Byun Andrew Jin Soo, Deshpande Harshawardhan U, Stover Jessi, Kangas Brian D, Kohut Stephen J
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
Division of Digital Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Neuropsychopharmacology. 2025 Feb 28. doi: 10.1038/s41386-025-02068-5.
Adolescent cannabinoid exposure has been implicated in enduring modifications to adult brain circuitry; however, well-controlled, systematic analyses investigating dose-dependent effects of chronic delta-9-tetrahydrocannabinol (THC) exposure on brain connectivity are lacking. It is hypothesized that large-scale intrinsic networks, such as default mode (DMN), central executive (CEN), and salience networks (SN), are critically involved in vulnerability to deficits in cognitive processing often associated with adolescent cannabis use. The present study aimed to elucidate the effects of chronic THC exposure on functional connectivity (FC) of these putative large-scale networks in nonhuman primates. Separate groups of adolescent squirrel monkeys (aged 2.0-yrs [female] and 2.5-yrs [male]) were administered intramuscular injections of vehicle or THC daily (0.32 or 3.2mg/kg) for 6-months during adolescence. Resting state functional connectivity from scans conducted in awake subjects was measured before dosing, at 6-months of chronic dosing, and 60-days following discontinuation of daily THC exposure. Utilizing two distinct analytical methodologies, we observed a non-linear, dosage-dependent alteration in DMN-CEN FC across scan intervals. Specifically, exposure to a low THC dosage increased FC during chronic exposure compared to both the pre-dosing and discontinuation periods. This pattern, however, was not observed in either the vehicle or high THC dosage groups. Dual-regression unveiled a similar non-linear effect within the CEN, but not DMN, suggesting the effect on DMN-CEN FC may be driven by modifications within the CEN. Taken together, these results suggest adolescent THC exposure differentially affects large-scale brain networks and contributes to a nuanced understanding of CEN's role in disrupting brain connectivity following chronic THC exposure.
青少年接触大麻素与成年大脑神经回路的持久改变有关；然而，缺乏对慢性δ-9-四氢大麻酚（THC）暴露对大脑连接性的剂量依赖性影响进行充分控制的系统分析。据推测，大规模内在网络，如默认模式网络（DMN）、中央执行网络（CEN）和突显网络（SN），在青少年使用大麻常伴有的认知加工缺陷易感性中起关键作用。本研究旨在阐明慢性THC暴露对非人类灵长类动物中这些假定的大规模网络功能连接（FC）的影响。将不同组的青少年松鼠猴（2.0岁[雌性]和2.5岁[雄性]）在青春期期间每天进行肌肉注射媒介物或THC（0.32或3.2mg/kg），持续6个月。在给药前、慢性给药6个月时以及每日THC暴露停止后60天，测量清醒受试者扫描的静息态功能连接。利用两种不同的分析方法，我们在各个扫描间隔中观察到DMN-CEN功能连接存在非线性、剂量依赖性改变。具体而言，与给药前和停药期相比，低剂量THC暴露在慢性暴露期间增加了功能连接。然而，在媒介物组或高剂量THC组中均未观察到这种模式。双回归揭示了CEN内存在类似的非线性效应，但DMN内未观察到，这表明对DMN-CEN功能连接的影响可能由CEN内的改变驱动。综上所述，这些结果表明青少年THC暴露对大规模脑网络有不同影响，并有助于更细致地理解CEN在慢性THC暴露后破坏大脑连接性中的作用。
