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Features of Duration Mismatch Negativity Around the Onset of Overt Psychotic Disorders: A Longitudinal Study

立野 貴大 富山大学

2022.03.23

概要

〔背景・目的〕
ミスマッチ陰性電位（mismatch negativity; MMN）は脳波を用いて測定される事象関連電位の一種であり、前注意的な感覚処理を反映するとされる。MMNは多くの研究で精神病患者において振幅が低下していることが報告されており、精神病のバイオマーカーとしての応用可能性への期待が高まっている。最近の研究では、精神病を発症するリスクが高い状態とされるAt-risk mental state(ARMS)を前方視的に観察し、将来精神病に移行したARMSは精神病発症前に持続長MMN（duration MMN; dMMN）の振幅がすでに低下していることが多く報告されていることから、ARMSにおける将来の精神病発症の生物学的予測因子としての役割が示唆されている。また精神病の様々な段階（ARMS、初発、慢性期）におけるdMMNの横断研究では、その振幅は病期の進行に従い低値となり、さらに、精神病における少数の縦断研究ではMMNが経時的に減少することが報告されている。しかしARMSを前方視的に追跡しMMNを縦断的に調査した研究報告はほとんどない。これらを背景に、本研究ではARMSのMMNの特徴を横断的および縦断的に調べることを目的とした。

〔方法〕
本研究では、ARMS39名と健常対照者22名を対象とし、平均約2年の間隔をおいてベースライン時(Time1)とフォローアップ時(Time2）の2回、dMMN振幅の測定と臨床評価を行った。ARMS39名中11名が追跡期間中平均約1.7年後に精神病を発症した。これらの群をARMS-Pと定義した。また、少なくとも2年間の臨床経過観察期間中に精神病を発症しなかった群をARMS-NPと定義した。ベースラインのdMMN振幅を、ARMS-P、ARMS-NPおよび健常対照者の3群において一元配置共分散分析を用いて比較した。次に、MMNの経時的な変化を検出するために，3群を繰り返しのある一元配置共分散分析を用いて比較した。本研究のプロトコルは富山大学倫理審査委員会の承認を得て行われた。また、ヘルシンキ宣言に基づきすべての対象者および対象者が20歳未満の場合は親または保護者からも書面による同意を得た。

〔結果〕
Time1のdMMN振幅は健常対照者、ARMS-NP、ARMS-Pそれぞれ−7.25±1.52μV、−6.89±1.59μV、−4.89±1.70μVであった。ARMS-Pは、健常対照者およびARMS-NPと比較して、ベースラインのdMMN振幅は有意に小さかった（F[2,56]=6.35,p=0.003）。Time2のdMMN振幅は−7.18±1.50μV、−7.00±1.78μV、−3.32±0.88μVであり、ARMS-PではTime1と比較してTime2でdMMN振幅が有意に減少した（p＝0.014）が、ARMS-NPおよび健常対照者では減少しなかった（それぞれp＝0.998,p＝1.000）。


〔考察〕
今回のARMSにおける横断研究において、ARMS-Pは、健常対照群やARMS-NPに比べて、ベースラインでdMMNの振幅が有意に低かった。MMNはNMDA受容体システムとの関連が深いことが知られているが、統合失調症ではNMDA受容体の機能不全が存在し、それがMMN振幅の低値をもたらすと考えられている。今回の研究結果よりNMDA受容体機能不全が精神病素因のある対象者において発症前に既に存在していることが示唆された。

次に、ARMS-Pは精神病への移行期にdMMN振幅の経時的な低下を示したが，健常対照群とARMS-NPはそのような変化を示さなかった。MMNの発生源は上側頭回であると考えられており、ARMS-Pにおける振幅低下は、同部位において報告されている初回エピソード統合失調症やARMS-Pにおける経時的な体積減少と関連すると考えられた。その背景となる病態生理としてはNMDA受容体の機能低下によるグルタミン酸の過剰により、精神病発症前後で有害な神経毒性をもたらした可能性が示唆された。

以上よりdMMNの低振幅は精神病発症前においても特徴的なマーカーとして存在することおよび、精神病発症に関連する動的な病理学的プロセスが存在する可能性が考えられた。限界として、症例数が少ないこと、抗精神病薬投与量、IQ、観察期間など十分な統制が得られていなかったことが挙げられた。今後は症例数を増やし、より人口統計学的にマッチしたコホートにおける研究が必要である。

〔総括〕
本研究では、これまでの研究と同様dMMN振幅の低下が精神病発症前にすでに存在しており、更に、精神病発症前後で低下してゆくことを初めて見出した。このことから、dMMN測定は精神病発症のハイリスク者における将来の精神病発症の生物学的予測因子として応用できる可能性がある。

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