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Minicolumnar abnormalities in autism

Abstract

Autism is characterized by qualitative abnormalities in behavior and higher order cognitive functions. Minicolumnar irregularities observed in autism provide a neurologically sound localization to observed clinical and anatomical abnormalities. This study corroborates the initial reports of a minicolumnopathy in autism within an independent sample. The patient population consisted of six age-matched pairs of patients (DSM-IV-TR and ADI-R diagnosed) and controls. Digital micrographs were taken from cortical areas S1, 4, 9, and 17. The image analysis produced estimates of minicolumnar width (CW), mean interneuronal distance, variability in CW (V CW), cross section of Nissl-stained somata, boundary length of stained somata per unit area, and the planar convexity. On average CW was 27.2 μm in controls and 25.7 μm in autistic patients (P = 0.0234). Mean neuron and nucleolar cross sections were found to be smaller in autistic cases compared to controls, while neuron density in autism exceeded the comparison group by 23%. Analysis of inter- and intracluster distances of a Delaunay triangulation suggests that the increased cell density is the result of a greater number of minicolumns, otherwise the number of cells per minicolumns appears normal. A reduction in both somatic and nucleolar cross sections could reflect a bias towards shorter connecting fibers, which favors local computation at the expense of inter-areal and callosal connectivity.

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Acknowledgments

We are grateful to the following institutions for the provision of the specimens: Mount Sinai School of Medicine (New York, NY, USA), University of Würzburg Morphological Brain Research Unit (Würzburg, Germany), University of Maryland Brain and Tissue Bank for Developmental Disorders (Baltimore, MD, USA), Harvard Brain Tissue Research Center (Belmont, MA, USA), New York State Institute for Basic Research in Developmental Disabilities (Staten Island, NY, USA) and the US Autism Tissue Program (Princeton, NJ, USA). We thank E.K. Broschk and A. Bahrkel for their technical support. This article is based upon work supported by the Stanley Medical Research Foundation (H.H., C.S., P.R.H. and M.F.C.), the Korczak Foundation (H.v.E.), the National Alliance for Autism Research (C.S. P.R.H. and M.F.C.), the McDonnell Foundation (P.R.H.) and NIMH grants MH61606 (M.F.C.), MH62654 (M.F.C.), MH69991 (M.F.C), NIH MH66392 (P.R.H).

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Correspondence to Manuel F. Casanova.

Appendix: Cognitive/functional level of the autistic patients in this study

Appendix: Cognitive/functional level of the autistic patients in this study

A1

  • Regression at 24 months of age

  • Normal or early attainment of all developmental milestones before 2 years of age

  • Articulation of 2–3 word sentences with difficulty, echoing

  • No spontaneous use of pointing

  • Inconsistency in responding to his own name

  • Inability to socially greet someone

  • No sensitivity to noise

  • Stereotypic rather than creative/imaginative play

  • Poor eye contact

  • No unusual preoccupations or rituals, other than spinning wheels on transportation toys

  • Anxiety when routines were changed

  • No aggression toward others or himself

  • Tantrums

  • Sometimes walking on his toes; no spinal problems; very agile

  • Age-appropriate growth profile

  • No idiosyncratic hand or finger mannerisms

  • No neurocutaneous stigmata or musculoskeletal abnormalities

  • Immature pencil grip when attempting graphomotor tasks

A2

  • Motor milestones met within normal limits; never toilet trained

  • Somewhat delayed fine and gross motor skills

  • Isolated and withdrawn, in addition to engaging in repetitive behaviors, at 18 months of age

  • Language delays

  • Lack of speech and low frustration tolerance

  • Speech therapy, physical therapy, and occupational therapy

  • No consistent use of any words at the age of 5

  • No imitation of others’ actions or direction of others’ attention to things of interest to her

  • Qualitative impairments in reciprocal social interaction

  • Reduced eye contact and difficulty regulating eye contact in social situations

  • Inappropriate facial expressions, such as laughing and crying for no apparent reason

  • Occasional engagement in imaginative play by herself; no engagement in imaginative play with others

  • Very little interest in other children

  • Repetitive play

  • Repetitive body movements, such as finger flicking and hand flapping

A3

  • Motor milestones were met within normal limits; fully toilet trained

  • Use of single words at 18 months of age

  • No development of phrase speech by 3 or 4 years of age

  • Echoing at 3 years of age, occurring only occasionally by the age of 8

  • Poor eye contact between 4 and 5 years of age, with improvement during development

  • Speech therapy, physical therapy, and occupational therapy

  • Ability to speak in simple sentences, using verbs and other grammatical markings, by 8 years of age

  • Difficulty engaging in reciprocal conversation on topics the patient himself introduced

  • Difficulty answering direct questions

  • Difficulty pronouncing certain words

  • Regular use of stereotyped words and phrases

  • Difficulty spontaneously imitating the action of others

  • Pointing to make requests

  • Inattentive to those talking to him

  • Well-developed receptive language skills

  • Qualitative impairments in reciprocal social interaction

  • Inability to express or explain his own pain

  • Typical range of facial expressions, but occasionally inappropriate, such as laughing for no apparent reason

  • Engagement in some pretend play on his own at the age of 8

  • Difficulty engaging in reciprocal social play

  • Repetitive play

  • Stereotyped whole body movements, such as jumping up and down on his tiptoes

  • Extremely affectionate, loving, and kind-hearted

  • Well-developed visuospatial skills

  • Excellent memory

A4

  • Severe hypotonia at 6 months of age

  • Ability to sit up without support at 7 months of age

  • No walking without support until 4 years of age

  • Never toilet trained

  • Developmental delays at 29 months of age

  • Delays in both fine and gross motor skills

  • Physical therapy, occupational therapy, and intensive speech therapy

  • Qualitative impairments in communication

  • Language delays evident at 15 months of age, using a few single words inconsistently

  • Ability to sign a few words learned at about 18 months of age but lost by the age of 4

  • Rare spontaneous use of conventional or instrumental gestures between 4 and 5 years of age, only occasional looking up when someone would enter the room without calling patient’s name

  • Vocalization in the form of jargon and consonant–vowel sounds that were not consistently directed at anyone, at 13 years of age

  • Ability to follow only simple directions at 13 years of age

  • Rare spontaneous imitation of another person’s actions

  • Frequent screaming

  • Hypersensitivity to certain noises

  • Qualitative impairments in reciprocal social interaction

  • Ability to make brief make eye contact with familiar adults

  • Vocalizing, jumping up and down, and flapping his arms and hands to express excitement

  • Struggle to understand emotional experience of others

  • Limited range of facial expressions between 4 and 5 years of age, but sufficient by the age of 13 for the patient’s parents to understand the major emotions that he experienced, such as happiness, anger, and frustration

  • Inappropriate facial expressions, such as laughing for no apparent reason, worsening with age

  • No engagement in imaginative play by himself or with others between the ages of 4 and 5, playing next to other children

  • Rare interaction with siblings and unresponsiveness to their social approaches or the approaches of less familiar children

  • Repetitive play

  • Anxiety caused by minor changes in his routine and changes to his immediate environment

  • Difficulty processing new environments

  • Many unusual sensory interests

  • History of aggression towards family members, especially between the ages of 10 and 11, sometimes at school

  • Occasional self-injurious behavior, such as head banging

  • Affectionate, good natured, and sweet

A5

  • Delayed motor milestones

  • Delayed language development

  • Use of single words, such as “dog” and “hi,” at approximately 3 years of age

  • Ability to speak in short phrases at age 5; no progress beyond spontaneous use of two word combinations; no ability to speak three word phrases spontaneously

  • Language regression at age 5 following a grand mal seizure

  • Occupational and physical therapy, music and art therapy as well as speech and language, social and life skills training

  • No interest in her peers between the ages of 4 and 5

  • Qualitative impairments in communication

  • Some difficulty coordinating her gaze

  • Occasional imitation of noises she had heard; no spontaneous imitation of the actions of others

  • No engagement in any form of pretend play

  • Qualitative impairments in social interaction

  • Difficulty making and maintaining eye contact

  • Exceptional visuospatial skill

  • Greater interest in certain parts of toys rather than using the toy as it was intended

  • No unusual hand or finger mannerisms

  • Bouncing up and down while bent over at the waist with arms pulled in tightly to chest to express excitement

  • No unusual sensory interests

  • Sensitivity to bright lights and excessive noise

  • Tactile defensiveness, responding negatively to being touched by others

A6

  • Speech delay, rocking, hyperactivity to the point of breaking several playpens, and periodic crying spells at 26 months of age

  • Poor eye contact, failure to attend to the breast while feeding, and crying spells as early as 7 months of age (noted retrospectively)

  • Independent walking not delayed, noted at 14 months

  • No word use until 9 years of age; no phrase use

  • Gradual loss of interest of toileting self-care skills

  • Disrupted sleeping habits

  • Poor eye contact

  • Absence of social smiling and limited facial expression

  • No imaginative play with others, nor interest in other children

  • Absence of shared attention skills

  • Lack of empathy

  • Use of other’s body to communicate

  • Laughing for no apparent reason at 4–5 years of age

  • No use of any form of gesture to communicate, including pointing and head shaking, and no imitation of others

  • Repetitive behaviors including circumscribed interest in listening to music all day, repetitive toy play, insistence on carrying out certain rituals, smelling everything (including non-food items), hand and finger mannerisms, and rocking

  • Extreme anxiety with any change in his routine (leading to self-hitting)

  • Sound sensitivity, hyperactivity, and aggression toward others (punching)

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Casanova, M.F., van Kooten, I.A.J., Switala, A.E. et al. Minicolumnar abnormalities in autism. Acta Neuropathol 112, 287 (2006). https://doi.org/10.1007/s00401-006-0085-5

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  • DOI: https://doi.org/10.1007/s00401-006-0085-5

Keywords

  • Autistic disorder/pathology
  • Child development disorders
  • Pervasive
  • Neocortex
  • Neuropil
  • Pyramidal cells