Sensory and sensorimotor gating in children with multiple complex developmental disorders (MCDD) and autism
Introduction
Autism is one of the best defined and validated psychiatric disorders in childhood. It is characterized by problems in social interaction, social communication and restricted and repetitive behaviors and interests (Lord and Bailey, 2003). Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) represents a heterogeneous group of patients failing to meet the full diagnostic criteria for an autistic disorder (Lord and Bailey, 2003). This group of patients is not rare and even outnumbers the group of autistic patients up to three times (Wing and Gould, 1979, Fombonne, 2003, Fombonne, 2005). Autism Spectrum Disorders (ASD), including autism, Asperger's syndrome and PDD-NOS, are frequently diagnosed childhood-psychiatric illnesses. Recent epidemiological figures indicate a prevalence of 0.7% in the general population (MMWR Surveillance Summaries, 2007). Because of the lack of homogeneity in symptoms of patients with PDD-NOS, more homogenous subgroups have been proposed. One of these subgroups is Multiple Complex Developmental Disorder (MCDD). The subgroup MCDD was first clearly described by Cohen et al. (1986), who proposed a cut-off point for the symptom category and amount of symptoms. Evidence for the existence of this subcategory of patients was further underlined in two later studies (Towbin et al., 1993, van der Gaag et al., 1995). MCDD patients are characterized by impaired regulation of affective state and anxiety, impaired social behavior/sensitivity and impaired cognitive processing (thought disorder) (Cohen et al., 1986, Towbin et al., 1993, van der Gaag et al., 1995, Buitelaar and van der Gaag, 1998, Ad-Dab'bagh and Greenfield, 2001). Although children with MCDD share impairments in social behavior and sensitivity with autistic patients, they are found to be more impaired than children with autism on thought disorders (psychotic thinking), primitive anxieties, and aggression (van der Gaag et al., 1995, Buitelaar and van der Gaag, 1998). Interestingly, Sprong et al. (2008) found evidence indicating that patients with MCDD are at high risk for developing psychosis later in life, and may therefore also be at higher risk for developing schizophrenia.
In order to characterize subjects with MCDD better, and to underline that the large group of patients with PDD-NOS includes different subtypes, there is a great need for endophenotypic markers that could distinguish these possible subtypes from each other. For schizophrenia several psychophysiological deficits have been suggested to be endophenotypic for the disease. Two of these psychophysiological measures are thought to assess different aspects of stimulus filtering, i.e. the prepulse inhibition (PPI) of the acoustic startle reflex and gating of the auditory evoked potential (P50 suppression). In PPI a startle reflex to an intense stimulus is muted or inhibited in magnitude when preceded by a weak stimulus (the prepulse). In humans, the eyeblink component of the startle reflex is usually assessed as the basis for calculating PPI, using electromyographic (EMG) recordings of the orbicularis oculi muscle. Similar to PPI, also P50 suppression involves an inhibitory influence of an initial stimulus to the response to a second (identical) stimulus. P50 gating can be reliably assessed in children between 10 and 14 years of age, showing the same ratio of P50 suppression as adults (Myles-Worsley et al., 1996). Similarly, adult levels of PPI are already evident by age 8 (reviewed in: Braff et al. (2001)). An advantage of both paradigms is that they require neither motivation nor major cooperation.
Abnormalities in PPI and P50 suppression have been clearly demonstrated across the schizophrenia spectrum, including probands, their unaffected relatives, and schizotypal patients (for a review: Braff et al. (2001)). Reduced PPI is also found in antipsychotic naïve, first episode patients with schizophrenia, indicating that neither medication, nor disease progress accounts for this gating deficit (e.g. Mackeprang et al., 2002, Aggernaes et al., 2010). PPI deficits correlate significantly with symptoms of thought disorder and appear associated with greater distractibility, an earlier age of onset, and more severe positive and negative symptoms in schizophrenia (Braff et al., 1999, Braff et al., 2001). Similarly to PPI, P50 suppression deficits are found in both medicated and antipsychotic naïve, first episode patients with schizophrenia (e.g. Freedman et al., 1983, Brockhaus-Dumke et al., 2008, Oranje et al., 2013). There is evidence suggestive for an association between P50 suppression and measures of attention, but multiple studies have failed to document a cross-sectional or longitudinal relationship between P50 suppression and positive, negative or other symptoms of schizophrenia (for a review: Potter et al. (2006)). It has been speculated (for schizophrenia-spectrum patients) that different patterns of inhibitory deficits may be associated with different clinical profiles (Cadenhead et al., 2002, Swerdlow et al., 2006) although, to our knowledge, there is currently no available evidence supporting this.
Currently, there have only been a few reports on PPI in autism spectrum disorders. To our knowledge, only four of such studies have been published so far: Ornitz et al. (1993) (54 autistic patients); McAlonan et al. (2002) (10 Asperger patients); Perry et al. (2007) (14 autistic patients) and Yuhas et al. (2011) (15 autistic patients). McAlonan et al. (2002) found reduced PPI in adults with Asperger disorder compared to healthy controls, and Perry et al. (2007) reported PPI deficits in adults with autism compared to healthy controls. Yuhas et al. (2011) reported no PPI deficits in their idiopathic autistic patients. Finally, Ornitz et al. (1993) reported no significant differences between diverse groups of autism including children and adolescents, (aged 2.8–33 years, IQ 40–145, some with major medical co-morbidity) and a healthy control group. Similarly to PPI, research on P50 suppression in autistic patients (including children) is lacking. In two earlier reports from our research group we neither found P50 suppression deficits in children (Kemner et al., 2002) nor in adults (Magnee et al., 2009) with autism. Orekhova et al. (2008) found impaired P50 suppression in very young and mentally retarded children with autism, and found that it improved with age.
Given the fact that children with MCDD may be regarded as an at risk group for developing schizophrenia, the aim of the current study was to determine whether these children show early indicators of schizophrenia, i.e. reduced filtering of sensory information. An additional aim was to investigate whether children with MCDD could be differentiated from children with autism on their sensory filtering characteristics. To this extent, P50 suppression and PPI were assessed in a group of non-mentally retarded children and adolescents with MCDD and compared to autistic subjects and controls, matched on age and performance IQ. It was hypothesized that subjects with MCDD would show reduced PPI and P50 suppression compared to both autistic and control subjects.
Section snippets
Materials and methods
This study was approved by the institutional review board of the University Medical Center in Utrecht, the Netherlands, in accordance with the Declaration of Helsinki. Written and oral information was given, after which written informed consent was obtained from all legal guardians of the subjects.
PPI
A main effect of stimulus was found [F(1,30)=12,3; p=0.001] indicating a larger EMG activity in response to pulse alone trials than to prepulse–pulse trials, i.e. all three experimental groups showed significant levels of PPI. Neither a significant main effect of diagnose [F(2,30)=1.39; p=0.27] nor an interaction between diagnose and stimulus [F(2,30)=2.0; p=0.16] was found, indicating that all experimental groups showed similar amplitudes to pulse alone trials as well as to prepulse–pulse
Discussion
The present study was designed to investigate PPI and P50 suppression in a group of children with MCDD (a subcategory of PDD-NOS), children with autism and healthy controls, all matched on age and PIQ. Since children with MCDD have an enhanced risk of developing psychosis, it was expected that they would show similar abnormalities in PPI and P50 suppression as those usually reported in patients with schizophrenia. However, the main finding of this study is that no differences were found between
Acknowledgments
The authors would like to thank Emmie Schaffelaar and Gert Camfferman for their assistance to the study.
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