., … Winblad, B. (n.d.). A Strategic Research Agenda to the Biomarker-Based Diagnosis of Prodromal Alzheimer’s Disease, 1–39. http://discovery.ucl.ac.uk/1567593/1/Frisoni_Strategic_roadmap_early_diagnosis.pdf
Frisoni, G. B., Boccardi, M., Barkhof, F., Blennow, K., Cappa, S., Chiotis, K., … Winblad, B. (2017). Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. The Lancet Neurology, 16(8), 661–676. http://doi.org/10.1016/S1474-4422(17)30159-X
Jack, C. R. J., Bennet, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Elliot, C., … Sperling, R. (n.d.). NIA-AA Research Framework: Towards a Biological Definition of Alzheimer’s Disease. https://alz.org/aaic/_downloads/draft-nia-aa-7-18-17.pdf
Vanderschaeghe, G., Dierickx, K., Vandenberghe, R., 2018. Review of the Ethical Issues of a Biomarker-Based Diagnoses in the Early Stage of Alzheimer’s Disease. J. Bioeth. Inq. 1–12.
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6. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc. Elsevier; 2011;7(3):280–92.
7. Jessen F, Amariglio RE, Van Boxtel M, Breteler M, Ceccaldi M, Chételat G, et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc. Elsevier; 2014;10(6):844–52.
8. Zwan MD, Bouwman FH, Konijnenberg E, van der Flier WM, Lammertsma AA, Verhey FRJ, et al. Diagnostic impact of [18 F] flutemetamol PET in early-onset dementia. Alzheimers Res Ther. BioMed Central; 2017;9(1):2.
9. Cavedo E, Lista S, Khachaturian Z, Aisen P, Amouyel K, Herholz K, et al. The Road Ahead to Cure Alzheimer’s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations. J Pre Alzherims Dis. 2014;1(3):181–202.
10. Jack CR, Bennet DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, et al. A new classification system for AD , independent of cognition A / T / N : An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87:539–47.
11. Wirth M, Madison CM, Rabinovici GD, Oh H, Landau SM, Jagust WJ. Alzheimer’s disease neurodegenerative biomarkers are associated with decreased cognitive function but not β-amyloid in cognitively normal older individuals. J Neurosci. Soc Neuroscience; 2013;33(13):5553–63.
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14. Henriques AD, Benedet AL, Camargos EF, Rosa-Neto P, Nóbrega OT. Fluid and imaging biomarkers for Alzheimer’s disease: Where we stand and where to head to. Exp Gerontol [Internet]. Elsevier; 2018;(January):1–9. Available from: http://dx.doi.org/10.1016/j.exger.2018.01.002
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Contributor: Briana Brukilacchio, M.Ed., The University of Texas at Austin, PhD Program in School Psychology
An estimated 15% of all patients with focal epilepsy syndromes do not experience substantial relief when treated with anticonvulsant medications alone . For these patients with intractable epilepsy, surgical intervention is often indicated . In order to maximize postoperative benefits and minimize the risk of associated impairments, such patients undergo presurgical epilepsy evaluations prior to treatment . Evaluations are conducted by a multidisciplinary team and typically include reports of clinical semiology (signs and symptoms of the seizure activity), structural and functional neuroimaging, electroencephalography (EEG) video telemetry, and neuropsychological testing. Primary goals of the presurgical evaluation are to map the epileptogenic area (a conceptual area of the cortex, believed to be indispensable in the generation of seizure activity; [1, 4]) and eloquent cortex (critical language, sensorimotor, and memory areas which are avoided as much as possible during surgery) to guide surgical procedures and predict postsurgical functioning. With regard to language, the primary objective is to identify the dominant hemisphere involved in language functions (i.e. language laterality ), although noninvasive imaging modalities have made it possible to map discrete language functions with improved spatial and temporal detail.
The intracarotid amobarbital procedure (Wada test; ) remains the current gold-standard in a clinical evaluation of language laterality. However, the procedure can include medical complications in up to 3% of cases and provides relatively crude hemispheric data . Limitations of the Wada test have led to developments in non-invasive neuroimaging modalities [8, 9], primarily functional Magnetic Resonance Imaging (fMRI) and magnetoencephalography (MEG). fMRI measures blood oxygenation levels as a proxy for brain activity in response to cognitive tasks. An alternative method known as resting state fMRI, tracks blood oxygenation levels in the absence of an explicit task as a proxy for large-scale brain activity . Alternatively, MEG measures electromagnetic fluctuations outside the skull as a proxy for brain activity and this method has higher spatial and temporal sensitivity compared to fMRI. The most common MEG analysis used in language laterality is dipole fitting, which fits single or multiple dipoles within the brain and indicates their corresponding strength and orientation . An advanced method of signal processing and source localization in MEG, called beamforming, has recently allowed for meaningful data to be extracted from patients with metal implants (e.g. shunts, braces, and vagus nerve stimulators) which normally cause artifacts that render neuroimaging data uninterpretable .
Noninvasive imaging tools are used with a wide variety of language tasks and analytic methods, therefore they have contributed substantially to language mapping in presurgical epilepsy cases. Laterality indices can be quantified and classified by adjusting a multitude of parameters including p-values at a voxel level, threshold levels, baseline and active windows, etc. . Language laterality has been assessed across numerous tasks, including a variety of verbal fluency tasks (e.g. phonemic fluency, verb generation), passive speech listening, text reading, phonemic judgment, semantic decision, sentence comprehension, and naming . Although the strength and pattern of lateralization varies across tasks and is thought to represent true variability in language networks, laterality indices are strongest in verbal fluency tasks . For instance, verb generation and phonemic fluency tasks produce strong laterality indices in frontal regions [13, 14, 15], and semantic fluency tasks produce strong laterality indices in temporoparietal regions .
There are numerous challenges and potential gains associated with the implementation of fMRI, MEG, and other noninvasive imaging modalities in presurgical evaluations. Challenges primarily include the lack of normative data against which patients can be compared (especially in pediatrics ) and insufficient guidelines to direct task selection, analysis, and interpretation [3, 5]. For these reasons, the Wada test remains the current gold-standard in clinical practice, although many epilepsy centers have integrated fMRI and MEG into presurgical evaluations to further validate or expand upon neuropsychological findings .
A particularly promising application for noninvasive imaging is the development of passive language tasks. Noncompliant and pediatric patients experience difficulty with standard task demands, such as verbal fluency paradigms. However, passive tasks (e.g. listening to a story) require minimal attentional and linguistic demands, therefore they may yield valid laterality indices in patients who otherwise would be considered untestable due to clinical complications or developmental limitations .
Title: Language lateralization of a bilingual person with epilepsy using a combination of
fMRI and neuropsychological assessment findings
Citation: O’Grady, C., Omisade, A., & Sadler, R. M. (2016). Language lateralization of a bilingual person with epilepsy using a combination of fMRI and neuropsychological assessment findings. Neurocase, 22(5), 436-442.
Abstract: This report describes the findings of language functional magnetic resonance imaging (fMRI) in a left-handed Urdu and English speaker with right hemisphere-originating epilepsy and unclear language dominance. fMRI is a reliable method for determining hemispheric language dominance in presurgical planning. However, the effects of bilingualism on language activation depend on many factors including age of acquisition and proficiency in the tested language, and morphological properties of the language itself. This case demonstrates that completing fMRI in both spoken languages and interpreting the results within the context of a neuropsychological assessment are essential in arriving at accurate conclusions about language distribution in bilingual patients.
1. Engel, J. (1993). Update on surgical treatment of the epilepsies Summary of The Second International Palm Desert Conference on the Surgical Treatment of the Epilepsies (1992). Neurology, 43(8), 1612-1612.
2. Rosenow, F., & Lüders, H. (2001). Presurgical evaluation of epilepsy. Brain, 124(9), 1683-1700.
3. Bradshaw, A. R., Bishop, D. V., & Woodhead, Z. V. (2017). Methodological considerations in assessment of language lateralisation with fMRI: a systematic review. PeerJ, 5, e3557.
4. Jehi, L. (2018). The Epileptogenic Zone: Concept and Definition. Epilepsy Currents, 18(1), 12-16.
5. Bradshaw, A. R., Thompson, P. A., Wilson, A. C., Bishop, D. V., & Woodhead, Z. V. (2017). Measuring language lateralisation with different language tasks: a systematic review. PeerJ, 5, e3929.
6. Wada, J., & Rasmussen, T. (1960). Intracarotid injection of sodium amytal for the lateralization of cerebral speech dominance: experimental and clinical observations. Journal of Neurosurgery, 17(2), 266-282.
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8. Gaillard, W. D. (2000). Structural and functional imaging in children with partial epilepsy. Mental retardation and developmental disabilities research reviews, 6(3), 220-226.
9. Verrotti, A., Pizzella, V., Trotta, D., Madonna, L., Chiarelli, F., & Romani, G. L. (2003). Magnetoencephalography in pediatric neurology and in epileptic syndromes. Pediatric neurology, 28(4), 253-261.
10. Thomason, M. E., Dennis, E. L., Joshi, A. A., Joshi, S. H., Dinov, I. D., Chang, C., ... & Glover, G. H. (2011). Resting-state fMRI can reliably map neural networks in children. Neuroimage, 55(1), 165-175.
11. Ebersole, J. S. (1997). Magnetoencephalography/magnetic source imaging in the assessment of patients with epilepsy.Epilepsia, 38(s4).
12. Stapleton-Kotloski, J. R., Kotloski, R. J., Boggs, J. A., Popli, G., O’Donovan, C. A., Couture, D. E., ... & Godwin, D. W. (2014). Localization of interictal epileptiform activity using magnetoencephalography with synthetic aperture magnetometry in patients with a vagus nerve stimulator. Frontiers in neurology, 5, 244.
13. Kleinhans, N. M., Müller, R. A., Cohen, D. N., & Courchesne, E. (2008). Atypical functional lateralization of language in autism spectrum disorders. Brain research, 1221, 115-125.
14. Ruff, I. M., Brennan, N. P., Peck, K. K., Hou, B. L., Tabar, V., Brennan, C. W., & Holodny, A. I. (2008). Assessment of the language laterality index in patients with brain tumor using functional MR imaging: effects of thresholding, task selection, and prior surgery. American journal of neuroradiology, 29(3), 528-535.
15. Sanjuán, A., Bustamante, J. C., Forn, C., Ventura-Campos, N., Barrós-Loscertales, A., Martínez, J. C., ... & Ávila, C. (2010). Comparison of two fMRI tasks for the evaluation of the expressive language function. Neuroradiology, 52(5), 407-415.
16. Jensen-Kondering, U. R., Ghobadi, Z., Wolff, S., Jansen, O., & Ulmer, S. (2012). Acoustically presented semantic decision-making tasks provide a robust depiction of the temporo-parietal speech areas. Journal of Clinical Neuroscience,19(3), 428-433.
17. Collinge, S., Prendergast, G., Mayers, S. T., Marshall, D., Siddell, P., Neilly, E., ... & Zaman, A. (2017). Pre-surgical mapping of eloquent cortex for paediatric epilepsy surgery candidates: Evidence from a review of advanced functional neuroimaging. Seizure-European Journal of Epilepsy, 52, 136-146.
18. Arya, R., Wilson, J. A., Fujiwara, H., Vannest, J., Byars, A. W., Rozhkov, L., ... & Horn, P. S. (2018). Electrocorticographic high‐gamma modulation with passive listening paradigm for pediatric extraoperative language mapping. Epilepsia, 59(4), 792-801.
Bradshaw, A. R., Thompson, P. A., Wilson, A. C., Bishop, D. V., & Woodhead, Z. V. (2017). Measuring language lateralisation with different language tasks: a systematic review. PeerJ, 5, e3929.
Collinge, S., Prendergast, G., Mayers, S. T., Marshall, D., Siddell, P., Neilly, E., ... & Zaman, A. (2017). Pre-surgical mapping of eloquent cortex for paediatric epilepsy surgery candidates: Evidence from a review of advanced functional neuroimaging. Seizure-European Journal of Epilepsy, 52, 136-146.
Arya, R., Wilson, J. A., Fujiwara, H., Vannest, J., Byars, A. W., Rozhkov, L., ... & Horn, P. S. (2018). Electrocorticographic high‐gamma modulation with passive listening paradigm for pediatric extraoperative language mapping. Epilepsia, 59(4), 792-801.
Additional Media and Resources
Guide to MEG by the Martinos Center at Massachusetts General Hospital: http://www.nmr.mgh.harvard.edu/meg/pdfs/talks/Cleve_Cohen_WithNotes2g.pdf
MATLAB Tutorial on Beamforming for MEG: http://www.fieldtriptoolbox.org/tutorial/natmeg/beamforming
Video of Wada Test by the Cleveland Clinic: https://youtu.be/N5_nX_LZ834
Video Description of the Epilepsy Presurgical Evaluation from the Epilepsy Foundation of America: https://youtu.be/UilImOfg7DM
Guidelines for using fMRI for presurgical evaluation of epilepsy: https://www.neurologyadvisor.com/epilepsy/epilepsy-surgery-evaluation-with-functional-mri-guidelines/article/632221/
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