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.

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)