PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - REVIEW ARTICLE Elucidating the neurophysiological underpinnings of autism spectrum disorder: new developments C. Luckhardt • T. A. Jarczok • S. Bender Received: 29 November 2013 / Accepted: 19 June 2014 / Published online: 25 July 2014 Ó Springer-Verlag Wien 2014 Abstract The study of neurophysiological approaches together with rare and common risk factors for Autism Spectrum Disorder (ASD) allows elucidating the specific underlying neurobiology of ASD. Whereas most neuro- physiologically based research in ASD to date has focussed on case–control differences based on the DSM- or ICD- based categorical ASD diagnosis, more recent studies have aimed at studying genetically and/or neurophysiologically defined homogeneous ASD subgroups for specific neuronal biomarkers. This review addresses the neurophysiological investigation of ASD by evoked and event-related poten- tials, by EEG/MEG connectivity measures such as coher- ence, and transcranial magnetic stimulation. As an example of classical neurophysiological studies in ASD, we report event-related potential studies which have illustrated which brain areas and processing stages are affected in the visual perception of socially relevant stimuli. However, a para- digm shift has taken place in recent years focussing on how these findings can be tracked down to basic neuronal functions such as deficits in cortico-cortical connectivity and the interaction between brain areas. Disconnectivity, for example, can again be related to genetically induced shifts in the excitation/inhibition balance. Genetic causes of ASD may be grouped by their effects on the brain’s system level to identify ASD subgroups which respond differentially to therapeutic interventions. Keywords Autism Á Visual event-related potential Á Mirror neuron Á Connectivity Á Transcranial magnetic stimulation Á Excitation Á Inhibition Introduction Autism spectrum disorder (ASD) is a neurodevelopmental disorder which is characterised by difficulties in reciprocal social communication and interaction, as well as stereo- typed and repetitive behaviours and interests. The disorder is genetically influenced with a heritability of *80 % (Lichtenstein et al. 2010). ASD is a complex, heteroge- neous disorder, with monogenetic disorders, rare single nucleotide (SNVs) and copy number variants (CNV) as well as common variation underlying the disorder. Repli- cated genetic risk variants are related to early brain development, by influencing synaptogenesis, neurotrans- mission, micro- and macroanatomic structure and function (Freitag et al. 2010; Berg and Geschwind 2012; Abrahams and Geschwind 2010). An innovative approach to study the biological role of genetic risk factors on ASD development are imaging genetic studies (Ameis and Szatmari 2012). For example, variants in neurexin-1 (NRXN1) and contac- tin-associated protein-like 2 (CNTNAP2) were associated with specific brain anatomy in ASD, and oxytocin receptor genetic variation influenced limbic structure and function in healthy individuals (Tost et al. 2010; Meyer-Lindenberg et al. 2011). To better understand common, but also spe- cific, genetic risk factor related, underpinnings of ASD, the combination of genetic and brain imaging data will provide insights in the pathophysiology of ASD, and ultimately will help to identify targets for a causal therapy. The develop- ment of biomarkers for ASD as well as for genetically defined, more homogeneous ASD subtypes is crucial for C. Luckhardt and T. A. Jarczok have contributed equally to the manuscript. C. Luckhardt (&) Á T. A. Jarczok Á S. Bender Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Deutschordenstraße 50, 60528 Frankfurt am Main, Germany e-mail: Christina.Luckhardt@kgu.de 123 J Neural Transm (2014) 121:1129–1144 DOI 10.1007/s00702-014-1265-4