Development of Sensory Gamma Oscillations and Cross-Frequency Coupling from Childhood to Early Adulthood

Christopher P. Walkerand Nicola R. Polizzotto contributed equally to the manuscript.Given the importance of gamma oscillations in normal and disturbedcognition, there has beengrowing interestin their developmentaltra-jectory. In the current study, age-related changes in sensory corticalgamma were studied using the auditory steady-state response(ASSR), indexing cortical activity entrained to a periodic auditorystimulus.Alargesample(n=188) aged8–22years hadelectroence-phalography recording of ASSR during 20-, 30-, and 40-Hz clicktrains, analyzed forevoked amplitude, phase-locking factor (PLF) andcross-frequency coupling (CFC) with lower frequency oscillations.Both 40-Hz evoked power and PLF increased monotonically from 8through 16 years, and subsequently decreased toward ages 20–22years. CFC followed a similar pattern, with strongest age-relatedmodulation of 40-Hz amplitude by the phase of delta oscillations. Incontrast, the evoked power, PLFand CFCfor the 20- and 30-Hz stimu-lation were distinct from the 40-Hz condition, with flat or decreasingprofiles fromchildhood toearlyadulthood. The inverted U-shaped de-velopmental trajectoryof gamma oscillations may be consistent withinteracting maturational processes—such as increasing fast GABAinhibition that enhances gamma activity and synaptic pruning thatdecreases gamma activity—that may continue from childhoodthrough to adulthood.Keywords: cross-frequency coupling, development, GABA, gammaoscillations, phase-locking factor, synaptic pruningIntroductionSynchronous gamma-band (30–80 Hz) oscillations are animportant mechanism for coordinating neural activity in theservice of cognitive and sensory processing. Altered gammaoscillations have also been implicated in the pathophysiologyof neuropsychiatric disorders such as schizophrenia andautism. Accordingly, investigating the normal developmentaltrajectoryofgamma oscillations isof vital importanceto under-standing the neurophysiologic underpinnings of normal cogni-tive development and how pathophysiologic disturbances ingamma activity in neurodevelopmental disorders can give riseto deviations from thistrajectory.Gamma oscillations have been most studied in humansusing electroencephalography (EEG), which records at thescalp the summed effect of the synchronous postsynapticactivity in a large number of cortical pyramidal neurons(Nunez and Srinivasan 2005). As various structural and func-tional processesthat support gamma oscillations involve a pro-tracted neurodevelopmental course from childhood through toadulthood, the development of gamma oscillations would beexpected to followa similarlyextended trajectory before reach-ing the mature state. For instance, structural magnetic reson-ance imaging (MRI) studies find that gray matter thickness inauditory cortical areas (posterior superior temporal gyrus) de-crease linearly from childhood into early adulthood (Gogtayet al. 2004). Such macro-level observations of gray matterchanges are thought to reflect synaptic pruning over develop-ment. Early studies by Huttenlocher and Dabholkar (1997)suggested that auditory and visual regions completed pruningprocesses in early adolescence while prefrontal cortex had amore extended course into mid-adolescence. However, theseinterpretations were limited by sparse sampling over the ado-lescence and adulthood periods, and more recent studies withdenser sampling over this range have indicated that synapticelimination continues beyond adolescence into the thirddecade of life (Petanjek et al. 2011). Such structural changesare accompanied by extensive changes in components ofGABA neurotransmission (Beneyto and Lewis 2011) that couldcritically change the functional capacity to produce gammaoscillations. Parvalbumin (PV) fast-spiking cells are a subclassof GABA interneurons that, given their nonadapting firing andpostsynaptic GABA-A receptors that possess fast kinetics, cansupport sustained, high-frequency firing. These propertiesallow PV fast-spiking interneurons to play their critical role inthe temporal regulation of gamma oscillations through feed-back inhibitory coupling with pyramidal cells (Bartos et al.2007; Buzsaki and Wang 2012). Interestingly, during develop-ment, GABA-A receptors shift their subunit composition fromalpha-2 to alpha-1 subtypes, resulting in a shift from slower tofaster inhibitory decay kinetics (Hashimoto et al. 2009). Sincethe frequency of gamma oscillations depends critically on thedecay time course for inhibition (Bartos et al. 2007), such ashift could increasingly provide the means to support higherfrequency oscillations. This developmental shift also follows aprotracted temporal course, beginning postnatally and conti-nuing through to adulthood (Hashimoto et al. 2009). Thus,both structural refinements and molecular changes occur witha protracted course but exactly how these interact and give riseto physiologic changes over development in the form ofgamma oscillations requires explicit investigation.Steady-state responses to trains of periodic stimuli havebeen extensively used to examine oscillations in auditory,visual, and somatosensory modalities (Colon et al. 2012) andhave the advantage of a high signal-to-noise ratio (Vialatteet al. 2010). Auditory steady-state responses (ASSRs) havebeen used to study the development of gamma oscillations