Holliday William B, Gurnsey Kate, Sweet Robert A, Teichert Tobias
From the Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA (Holliday, Gurnsey, Sweet, Teichert); the Department of Neurology, University of Pittsburgh, Pittsburgh, PA (Sweet); the Mental Illness Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA (Sweet); and the Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA (Teichert).
J Psychiatry Neurosci. 2017 Dec 13;43(1):170093. doi: 10.1503/jpn.170093.
The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state.
We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulus-onset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-d-aspartate receptor channel blockers ketamine and MK-801 as well as the γ-aminobutyric acid (GABA) A receptor-positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components.
Ketamine, MK-801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components.
The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex.
The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive.
可从无创脑电图记录中得出的听觉诱发N1成分的振幅会随着后续音调之间时间的变化而增加。精神分裂症患者的N1振幅在较低的渐近线处达到饱和，从而导致动态范围减小。N1动态范围减小被认为是该疾病患者感觉记忆功能改变的一种电生理生物标志物。迄今为止，尚不清楚是什么决定了N1动态范围，以及是什么导致精神分裂症患者的N1动态范围减小。在此，我们检验这样一种假设，即N1动态范围减小是由于兴奋/抑制（E/I）平衡向兴奋不足或抑制占主导状态转变所致。
我们记录了4只猕猴在被动聆听随机音高和刺激起始异步（SOA）的声音序列时的听觉诱发电位（AEP）。三项独立实验测试了N-甲基-D-天冬氨酸受体通道阻滞剂氯胺酮和MK-801以及γ-氨基丁酸（GABA）A受体正向变构调节剂咪达唑仑对假定的猴N1同源物和其他4种AEP成分动态范围的影响。
氯胺酮、MK-801和咪达唑仑降低了最长SOA时的N1峰值振幅。其他AEP成分也受到了影响，但显示出对谷氨酸能和GABA能药物不同的敏感性模式。不同的敏感性模式表明维持各个成分E/I平衡的神经回路存在差异。
该研究使用了全身药理学干预，其作用靶点可能在听觉皮层之外。
N1动态范围可能是E/I平衡改变的一个标志。精神分裂症患者N1动态范围减小可能表明听觉皮层处于兴奋不足或抑制占主导的状态。这可能是对兴奋性驱动原发性缺陷的不完全补偿的结果。
