Toward a better understanding of the savant brain

Toward a better understanding of the savant brain

Available online at Comprehensive Psychiatry 53 (2012) 706 – 717 Toward a better understandi...

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Available online at

Comprehensive Psychiatry 53 (2012) 706 – 717

Toward a better understanding of the savant brain Neva M. Corrigan a,⁎, Todd L. Richards a , Darold A. Treffert b , Stephen R. Dager a, c, d a

Department of Radiology, University of Washington, Seattle, WA 98195, USA b University of Wisconsin Medical School, Madison, WI 54935, USA c University of Washington Autism Center, Seattle, WA 98195, USA d Department of Bioengineering, University of Washington, Seattle, WA 98195, USA

Abstract Objective: The objectives of this study are to investigate the neuroanatomy, regional brain connectivity, and neurochemistry of a prodigious artistic savant; to place these findings within the context of existing neuroimaging literature of savant syndrome; and to discuss the utility of newer imaging modalities to extend our current understanding of mechanisms underlying savant skills. Methods: High-resolution magnetic resonance (MR) imaging, J-resolved MR spectroscopy, and diffusion tensor imaging data were acquired during a single scanning session for a 63-year-old male autistic savant with prodigious artistic skills. Regional and compartmental brain volumes, N-acetyl aspartate, choline, creatine, glutamate and γ-aminobutyric acid concentrations, fractional anisotropy values, and white matter bundle volumes as well as axial, radial, and mean diffusivities were calculated. Results: No gross anatomical differences were observed. By morphological assessment, cerebral volume (1362 mL) was larger than normative literature values for adult males. The corpus callosum was intact and did not exhibit abnormal structural features. The right cerebral hemisphere was 1.9% larger than the left hemisphere; the right amygdala and right caudate nuclei were 24% and 9.9% larger, respectively, compared with the left side. In contrast, the putamen was 8.3% larger on the left side. Fractional anisotropy was increased on the right side as compared with the left for 4 of the 5 bilateral regions studied (the amygdala, caudate, frontal lobe, and hippocampus). Fiber tract bundle volumes were larger on the right side for the amygdala, hippocampus, frontal lobe, and occipital lobe. Both the left and the right hippocampi had substantially increased axial and mean diffusivities as compared with those of a comparison sample of nonsavant adult males. The corpus callosum and left amygdala also exhibited high axial, radial, and mean diffusivities. MR spectroscopy revealed markedly decreased γ-aminobutyric acid and glutamate in the parietal lobe. Conclusions: Although examination of brain gross morphometry demonstrated no clinically remarkable abnormalities, utilization of conventional as well as newer MR imaging technologies revealed several atypical structural and chemical features that may be involved in the special skills of this prodigious savant. The multimodal imaging approach presented in this study is suitable for the evaluation of larger samples of savants with a diverse range of talents to investigate common brain features that may underlie the exceptional cognitive capabilities characteristic of savant syndrome. Given the high co-occurrence of the two syndromes, elucidating the underlying neurophysiologic basis of savant syndrome may also lead to a better understanding of autism spectrum disorder. © 2012 Elsevier Inc. All rights reserved.

1. Introduction Individuals with savant syndrome have circumscribed areas of substantial or even outstanding cognitive abilities, although they may also exhibit impairments in many domains of functioning. Treffert [1,2] has presented extensive overviews of savant syndrome. Reported savant skills include “lightning-speed” numerical calculation, calendrical calculation, perfect pitch, artistic skills, and ⁎ Corresponding author. E-mail address: [email protected] (N.M. Corrigan). 0010-440X/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.comppsych.2011.11.006

exceptional musical abilities. Some individuals with savant syndrome possess more than one special skill. Individuals whose talents are exceptional and well beyond the range of normal functioning are referred to as prodigious savants. Despite the diverse range of skills that have been observed, one consistent feature is an extraordinary memory capacity. Individuals with savant syndrome are also highly attentive to their specialized ability and will spend substantial time and energy practicing their unique talent. For unknown reasons, savant syndrome is more commonly observed in individuals with autism spectrum disorder (ASD) than among the general population. It is estimated that 10% of individuals

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with ASD have some type of special skill or savant characteristic. Conversely, approximately 50% of individuals with savant skills have a concurrent diagnosis of ASD. In both ASD and savant syndrome, males are more typically affected, with males with savant syndrome outnumbering females by a 6:1 ratio [3]. Investigation of the neurologic basis of savant syndrome is largely in its nacency. Although people have long been intrigued by these rare individuals with “supernormal” cognitive powers (e.g. [4]), the study of brain mechanisms that underlie special skills was long limited to behavioral observations, psychologic testing, analysis of postmortem brains, and case reports of specific, focal neurologic events. Although savant skills are quite diverse in nature, they are activities commonly associated with the right cerebral hemisphere. Theories to explain the existence of these skills in savant syndrome have included ancestral or inherited memory, utilization of alternate memory circuits, left hemispheric maldevelopment or damage with right hemispheric compensation, and right hemisphere disinhibition [1]. 1.1. Neuroimaging tools Recent advances in brain imaging technology provide new tools for probing mechanisms that underlie brain function and have the potential to help unravel the mystery of savant syndrome. The following is a description of newer magnetic resonance (MR) techniques and their relevance to the investigation of savant syndrome. 1.1.1. Structural imaging High-resolution MR imaging (MRI) produces structural images of the brain that allow for characterization of anatomical features, providing detailed information on regional tissue composition and cerebral and subcortical morphometry, which are affected by the underlying cellular architecture and chemical composition. Alterations in brain cytoarchitecture may help explain exceptional abilities in both autistic savants and the intellectually gifted [5]. Alterations in brain cytoarchitecture [6] as well as regional volume alterations have also both been associated with ASD [7]. White matter, gray matter, and cerebral spinal fluid compartmental volumes can be calculated by performing segmentation of high-resolution structural MR images. Because gray and white matter are different in terms of both anatomy and function, these compartmental volumes can provide an indication of the cumulative effect of patterns of normal or abnormal physiologic changes during development or later in life [8,9]. 1.1.2. Functional imaging Functional imaging techniques such as single photon emission tomography (SPECT), positron emission tomography (PET), and functional MRI (fMRI) provide spatial maps of changes in brain activation, allowing the identification of brain regions used during the performance of a specific task.


These techniques are based on the detection of regional increases in blood flow or blood oxygenation that arise from increased neuronal activity. Positron emission tomography and SPECT are nuclear medicine imaging techniques that measure signal from radioisotopes intravenously injected into the blood stream. Positron emission tomography has a spatial resolution of approximately 4 mm, and SPECT has a spatial resolution of approximately 8 mm. Functional MRI uses signal from endogenous oxyhemoglobin and deoxyhemoglobin rather than externally administered radioisotopes. The spatial resolution of fMRI is currently as low as 1 mm on 3T system, and the temporal resolution, on the order of 1 second or less, is also substantially better than that of PET and SPECT, which have temporal resolutions on the order of minutes. Functional MRI has become the most commonly used imaging method to investigate functional locations of brain activity that may underlie exceptional abilities in savant syndrome [10]. 1.1.3. Diffusion tensor imaging Diffusion tensor imaging (DTI) allows for the noninvasive mapping of the translational motion of water molecules in brain tissue. These measurements provide information on the geometric and structural organization of tissue on a microscopic scale [11]. The diffusion tensor measures the speed (diffusivity) and direction of diffusion. Water typically diffuses faster along the axons of neurons, causing diffusion in white matter to be highly anisotropic. The degree of anisotropy is quantified by calculating a fractional anisotropy (FA) value from DTI images. This value, which ranges from 0 (representing free diffusion) to 1 (representing diffusion along a straight line), is affected by axonal packing density and arrangement as well as the degree of myelination and thickness of the axons [12]. Axial diffusivity is a measure of the speed of diffusion in the direction parallel to the axon fiber bundles, radial diffusivity is a measure of the speed of diffusion in directions perpendicular to the axon fiber bundles, and mean diffusivity is calculated as the average speed of diffusion both perpendicular and parallel to the axon fiber bundles [13]. These measures have been demonstrated to be valuable for relating white matter integrity and structural organization to cognitive task performance. For example, increased mean diffusivity in temporal and frontal lobe white matter have been reported to be correlated with decreased nonverbal memory performance in healthy adults [14], whereas fractional anisotropy has been reported to positively correlate with executive functioning [15], reading ability [16,17], and arithmetic skill [18]. 1.1.4. Magnetic resonance spectroscopy Magnetic resonance spectroscopy (MRS) measures the concentrations of certain MRS-visible chemicals that are abundant in the brain and underlie regional macroscopic structural and functional characteristics. Although different


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endogenous nuclei are amenable to MRS measurement, proton MRS (1H MRS), in particular, has been used to investigate the neurochemical underpinnings of several psychiatric disorders [19]. A variety of chemicals are measurable with 1H MRS, including N-acetyl aspartate (NAA), which helps to regulate synaptic production and maintenance and is considered to be a marker of neuronal viability as well as regional neuronal density; choline (Cho), a constituent of neuronal membranes and marker for cell turnover; creatine (Cre), an indirect indicator of the energy pool for oxidative metabolism; glutamate (Glu), the major excitatory neurotransmitter in the brain; and γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. Glutamate and GABA have previously been challenging to measure with 1H MRS due to overlapping spectral peaks. However, increased scanner field strength and emerging methodologies, including advanced spectral editing techniques such as J-resolved spectroscopy [20-22], allow for improved measurement of these neurotransmitters. 1.2. Neuroimaging of savant syndrome Numerous case studies have described a diverse range of behavioral and clinical characteristics of individuals with savant skills. However, only a handful of reports have used neuroimaging tools to investigate such individuals. These have largely been case studies of prodigious savants, typically with outstanding mathematical calculation or calendrical abilities. Objectives and methodologies have varied quite widely across studies, and the imaging approaches have primarily used structural and functional imaging. Although the number of studies is limited, they provide a tantalizing glimpse into the neurophysiologic basis of savant talents and reveal useful information for devising new questions and strategies for further investigation of this syndrome. The following is a brief overview of individual neuroimaging case studies of savant syndrome to date. An early MRI study of a 54-year-old prodigious male savant with numerous savant skills, including lightningspeed calculation abilities, perfect pitch, and an exceptional memory capacity, revealed remarkable gross anatomical abnormalities [23]. The investigators reported the complete absence of a corpus callosum, a prominent interhemispheric white matter tract which serves as the main conduit for communication between the left and the right hemispheres; the absence of both the anterior and posterior commissures, two smaller white matter networks also connecting the hemispheres; a small and malformed cerebellum; and left hemisphere abnormalities. These findings, which could explain the disabilities observed in many areas of functioning for this individual, were taken to suggest that, in this case, highly atypical brain structure might play a role in conferring prodigious talent. An fMRI study of a 26-year-old, right-handed male savant with Asperger syndrome as well as extraordinary numerical visual digit span memory abilities revealed that his brain

activation patterns differed from those of typical controls when memorizing sequences of digits [24]. The study found increased activation of the lateral prefrontal cortex in the savant as compared with typical controls during the performance of this specific task. The authors noted that the savant had synesthesia, which can confer structural meaning on series of digits that have no patterns, and that, in typical individuals, the lateral prefrontal cortex has been found to be more activated for the memorization of series of numbers that have patterns. The results were interpreted to suggest that the synesthesia allowed the savant to give structural meaning to meaningless patterns of numbers, resulting in the utilization of a different part of the brain when memorizing these number sequences than was used by individuals without this ability. A PET imaging study of a 22-year-old, right-handed male savant with autism disorder and prodigious calendar calculation abilities found that calendrical calculation activated a frontotemporal network that included the hippocampus, a network usually associated with delayed memory retrieval tasks in typical individuals [25]. The investigators speculated that, in some individuals with autism, certain brain circuits, such as the frontotemporal network, may be “overdeveloped,” leading to extraordinary calculation and memory abilities. Because autism is a brain developmental disorder, the authors speculated that disabilities associated with abnormal brain circuitry can in some cases result in unique capabilities. Single photon emission tomography imaging of a 16year-old, right-handed male savant with mental retardation but no diagnosis of autism and exceptional mental calculation abilities during a calculation task revealed surprisingly diffuse cerebral activity, with elevated perfusion across many brain regions, especially over the right parietal lobe [26]. The authors hypothesized that the outstanding ability for mental calculation in this subject was due to recruitment of more global neural circuitry resources during working memory processing than usual, perhaps as a result of inadequate usage of the frontal executive system. Magnetic resonance imaging of a 42-year-old, righthanded male savant with Asperger syndrome who exhibited both prodigious calculation skills as well as skilled artistic abilities revealed bilateral cortical thickening of the superior parietal lobe (a region involved in visual-spatial functioning as well as calculation abilities) and cortical thinning of the superior and medial prefrontal cortices (regions that are considered to be involved in social cognition, which is impaired in ASD) [27]. The authors interpreted regional increases in thickness to represent increased utilization of those regions and areas of reduced thickness to reflect decreased cortical utilization, supportive of a model wherein individuals having circumscribed areas of cortical impairments can tap into areas of strength to enhance their abilities, with increased utilization of these regions perhaps leading to further alterations in brain structure. Functional MRI was used to compare brain activity during calendar calculation for a 45-year-old savant with

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Asperger syndrome with exceptional calendrical calculation skills to that of a 35-year-old, self-taught mathematical prodigy without ASD [28]. The investigators' intent was to determine whether similar brain circuitry was used in the performance of this cognitive task. Results showed considerable differences in the activation patterns between these two individuals. The highly variable patterns of regional variation across multiple regions led the authors to conclude that the complex mental processing necessary for calendrical calculation was derived more from learning and idiosyncratic strategies for this type of processing rather than the use of a specific brain circuitry per se. A functional MRI study of two male savants with calendrical calculation skills and ASD was undertaken to determine whether the brain regions involved in calendrical calculation differed from those involved in mathematical calculation [29]. One savant was right handed, whereas the other was left handed. The authors found that many of the same parietal brain regions in the savants were activated when performing calendrical calculation as were activated for a mental arithmetic task. Moreover, the brain regions which showed increased activity during mental arithmetic have also been reported to be activated during arithmetic tasks in typical individuals without savant syndrome [30]. For the savant subjects, these regions showed increased activity when calendrical questions involved dates from remote years. The authors concluded that, for the savants, calendrical calculation utilized brain regions that overlapped with those used for mental arithmetic by both the savants as well as by typical individuals. They considered the exceptional calendrical calculation skills in these savants to be the result of their extensive practice and study of calendars. Structural MRI, fMRI, and DTI were performed on a 61year-old female savant with Asperger syndrome and visualspatial abilities [31]. These investigators found evidence of unique differences in the savant's brain structure and function as compared with three typical subjects. The savant subject was found to have substantially increased left lateral ventricular volume and intracranial volume; increased left cerebral white matter volume; and increased volumes of the left cingulate, bilateral amygdala, and bilateral entorhinal cortex. In addition, the FA of the left posterior/superior parietal region and corpus callosum were more than 2 SDs greater than the median for the typical subjects, and the FA of the temporal stem, superior temporal gyrus, and arcuate fasciculus were 2 SDs less than the median for the typical subjects. Cortical thickness was increased in the entorihina cortex and supplementary motor cortex as well as in the fusiform gyrus. Functional activation during a visual language task was increased in the bilateral parietal cortices and, for a music task, was increased in the medial prefrontal cortex. An 18-year-old male savant with Asperger syndrome and exceptional calendar memory was studied using PET and SPECT to identify brain regions involved in this skill [32]. The investigators found activation of the left frontal regions of the brain during calendrical calculation. Since the history


and clinical and behavioral evaluations of the savant revealed problems with executive functioning and previous studies have reported this finding in individuals with Asperger syndrome, the authors concluded that the subject had diminished frontal cortex functioning in many areas. The authors further suggested that results of their study support the idea that Asperger syndrome and savant characteristics are separate phenomena. They speculated that this individual's exceptional calendar memory could involve a distinct neuronal circuit that was developed through the excessive study of calendars and the process of learning. Another phenomenon that may be relevant to savant syndrome is the emergence of enhanced artistic abilities in elderly patients with the onset of frontotemporal dementia [33,34]. In a study of 69 individuals with frontotemporal dementia, 12 individuals or 17% demonstrated new or preserved musical or visual ability despite progressive cognitive and social impairment [35]. As the dementia progressed, these patients increasingly became disinterested in social and occupational responsibilities and more obsessive in pursuing and perfecting their creative activities, which encompassed a wide range of talents, including painting, photography, chess, and music. The physiologic basis for the emergence of abilities in these individuals is unknown. The authors suggest that individuals showing frontotemporal dementia along with enhanced artistic abilities may represent a distinct subset of the disorder. In the patients with enhanced artistic abilities, SPECT revealed a sparing of frontal regions, with degeneration of temporal regions. In light of the existence of savant syndrome, these individuals are intriguing due to their similar development of isolated, unusual skills despite a general reduction in cognitive functioning. Although highly diverse brain anatomical findings have been reported, as summarized above, an observation common to most neuroimaging studies of savant syndrome has been altered structural development and/or utilization of different neuronal pathways or cortical regions, as compared with typical individuals, when performing a task associated with a special skill. Although it is likely in some cases that the atypical brain features are largely congenital, it is also possible that the time that an individual savant spends on practicing his special abilities may cause changes and perhaps continuing alterations in brain structure and activation patterns later in life. One further consideration, evident from these case reports, is that the specific talent and level of ability as well as disability in savant syndrome are highly variable across individuals. To date, mathematical and calendrical calculations have received the most attention because these are the more common savant skills and can be performed within the confined environment of an MRI scanner. However, a more comprehensive study of individuals with a variety of savant skills may help provide clues as to brain mechanisms that underlie this syndrome in general. To date, there has been only the one DTI report [31] and no MRS studies, of which we are aware, to characterize


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individuals with savant syndrome. An approach that incorporates information from multiple MR techniques, each providing complimentary information regarding a specific aspect of brain functionality and is capable of assessing the brain at a cellular level, may be beneficial in gaining a fuller understanding of the neurophysiologic mechanisms that underlie savant skills. To demonstrate how these newer imaging techniques might be used to assess the brain in savant syndrome, a multimodal MR neuroimaging case study of a prodigious savant with extraordinary artistic talent and memory skills is presented. This exploratory study acquired high-resolution MRI to investigate brain structure, DTI to investigate integrity of white matter tracts in different regions of the brain, and MRS to investigate tissue-based brain chemical features. Evidence of alterations in structural features, lateralization of cerebral hemisphere and subcortical nuclei volumes, fiber tract characteristics, and concentrations of the brain chemicals NAA, Cho, Cre, Glu, and GABA were specifically assessed for.

Review Board, to participate in the study, which used investigational imaging pulse sequences. 3. Comparison subjects Data from 7 highly educated adult male nonsavant comparison subjects having a similar age range as the savant case subject (mean [SD] age, 58 [5.3] years; range, 50-66 years) were available for comparison of brain compartmental volumes, diffusion tensor, and spectroscopic imaging findings. Of the 7 comparison subjects, 6 were right handed. All comparison subjects had an advanced degree (4 PhD, 2 MD, 1 JD), which could potentially offset nonspecific effects of overlearning in the savant. Data from 6 of the comparison subjects were available for spectroscopic chemical concentration calculations. Data from 5 of the comparison subjects were available for DTI analysis. 4. Methods 4.1. Magnetic resonance data acquisition

2. Savant case subject The subject of this study is a 63-year-old, right-handed male with savant syndrome and a long-standing diagnosis of ASD. Institutionalized as a child, he has lived semiindependently as an adult, working for more than 30 years in dishwashing jobs. This individual is gifted with several special skills. One area of considerable talent is in music. He has perfect pitch and plays several musical instruments, of which his favorite is the accordion. He has substantial abilities with languages and can engage in basic conversations in twelve different languages. He also has remarkable abilities with sound imitation. His most exceptional ability, however, is in the area of art. His artistic skills were first recognized by his employers, who included some of his drawings in a monthly newsletter. Because the newsletter was published in black and white, all of his early work is in black and white. In conjunction with a change in guardianship as an adult, his artistic and memory skills were further recognized and encouraged, and his drawings began to incorporate color. He has become a highly regarded and accomplished graphic artist, whose works have been recognized through numerous exhibitions nationally as well as publication in a book. His medium is paper with pencil, marker, and crayon. His interest is in drawing collections, usually quite large, of items such as tools, birds, instruments, trains, flowers, and shoes, among many others. He takes a special interest in categorizing the physical world. Most of his drawing is from memory; however, he occasionally draws from reference books. His drawings, which are done freehand, are remarkable in their intricacy and level of detail. His prodigious skills are described in additional detail elsewhere [2,35]. He provided written informed consent, approved by the University of Washington Institutional

Magnetic resonance data were acquired on a Philips 3T Achieva scanner using an 8-channel radiofrequency head coil. T1-weighted images were acquired in the sagittal plane (3D MPRAGE pulse sequence; 160 slices; matrix 256 × 256 × 160; repetition time (TR) 7.46 ms; field of view (FOV) 220 × 220 × 160 mm; water fat shift 2.272 pixels; echo time (TE) 3.47 ms; flip angle 8; turbo factor 214; SENSE factor 3; inversion delay 850 ms; turbo field echo (TFE) shots 75). Diffusion tensor imaging data were acquired using a single-shot spin-echo echo-planar imaging pulse sequence with diffusion weighting (32 noncollinear encodings; b = 1000 s/mm 2; 78 slices; slice thickness 1.8 mm; matrix 128 × 128; FOV 200 × 200 mm; inplane voxel size 1.86×1.85 mm; TR 9349 ms; TE 67 ms; water fat shift 12.316 pixels; 2 averages). A B0 field map was acquired for the full brain to correct distortion in the DTI due to magnetic field inhomogeneities (TE 20 ms; TR 937 ms; slice thickness 4 mm; gap 0.5 mm; FOV 240 × 240 mm). Nonwater suppressed and water-suppressed two-dimensional MR spectroscopic imaging (MRSI) data were acquired for three contiguous slabs centered on the corpus callosum (spin-echo pulse sequence; TE 19 ms, TR 2000 ms; slice thickness 15 mm; gap 1.8 mm; SENSE factor 2 in both RL and AP directions; 512 spectral points; spectral width 2000; in-plane spatial matrix 32 × 32; FOV 220 × 220 mm; SENSE factor 3). J-resolved MR spectroscopy data were acquired for a large single voxel centered on the midline in the parietal lobe (PRESS single voxel pulse sequence; 48 TE steps [32-502 ms, 10-ms increments]; TR 2000 ms; spectral bandwidth 2000 Hz; voxel dimensions 20 × 20 × 20 mm; complex time points 2048; NEX 12). 4.2. Regional volumetric measurements Volumetric measurements of the left and right hemisphere cerebrum and bilateral amygdala, hippocampus, caudate

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nucleus, putamen, thalamus, frontal lobe, occipital lobe, and cerebellum were performed by a single rater using the semiautomated imaging analysis program MEASURE, as previously described [7]. Cerebral volumes excluded the ventricles, brainstem, and cerebellum and included the basal ganglia and corpus callosum. 4.3. Segmentation of brain tissue compartments The Medical Image Processing, Analysis and Visualization [36] segmentation plug-in [37] was used to segment the T1weighted structural imaging volume into gray matter, white matter, and cerebrospinal fluid (CSF) compartments. The volume of each tissue compartment was calculated by multiplying the number of voxels within the compartment by the three-dimensional volume of a single T1 MPRAGE voxel. 4.4. Spectroscopic data analysis N-acetyl aspartate, Cho, and Cre concentrations were estimated using the two-dimensional MRSI data. A multivoxel section of proton spectra (both water-suppressed and non–water-suppressed) was extracted and averaged from the MRSI voxels that overlapped the location of the voxel acquired in the J-resolved sequence. Metabolite and water spectra were processed with LCModel, using water referencing to obtain the chemical estimates, and corrected for partial volume contribution from CSF. γ-Aminobutyric acid and Glu concentrations were estimated from the J-resolved imaging sequences. Raw data were processed offline with in-house software that performed Gaussian-filtered Fourier transforms along both the chemical shift (f1) and echo time (f2) dimensions. The first Fourier transform resulted in the conversion of each FID to a frequency spectrum. Phasing and frequency shift corrections were applied to this output. The second Fourier transform converted the oscillating phases of each of the coupled metabolite peaks to their respective frequency components. After completion of this two-dimensional Fourier transform, power spectra were computed and concentration estimates were calculated using water referencing.


4.5. Diffusion tensor imaging data analysis Artifacts in the raw DTI data due to motion and eddy currents were corrected using the FSL FMRIB (The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain) software library Diffusion Toolbox [38,39]. The BioImage Suite software package [40] was used to calculate FA and fiber tract bundle volumes for the following regions: corpus callosum, L/R amygdala, L/R frontal lobe, L/R hippocampus, L/R caudate nucleus, and L/R occipital lobe. The FSL FMRIB software Diffusion Toolbox [38] was used to calculate diffusivities for these same regions.

5. Findings 5.1. Structural imaging Example midplane structural brain images in the sagittal, coronal, and axial planes for the savant case study are shown in Fig. 1. All gross anatomical structures were intact, including the corpus callosum, the cerebellum, and the anterior and posterior commissures. Regional brain volumes are listed in Table 1. A symmetry index was calculated according to: 2⁎(R − L)/(R + L)⁎100, where R represents the right hemispheric volume and L represents the left hemispheric volume. This yielded a percentage difference between the two hemispheres, with positive values indicating a right hemisphere preponderance [41]. The most notable hemispheric differences were for the amygdala, which was 24% larger on the right than on the left; the caudate nucleus, which was 9.9% larger on the right than on the left; and for the putamen, which was 8.3% larger on the left than on the right. The left and right cerebral hemispheres differed in volume by less than 2%. For comparison, literature values of volumes of the cerebrum, amygdala, caudate, and hippocampus for typical adults and adolescents are shown in Tables 2 and 3. The total cerebral volume of 1362 mL exceeded normative literature values for typical males [42-44], including males within the same age range, as well as younger males, by 16% to 31%. The degree of hemispheric

Fig. 1. Midsectional MRI images from the savant subject in the sagittal, coronal, and axial planes, respectively.


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Table 1 Regional volumes for the savant subject

Cerebrum Amygdala Hippocampus Caudate Putamen Thalamus Frontal Lobe Occipital Lobe Cerebellum

Left hemisphere (mL)

Right hemisphere (mL)

Total volume (mL)

Symmetry index

674.3 2.1 3.9 5.7 5.9 7.8 231.0 94.9

687.4 2.7 4.0 6.3 5.5 7.8 227.9 97.1

1361.7 4.8 7.9 12.1 11.4 15.6 458.9 191.9

1.93 23.97 0.76 9.93 −8.27 −0.64 −1.36 2.33





The symmetry index is calculated according to 2⁎(R − L)/(R + L)⁎100, where R represents the right hemispheric volume and L represents the left hemispheric volume. This yields a percentage of volume difference between the two hemispheres, where a positive symmetry index indicates a right hemisphere preponderance [34].

asymmetry observed in this study was similar to normative literature values, which generally are between 0% and 2%. The left and right amygdala volumes were larger than values reported for typical adults in the literature [45-48], shown in Table 3A, although it is not possible to make a direct comparison due to differences in the techniques used for measuring amygdala volumes across studies. However, the marked right-side biased asymmetry of the amygdala is much larger than what has been reported for normative adults in the literature. The caudate volumes also were larger than normative literature values [49-51], although again, it is difficult to make direct comparisons across studies due to variations in measurement techniques. The right-side biased asymmetry of this structure appears larger than for two reports, as shown in Table 3B, although one study of typical adults between 55 and 80 years of age reports caudate volumes that have a rightlateralized asymmetry of 8.2% [49], similar to that observed in this study. The hippocampus volumes and magnitude of asymmetry observed in this study did not appear to differ substantially from normative literature values [46-48,5254], as shown in Table 3C.

Example images of the case study subject's segmented brain volume in the sagittal, coronal, and axial planes are shown in Fig. 2, and the results from the segmentation analysis are shown in Table 4. Gray matter, white matter, and CSF volumes were all larger than for the comparison group. The gray and white matter tissue volumes did not exceed 2 SDs of the comparison group mean. The CSF volume exceeded the comparison group mean by more than 2.5 SDs. 5.2. Magnetic resonance spectroscopy The 2-dimensional J-resolved spectrum for the study subject is shown in Fig. 3. Concentrations of NAA, Cho, Cre, Glu, and GABA for the savant subject and the comparison group are shown in Table 5. The concentrations of NAA, Cho, and Cre for the savant subject were within 2 SDs of the mean of the comparison group. The savant subject's GABA and Glu concentrations were more than 2 SDs below the comparison group mean. 5.3. Diffusion tensor imaging Results from the diffusion tensor analysis for 5 different bilateral brain regions as well as the corpus callosum are shown in Tables 6 and 7. For the savant subject, the FA was larger in the right hemisphere for all bilateral regions measured, with the exception of the occipital lobe. The fiber tract bundle volumes were larger in the right hemisphere for all bilateral regions, with the exception of the caudate. The corpus callosum FA was reduced, but within 1 SD of the comparison group mean, and its bundle volume, although larger than the comparison group mean, was still within 1 SD. The FAs of the left hippocampus and right occipital lobe were more than 2 SDs lower than those of the comparison group. The most striking findings from the DTI analysis were for the hippocampus, where the axial diffusivities bilaterally exceeded that of the comparison group mean by 8 SDs or more, and the mean diffusivities bilaterally exceeded the comparison group mean by more than 3 SDs. Both the corpus callosum and the left amygdala had axial, radial, and mean diffusivities exceeding that of the comparison group mean by more than 3 SDs.

Table 2 Normative cerebral volumes from the literature Reference

Age (y)


Left hemisphere (mL)

Right hemisphere (mL)

Total volume (mL)

Symmetry index

Gur et al [45], 1991 Allen et al [43], 2002 Gur et al [45], 1991 Coffey et al [44], 1998

18-54 (mean, 28.4) 22-49 (mean, 32.1) 55-80 (mean, 68.5) 66-96 (mean, 75.4)

23M 23M 11M 129M

576 (48) 543 (—) 547 (53) 501 (49)

581 (47) 546 (—) 551 (53) 496 (51)

1156 1088 1098 997

0.90 0.57 0.84 -1.01

Left and right hemisphere volumes reported as mean (SD). (—) indicates a value that was not available in the published report. The symmetry index is calculated according to 2⁎(R − L)/(R + L)⁎100, where R is the right hemisphere volume and L is the left hemisphere volume.

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Table 3 Normative volumes of subcortical nuclei from the literature Reference

Age (y)


Left volume (mL)

Right volume (mL)

Total volume (mL)

Symmetry index

Groen et al [48], 2010 Pedraza et al [47], 2004

12-18 (mean, 15) N17

1.59 (0.16) 1.88 (0.50)

1.63 (0.14) 1.93 (0.53)

3.22 3.81

2.23 2.26

Maller et al [46], 2007 Laakso et al [45], 1995

60-64 (mean, 62.6) N49 y (mean, 72)

29 (24M, 5F) Meta-analysis, 2000 participants, 51 studies 238M 34 (14M, 20F)

1.32 (0.26) 2.01 (0.30)

1.27 (0.27) 1.88 (0.29)

2.59 3.88

−3.81 −6.70

17-24 (mean, 20) 20-56 (mean, 28.8) 55-80 (mean, 65)

21 (20M, 1F) 17 (15M, 2F) 60 (24M, 36F)

3.55 (0.36) 4.75 (0.78) 4.66 (0.57)

3.64 (0.44) 4.41 (0.51) 5.06 (0.56)

7.19 9.16 9.72

2.50 −7.40 8.23

Groen et al [48], 2010 Pedraza et al [47], 2004

12-18 (mean, 15) N17

4.59 (0.37) 2.98 (0.98)

4.55 (0.41) 3.06 (1.0)

9.14 6.04

−0.77 2.68

Raz et al [54], 2004 Maller et al [46], 2007 Erickson et al [49], 2011 MacLullich et al [53], 2002 Hackert et al [52], 2002

20-80 (mean, ∼47) 60-64 (mean, 62.6) 55-80 (mean, 65) 65-70 (mean, 67.8) 60-90 (mean, 73)

29 (24M, 5F) Meta-analysis, 3564 participants, 82 studies 200 (119F, 81M) 238M 60 (24M, 36F) 97M 511 (261M, 250F)

3.36 (—) 2.98 (0.42) 4.90 (0.80) 3.50 (0.46) 3.15 (0.46)

3.35 (—) 3.03 (0.45) 4.92 (0.80) 3.63 (0.52) 3.22 (0.44)

6.71 6.01 9.82 7.13 6.37

−0.30 1.79 0.41 3.54 2.20

A. Amygdala

B. Caudate Langen et al [51], 2007 Haznedar et al [50], 2006 Erickson et al [49], 2011 C. Hippocampus

Left and right volumes reported as mean (SD). (—) indicates a value that was not available in the published report. The symmetry index is calculated according to 2⁎(R − L)/(R + L)⁎100, where R is the right hemisphere volume and L is the left hemisphere volume.

6. Summary In this multimodal MR imaging study of a prodigious savant, there was no evidence of gross anatomical structural abnormalities. This individual had a large cerebrum (1362 mL) in comparison with published normative values for both younger males and males within the same age range. Although right and left hemispheric volume differences were less than 2%, the amygdala and caudate nucleus were highly asymmetric, with enlargement on the right side, whereas the putamen was substantially enlarged on the left side. Segmentation analysis revealed increased CSF volume (N2.5 SD) as compared with a laboratory comparison group.

The corpus callosum was anatomically intact by MRI and had a fractional anisotropy value that was similar to that of the comparison group, but this structure, along with the left amygdala, exhibited substantially larger axial, radial, and mean diffusivities than the comparison group. The bilateral hippocampi were also found to exhibit larger axial and mean diffusivities than the comparison group. The fractional anisotropy and diffusivity values of the corpus callosum, occipital lobes, frontal lobes, and caudate for the comparison subjects were similar to or, in some cases, slightly higher than those reported for healthy adult controls from other studies [13,55-58], although direct comparisons across studies are difficult to assess due to differing DTI analysis

Fig. 2. Example segmentation images derived from the savant subject's high-resolution T1 images.


N.M. Corrigan et al. / Comprehensive Psychiatry 53 (2012) 706–717

Table 4 Segmented tissue volumes and ratios


Table 5 Brain chemical concentrations in millimoles per liter


Comparison group

650.5 696.2 397.4 0.934 0.571

585.2 (63.4) 565.4 (76.3) 297.3 (34.7) 1.035 0.526

Volumes in milliliters, with mean (SD) for the comparison group. GM indicates gray matter; WM, white matter.

methodologies. Finally, MRS revealed substantially reduced GABA and Glu in the parietal lobe, but NAA, Cho, and Cre levels were within 2 SDs of the comparison group values. While it is important to note that differences in scanning and measurement procedures can affect absolute volume measurements and even asymmetry findings across studies [47], the apparent high right-sided enlargements observed for the amygdala and caudate for the savant in this study are intriguing because savant skills tend to be activities that are associated with the right cerebral hemisphere and because both of these structures, along with the neurotransmitters GABA and Glu, are thought to play a role in the neurobiology of learning. More specifically, the caudate is considered to be a key structure in an implicit or habit memory circuit, which uses neural circuitry that is separate from that used for explicit memory, which requires conscious recall and recognition [59]. The amygdala is thought to play an important role in regulating the relative use of the 2 memory circuits [60]. The neurotransmitters GABA and Glu as well as other neurotransmitters, including dopamine and acetylcholine, are thought to play important roles in mediating these memory circuits [59]. Fractional anisotropy and diffusivity measurements are increasingly being measured along with cognitive capabilities in young and adult individuals to seek correlates of both improved cognitive performance as well as cognitive decline. Increased fractional anisotropy is thought to

NAA Cho Cre Glu GABA


Comparison group mean (SD)

9.28 2.00 6.34 7.27 0.66

10.69 (1.38) 2.16 (0.37) 6.66 (0.87) 11.48 (1.98) 0.99 (0.15)

correspond to improved white matter structural organization, including increased directional coherence of individual myelin fibers or increased axonal packing density and, in some cases, increased myelination [12]. Mean diffusivity is a measure of the overall displacement of molecules, and this value can increase with increases in radial or axonal diffusivity. Studies have indicated that increases in radial diffusivity reflect decreased myelination and increases in axial diffusivity reflect axonal damage [61-63]. The findings of markedly increased mean, radial, and axial diffusivity in the hippocampus, corpus callosum, and the left amygdala of the savant case study as compared with the comparison sample may highlight differences in the integrity of the cerebral circuits involving these structures between the savant case study and comparison group. The relatively consistent increased fractional anisotropy in structures in the right hemisphere as compared with the left suggest that the savant case study may have a right-over-left hemispheric predominance in function, which has previously been suggested in savant syndrome. Further DTI investigation of individuals with savant syndrome may help to elucidate how white matter integrity and disruption or enhancement of individual fiber tracts may be correlated with the performance of specific savant skills. The subject for this case study has a long-standing diagnosis of ASD. Although the literature is somewhat inconsistent, several studies have found abnormally enlarged right-sided caudate volume in adults with ASD [51,64-66]. Amygdalar enlargement, right side greater than left side, has been reported

Fig. 3. Two-dimensional plot of the J-resolved MR spectroscopic data from the savant case study. Chemical shift is shown on the x-axis, and the j-coupling value for each chemical is shown on the y-axis. Gln/Glu/GSH indicates combined signal from glutamine, Glu, and glutathione; NAA (Asp protons) is the aspartate moiety of the NAA signal.

N.M. Corrigan et al. / Comprehensive Psychiatry 53 (2012) 706–717 Table 6 Fractional anisotropies and bundle volumes Savant Fractional anisotropy L amygdala R amygdala L hippocampus R hippocampus L caudate R caudate L frontal lobe R frontal lobe L occipital lobe R occipital lobe corpus callosum Bundle volume in cm 3 L amygdala R amygdala L hippocampus R hippocampus L caudate R caudate L frontal lobe R frontal lobe L occipital lobe R occipital lobe corpus callosum

0.33 0.39 0.37 a 0.40 0.36 0.38 0.37 0.38 0.41 0.36 b 0.44 7 15 36 49 33 27 72 91 24 38 b 124


Table 7 Axial, radial, and mean diffusivities (×10-3 mm 2/s) Comparison group mean (SD) 0.35 (0.01) 0.37 (0.01) 0.40 (0.01) 0.41 (0.01) 0.38 (0.04) 0.37 (0.02) 0.39 (0.02) 0.40 (0.01) 0.47 (0.03) 0.45 (0.02) 0.45 (0.02) 11 (3) 18 (2) 48 (7) 55 (8) 24 (8) 24 (5) 63 (8) 78 (12) 23 (3) 28 (3) 119 (14)


Indicates value is more than 2 SD and less than 3 SD beyond the comparison group mean. b Indicates value is more than 3 SD beyond the comparison group mean.

in young children with ASD [7,67-69], but available literature suggests that this abnormality does not usually persist into adulthood [68]. The GABAergic system has also been found to be abnormal in autism, with reduced GABA receptor density [70] as well as reduced concentrations of GABA and GABA/NAA in the frontal lobe in patients with autism disorder as compared with normal controls [71]. Glx has been reported to be low in ASD at younger ages [72,73], although there has been one report of an increase in Glu+Gln in adults with ASD in the amygdala-hippocampal region [74]. More generally, neuroimaging studies of individuals with ASD have demonstrated abnormalities of brain regional connectivity and brain chemistry as well as brain morphometry during early development. It is very likely that these early developmental changes have long-lasting effects on neural organization that could conceivably confer special abilities in some cases. Further investigation of similarities in the findings between ASD and savant syndrome may help explain the relatively high co-occurrence of the two disorders. The limited number of neuroimaging studies of savant syndrome performed to date have primarily focused on brain morphometric and functional imaging differences. As a result, the individuals studied have, for the most part, been those with extraordinary mental calculation skills, as these can be performed in a confined environment and do not involve movement, which can degrade the resulting imaging data quality. Designing a functional imaging study to include a

Axial diffusivity L amygdala R amygdala L hippocampus R hippocampus L caudate R caudate L frontal lobe R frontal lobe L occipital lobe R occipital lobe corpus callosum Radial diffusivity L amygdala R amygdala L hippocampus R hippocampus L caudate R caudate L frontal lobe R frontal lobe L occipital lobe R occipital lobe corpus callosum Mean diffusivity L amygdala R amygdala L hippocampus R hippocampus L caudate R caudate L frontal lobe R frontal lobe L occipital lobe R occipital lobe corpus callosum


Comparison group mean (SD)

1.39 b 1.26 a 1.53 b 1.49 b 1.40 1.44 1.15 1.15 1.25 1.21 1.58 b

1.29 (0.03) 1.20 (0.04) 1.36 (0.02) 1.33 (0.02) 1.33 (0.14) 1.29 (0.09) 1.27 (0.13) 1.28 (0.11) 1.19 (0.05) 1.15 (0.04) 1.44 (0.04)

0.99 b 0.82 1.00 a 0.96 a 0.93 1.00 0.76 0.77 0.80 0.74 1.00 b

0.88 (0.02) 0.79 (0.03) 0.86 (0.05) 0.81 (0.05) 0.91 (0.16) 0.88 (0.10) 0.88 (0.12) 0.89 (0.11) 0.72 (0.06) 0.66 (0.04) 0.86 (0.04)

1.13 b 0.97 1.18 b 1.13 b 1.09 1.15 0.89 0.90 0.95 0.90 a 1.20 b

1.02 (0.03) 0.93 (0.03) 1.03 (0.04) 0.99 (0.04) 1.05 (0.15) 1.01 (0.09) 1.01 (0.13) 1.02 (0.11) 0.88 (0.05) 0.83 (0.03) 1.05 (0.04)


Indicates value is greater than 2 SD and or less than 3 SD beyond the comparison group mean. b Indicates value is greater than 3 SD beyond the comparison group mean.

broader sample of individuals with savant syndrome would require development of a more generalizable functional imaging task protocol that would engage each individual's specific skill as well as be suitable for performance inside the bore of an MR scanner. Findings from this study, however, raise the possibility that multimodal structural and biochemical imaging studies can help to establish the neurophysiologic underpinnings of special skills. This approach may be more conducive to population-based studies of savant syndrome. As this is a single-case study and newer imaging modalities were applied that have not been reported in prior studies of savant syndrome, our findings cannot be generalized from this particular individual. In addition, our findings do not establish a causative relationship between the observed structural and biochemical alterations and the prodigious skills of this individual. It is also not clear which


N.M. Corrigan et al. / Comprehensive Psychiatry 53 (2012) 706–717

alterations may be a manifestation of ASD and not be specifically related to his special skills. However, taken as a whole, these observations provide a promising avenue for further exploration. In summary, this study used multiple MR imaging modalities to characterize the brain features of a prodigious savant. Our findings suggest abnormalities in brain regions and chemicals that have been associated with learning and memory in typical individuals. This multimodality imaging approach would need to be applied to larger samples of individuals with savant syndrome with a range of skills to reach an understanding of the neurophysiologic underpinnings of savant syndrome and features in common across these seemingly heterogeneous individuals. Further research investigating commonalities between individuals with ASD and individuals with savant syndrome could also contribute to our understanding of ASD and perhaps provide new insights into how we can better tap strengths and improve the prognosis of individuals with this disorder. Moreover, elucidating mechanisms that underlie the existence of savant syndrome might aid in better understanding the functioning of the human brain in general and help us to discover whether untapped extraordinary cognitive abilities are present in us all. Acknowledgment This study was supported by National Institutes of Health grant 1P50 HD055782. References [1] Treffert DA. Extraordinary people: understanding savant syndrome. Omaha (Neb): iUniverse, Inc.; 2006. [2] Treffert DA. Islands of genius. London: Jessica Kingsley Publishers; 2010. [3] Treffert DA. The savant syndrome: an extraordinary condition. A synopsis: past, present, future. Philos Trans R Soc Lond B Biol Sci 2009;364:1351-7. [4] Luria A. The mind of a mnemonist: a little book about a vast memory. New York: Basic Books; 1968. [5] Casanova MF, Switala AE, Trippe J, Fitzgerald M. Comparative minicolumnar morphometry of three distinguished scientists. Autism 2007;11:557-69. [6] Casanova MF, van Kooten IAJ, Switala AE, van Engeland H, Heinsen H, Steinbusch HWM, et al. Minicolumnar abnormalities in autism. Acta Neuropathol 2006;112:287-303. [7] Sparks BF, Friedman SD, Shaw DW, Aylward EH, Echelard D, Artru AA, et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology 2002;59:184-92. [8] Ge Y, Grossman RI, Babb JS, Rabin ML, Mannon LJ, Kolson DL. Age-related total gray matter and white matter changes in normal adult brain. Part I: volumetric MR imaging analysis. AJNR Am J Neuroradiol 2002;23:1327-33. [9] Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM, Zipursky RB, Lim KO. A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol 1994;51:874-87. [10] Purves D, Fitzpatrick D, Augustine GJ, Katz LC. Neuroscience. 2nd ed. Sunderland (Mass): Sinauer Associates, Inc.; 2011.

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