Martha R. Herbert

Localization of white matter volume increase in autism and developmental language disorder

Increased brain volume in autism appears to be driven mainly by an unexplained white matter enlargement, and we have reported a similar phenomenon in developmental language disorder (DLD). Localization of this enlargement would strongly guide research into its cause, tissue basis, and functional implications. We utilized a white matter parcellation technique that divides cerebral white matter into an outer zone containing the radiate compartment and an inner zone containing sagittal and bridging system compartments. In both high‐functioning autism and DLD, enlargement localized to the radiate white matter (all lobes in autism, all but parietal in DLD), whereas inner zone white matter compartments showed no volume differences from controls. Furthermore, in both autism and DLD, later or longer‐myelinating regions showed greater volume increases over controls. Neither group showed cerebral cortex, corpus callosum, or internal capsule volume differences from control. Radiate white matter myelinates later than deep white matter; this pattern of enlargement thus is consistent with striking postnatal head circumference percentile increases reported in autism. These findings suggest an ongoing postnatal process in both autism and DLD that is probably intrinsic to white matter, that primarily affects intrahemispheric and corticocortical connections, and that places these two disorders on the same spectrum.

Language-association cortex asymmetry in autism and specific language impairment

Language deficits are among the core impairments of autism. We previously reported asymmetry reversal of frontal language cortex in boys with autism. Specific language impairment (SLI) and autism share similar language deficits and may share genetic links. This study evaluated asymmetry of frontal language cortex in a new, independent sample of right‐handed boys, including a new sample of boys with autism and a group of boys with SLI. The boys with autism were divided into those with language impairment (ALI) and those with normal language ability (ALN). Subjects (right‐handed, aged 6.2–13.4 years) included 22 boys with autism (16 ALI and 6 ALN), 9 boys with a history of or present SLI, and 11 normal controls. MRI brain scans were segmented into grey and white matter; then the cerebral cortex was parcellated into 48 gyral‐based divisions per hemisphere. Group differences in volumetric asymmetry were predicted a priori in language‐related regions in inferior lateral frontal (Brocas area) and posterior superior temporal cortex. Language impaired boys with autism and SLI both had significant reversal of asymmetry in frontal language‐related cortex; larger on the right side in both groups of language impaired boys and larger on the left in both unimpaired language groups, strengthening a phenotypic link between ALI and SLI. Thus, we replicated the observation of reversed asymmetry in frontal language cortex reported previously in an independent autism sample, and observed similar reversal in boys with SLI, further strengthening a phenotypic link between SLI and a subgroup of autism. Linguistically unimpaired boys with autism had similar asymmetry compared with the control group, suggesting that Brocas area asymmetry reversal is related more to language impairment than specifically to autism diagnosis. Ann Neurol 2004

Abnormal asymmetry in language association cortex in autism

Autism is a neurodevelopmental disorder affecting cognitive, language, and social functioning. Although language and social communication abnormalities are characteristic, prior structural imaging studies have not examined language‐related cortex in autistic and control subjects. Subjects included 16 boys with autism (aged 7–11 years), with nonverbal IQ greater than 80, and 15 age‐ and handedness‐matched controls. Magnetic resonance brain images were segmented into gray and white matter; cerebral cortex was parcellated into 48 gyral‐based divisions per hemisphere. Asymmetry was assessed a priori in language‐related inferior lateral frontal and posterior superior temporal regions and assessed post hoc in all regions to determine specificity of asymmetry abnormalities. Boys with autism had significant asymmetry reversal in frontal language‐related cortex: 27% larger on the right in autism and 17% larger on the left in controls. Only one additional region had significant asymmetry differences on post hoc analysis: posterior temporal fusiform gyrus (more left‐sided in autism), whereas adjacent fusiform gyrus and temporooccipital inferior temporal gyrus both approached significance (more right‐sided in autism). These inferior temporal regions are involved in visual face processing. In boys with autism, language and social/face processing–related regions displayed abnormal asymmetry. These structural abnormalities may relate to language and social disturbances observed in autism.

Can children with autism recover? If so, how?

Although Autism Spectrum Disorders (ASD) are generally assumed to be lifelong, we review evidence that between 3% and 25% of children reportedly lose their ASD diagnosis and enter the normal range of cognitive, adaptive and social skills. Predictors of recovery include relatively high intelligence, receptive language, verbal and motor imitation, and motor development, but not overall symptom severity. Earlier age of diagnosis and treatment, and a diagnosis of Pervasive Developmental Disorder-Not Otherwise Specified are also favorable signs. The presence of seizures, mental retardation and genetic syndromes are unfavorable signs, whereas head growth does not predict outcome. Controlled studies that report the most recovery came about after the use of behavioral techniques. Residual vulnerabilities affect higher-order communication and attention. Tics, depression and phobias are frequent residual co-morbidities after recovery. Possible mechanisms of recovery include: normalizing input by forcing attention outward or enriching the environment; promoting the reinforcement value of social stimuli; preventing interfering behaviors; mass practice of weak skills; reducing stress and stabilizing arousal. Improving nutrition and sleep quality is non-specifically beneficial.

Local and long-range functional connectivity is reduced in concert in autism spectrum disorders

Long-range cortical functional connectivity is often reduced in autism spectrum disorders (ASD), but the nature of local cortical functional connectivity in ASD has remained elusive. We used magnetoencephalography to measure task-related local functional connectivity, as manifested by coupling between the phase of alpha oscillations and the amplitude of gamma oscillations, in the fusiform face area (FFA) of individuals diagnosed with ASD and typically developing individuals while they viewed neutral faces, emotional faces, and houses. We also measured task-related long-range functional connectivity between the FFA and the rest of the cortex during the same paradigm. In agreement with earlier studies, long-range functional connectivity between the FFA and three distant cortical regions was reduced in the ASD group. However, contrary to the prevailing hypothesis in the field, we found that local functional connectivity within the FFA was also reduced in individuals with ASD when viewing faces. Furthermore, the strength of long-range functional connectivity was directly correlated to the strength of local functional connectivity in both groups; thus, long-range and local connectivity were reduced proportionally in the ASD group. Finally, the magnitude of local functional connectivity correlated with ASD severity, and statistical classification using local and long-range functional connectivity data identified ASD diagnosis with 90% accuracy. These results suggest that failure to entrain neuronal assemblies fully both within and across cortical regions may be characteristic of ASD.

MRI-based brain volumetrics: emergence of a developmental brain science

MRI-based brain volumetrics is an established methodology of great versatility and reliability with a broad range of potential applications in medicine and basic human brain science. We consider here, more theoretical implications of brain tissue volumes. Specifically, we suggest that volume is an evolutionarily and developmentally regulated fundamental property of tissue, in this instance the brain and its component structures. Within this framework (1), regularities in relative variation of volumes with respect to mean volume of a structure are viewed as systematic manifestations of the rules of histogenetic process (2), regularities in the relative strength of correlation of volumes of structures are suggested to reflect constraints which serve systematically the requirements of neural systems operation. These hypotheses, if supported by extensive observation, may guide the design of applications of MRI based volumetric analysis of the human brain.

Therapy for paraneoplastic neurologic syndromes in six patients with protein a column immunoadsorption

Background. Paraneoplastic neurologic syndromes, although rare, cause significant morbidity and mortality. They are thought to be immunologically mediated, but to date those involving the central nervous system (CNS) have not been particularly responsive to immunologic therapy. The use of the novel immunomodulator, protein A immunoadsorption, was explored to address this question.

Adjustment for Whole Brain and Cranial Size in Volumetric Brain Studies: A Review of Common Adjustment Factors and Statistical Methods

In this article we address analytic challenges inherent in brain volumetrics (i.e., the study of volumes of brains and brain regions). It has sometimes been assumed in the literature that deviations in regional brain size in clinical samples are directly related to maldevelopment or pathogenesis. However, this assumption may be incorrect; such volume differences may, instead, be wholly or partly attributable to individual differences in overall dimension (e.g., for head, brain, or body size). What quantitative approaches can be used to take these factors into account? Here, we provide a review of volumetric and nonvolumetric adjustment factors. We consider three examples of common statistical methods by which one can adjust for the effects of body, head, or brain size on regional volumetric measures: the analysis of covariance, the proportion, and the residual approaches. While the nature of the adjustment will help dictate which method is most appropriate, the choice is context sensitive, guided by numerous considerations-chiefly the experimental hypotheses, but other factors as well (including characteristic features of the disorder and sample size). These issues come into play in logically framing the assessment of putative abnormalities in regional brain volumes.

Larger brain and white matter volumes in children with developmental language disorder

Developmental language disorder (DLD) is predominantly a language disorder, but children with DLD also manifest nonlanguage impairments, and neuroanatomical abnormalities have been found in multiple areas of the brain, not all languageassociated. We therefore performed a whole brain general segmentation analysis of all major brain regions on MRI scans of 24 DLD subjects (16M, 8F) and 30 controls (15M, 15F), ages 5.7 to 11.3 years. Children with DLD showed increased total brain volume, driven predominantly by a substantial increase in the volume of cerebral white matter. Cerebral cortex and caudate were relatively but not absolutely smaller in DLD. These findings are discussed in relation to issues of specificity vs. generality as they arise in debates about (1) modular vs. general processing deficits and connectionist modeling in DLD, (2) languagespecific vs. pervasive, non-specific deficits in DLD and (3) specificity of the disorder vs. overlap with other disorders, notably autism.

Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale

Functional connectivity is abnormal in autism, but the nature of these abnormalities remains elusive. Different studies, mostly using functional magnetic resonance imaging, have found increased, decreased, or even mixed pattern functional connectivity abnormalities in autism, but no unifying framework has emerged to date. We measured functional connectivity in individuals with autism and in controls using magnetoencephalography, which allowed us to resolve both the directionality (feedforward versus feedback) and spatial scale (local or long-range) of functional connectivity. Specifically, we measured the cortical response and functional connectivity during a passive 25-Hz vibrotactile stimulation in the somatosensory cortex of 20 typically developing individuals and 15 individuals with autism, all males and right-handed, aged 8-18, and the mu-rhythm during resting state in a subset of these participants (12 per group, same age range). Two major significant group differences emerged in the response to the vibrotactile stimulus. First, the 50-Hz phase locking component of the cortical response, generated locally in the primary (S1) and secondary (S2) somatosensory cortex, was reduced in the autism group (P < 0.003, corrected). Second, feedforward functional connectivity between S1 and S2 was increased in the autism group (P < 0.004, corrected). During resting state, there was no group difference in the mu-α rhythm. In contrast, the mu-β rhythm, which has been associated with feedback connectivity, was significantly reduced in the autism group (P < 0.04, corrected). Furthermore, the strength of the mu-β was correlated to the relative strength of 50 Hz component of the response to the vibrotactile stimulus (r = 0.78, P < 0.00005), indicating a shared aetiology for these seemingly unrelated abnormalities. These magnetoencephalography-derived measures were correlated with two different behavioural sensory processing scores (P < 0.01 and P < 0.02 for the autism group, P < 0.01 and P < 0.0001 for the typical group), with autism severity (P < 0.03), and with diagnosis (89% accuracy). A biophysically realistic computational model using data driven feedforward and feedback parameters replicated the magnetoencephalography data faithfully. The direct observation of both abnormally increased and abnormally decreased functional connectivity in autism occurring simultaneously in different functional connectivity streams, offers a potential unifying framework for the unexplained discrepancies in current findings. Given that cortical feedback, whether local or long-range, is intrinsically non-linear, while cortical feedforward is generally linear relative to the stimulus, the present results suggest decreased non-linearity alongside an increased veridical component of the cortical response in autism.