健康与遗传心理学研究室知识库

近年来提出，抑制功能损伤可能是持续使用毒品的一个重要原因，其中反应抑制缺陷和冲动性觅药行为紧密相关，但这些理论尚未得到充分的实验证据证实，对相关神经基础的研究结果也很不一致，而针对纯海洛因吸毒者的行为抑制脑成像研究报道极少。

在各种抑制缺陷的实验范式中，stop-signal范式最能反映反应抑制能力，与冲动性觅药行为的性质也最为接近的。本研究采用stop-signal实验范式，刘100多名慢性海洛因依赖者进行了较为系统的行为学和脑成像研究。

行为学研究显示:(1）慢性海洛因成瘾者对运动信号的反应时间似乎不受停止信号的影响;(2)在完成任务的策略上，海洛因依赖者倾向于更小的等待效应、更强的冲动性，同时对错误反应的监控和即时调整能力下降;(3)海洛因依赖组的停止信号反应时(SSRT)值显著长于控制组被试。这些结果确认了海洛因依赖者的行为抑制能力受损。进一步相关分析表明，海洛因依赖者的SSRT与其成瘾严重性指数((ASI)的四个分项指标呈正相关，其中与和药物使用情况的相关最高，说明成瘾药物的使用可能是造成海洛因依赖者抑制功能损害的主要原因。

fMIR结果显示:(1）成瘾组和控制组在M1、SMA等运动执行区的激活没有显著差异;(2)但在要求对行为进行控制时，成瘾组在右侧背外侧前额叶、右侧腹侧前额叶、扣带回前部等脑区的激活强度都显著弱于控制组被试，而在双侧纹状体和杏仁核，成瘾组的激活强于控制组(显著或边缘显著)。右侧前额叶被认为是执行抑制功能的主要脑区，扣带回和错误监控等能力密一切相关，而杏仁核一直被视为是冲动性、情绪控制的关键结构。这些脑区构成冲动与控制的神经环路，海洛因依赖者抑制功能损伤可能与这个环路的活动异常有关。

脑结构测量显示:(1)长期用药导致海洛因依赖患者前额叶广泛区域(包括双侧背外侧前额叶、额叶眶部、腹内侧额叶)和扣带回灰质密度下降;(2)这种灰质密度下降随着患者药物依赖程度的加重而加剧;(3)未见明显的脑中部核团的灰质密度下降;(4)本研究被试灰质密度下降的程度比以往文献报告要轻，因此，被试年龄较轻以及纯海洛因可能是原因。

总之，本研究结果不但确认了纯海洛因依赖者抑制能力受损，而且证明其神经基础为冲动相关脑区活动增强和参与认知控制脑区活动减弱;而脑结构测量进一步提示，药物导致前额叶结构损伤可能是药物成瘾的根木原因。

In recent years, deficit of inhibition has been suggested to play an important role in persistent drug use. Response inhibition resembles the compulsive drug seeking behavior and is believed to be associated with addiction inhibition deficits. Yet, empirical evidence for these speculations is insufficient, and results of the neuroimaging studies are mixed. Only very few studies have been conducted in pure heroin users.

Among those paradigms for studying response inhibition deficits, the stop signal task is an ideal one that models compulsive drug seeking behavior. We conducted a series of behavioral and neuroimaging studies, using the stop signal task, to investigate response inhibition and its neural correlates in about 100 heroin users. The behavioral data showed that: (i) reaction time in the go trial was not affected by stop signals in heroin users; (ii) compared to the control group, heroin users had shorter waiting time, stronger impulsivity, but less flexibility, and theil0 error monitoring and flexible adjustment ability were also damaged; (iii) the stop signal reaction rime (SSRT) of heroin users was significantly longer than the control group.

These results converge to impairment of inhibition functions in heroin users. Further correlational analysis showed that the SSRT of heroin users had significant positive correlation with four factor scores of addiction severity index (ASI), with highest correlation coefficient between SSRT and drug use, suggesting that drug use is the main factor account for inhibition deficits.

The fMRI study demonstrated that: (i) there was no significant difference in activation of the primary motor cortex and supplementary motor area between two experimental groups; (ii) relative to the control group, heroin users had weaker activation in the right dorsal lateral prefrontal cortex, right inferior prefrontal cortex, and anterior cingulated cortex, but stronger activation in bilateral striatum and amygdala. It is has been reported that the right prefrontal cortex is the main substrate for inhibition, while the anterior cingulated cortex is associated_with error monitoring, and the amygdale with impulsivity and emotion control. These brain regions together constitute a network for impulsivity and inhibitory functions. Our study documented significant changes within this network in heroin users.

We next investigated the gray matter changes of heroin users and demonstrated remarkable decreases in the gray matter density of the prefrontal cortex (including bilateral dorsalateral prefrontal cortex, obital frontal cortex, inferior prefrontal cortex) and anterior cingulated cortex. The gray matter density in most of these regions was negatively correlated with duration of drug use. No significant decrease was found in the subcortical structures. It is interesting that gray matter decrease in our heroin addicts was less significant than in previous studies9 likely because our subjects were younger and pure heroin users without contamination of other drugs.

In sum, our behavioral study confirmed the impairment of inhibition in heroin users, and our fMRI study demonstrated stronger activation in the brain regions for impulsivity and weaker activation in the regions for inhibition. Our volumetric study further suggests that the critical substrate underlying these functional changes is the decrease of the gray matter density in the prefrontal areas.