Avalos-Alais Sofia, Jedynak Maciej, Boyer Anthony, Chanteloup-Forêt Blandine, Pinheiro Cristiana, Cline Christopher C, Parmigiani Sara, Alemán-Gómez Yasser, Hagmann Patric, Keller Corey J, David Olivier
Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, 13005 Marseille, France.
Université Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France.
Brain. 2025 Sep 9. doi: 10.1093/brain/awaf317.
The lateral prefrontal cortex (LPFC) serves as a critical hub for higher-order cognitive and executive functions in the human brain, coordinating brain networks whose disruption has been implicated in many neurological and psychiatric disorders. While transcranial brain stimulation treatments often target the LPFC, our current understanding of connectivity profiles guiding these interventions based on electrophysiology remains limited. Here, we present a high-resolution probabilistic map of bidirectional effective connectivity between the LPFC and widespread cortical and subcortical regions. This map is derived from intracranial evoked potential analysis of 48,797 intracranial direct electrical stimulation runs across 759 implantations in 724 patients with refractory epilepsy (368 male, 354 female, two unspecified; mean age 24±13.5 years). We mapped probabilistic connectivity between brain parcels with adaptive resolution - higher resolution in the LPFC in the hemisphere of interest and lower elsewhere - maintaining statistical power while achieving 95% average confidence interval of ∼0.03 for connectivity probability estimates. In addition, the significance threshold (p-value) for probabilistic connectivity was obtained from surrogate distributions. Overall, we observed remarkable symmetry between afferent and efferent connectivity patterns of the LPFC, with a slight preference for efferent connections (mean slope = 0.92±0.09, mean R² = 0.93±0.025). For example, connections between the inferior frontal gyrus (IFG) and anterior cingulate showed notable directional asymmetry. The IFG strongly projected to most brain networks compared to other LPFC regions, with the strongest connectivity to the ventral attention network (0.26±0.01 compared to values between 0.15 and 0.21 in other LPFC regions). Posterior DLPFC demonstrated stronger connectivity to brain networks compared to anterior DLPFC regions (eg. 0.21±0.01 vs 0.15±0.01 for connectivity to ventral attention network), with the exception of the limbic cortex. All LPFC subregions strongly projected to the fronto-parietal (greater than 0.17) and ventral attention (greater than 0.15) networks, with moderate connections to the default network (between 0.1 and 0.15, with the maximum corresponding to superior DLPFC). Finally, latency analysis suggested that the left LPFC's influence on ipsilateral emotion-related regions is primarily polysynaptic, with particularly strong pathways from IFG to amygdala (0.16±0.02) and hippocampus (0.12±0.01). Taken together, these comprehensive connectivity maps provide a new detailed electrophysiological foundation for understanding the functional anatomy of LPFC and guiding targeted brain stimulation protocols.
外侧前额叶皮层（LPFC）是人类大脑中高阶认知和执行功能的关键枢纽，协调着大脑网络，这些网络的破坏与许多神经和精神疾病有关。虽然经颅脑刺激治疗通常以LPFC为靶点，但我们目前基于电生理学对指导这些干预的连接图谱的理解仍然有限。在这里，我们展示了LPFC与广泛的皮层和皮层下区域之间双向有效连接的高分辨率概率图谱。该图谱来自于对724例难治性癫痫患者（368例男性，354例女性，2例未注明；平均年龄24±13.5岁）的759次植入进行的48797次颅内直接电刺激运行的颅内诱发电位分析。我们用自适应分辨率绘制了脑区之间的概率连接——在感兴趣半球的LPFC中分辨率较高，其他地方较低——在保持统计功效的同时，实现了连接概率估计的95%平均置信区间约为0.03。此外，概率连接的显著性阈值（p值）是从替代分布中获得的。总体而言，我们观察到LPFC的传入和传出连接模式之间具有显著的对称性，对传出连接略有偏好（平均斜率 = 0.92±0.09，平均R² = 0.93±0.025）。例如，额下回（IFG）和前扣带回之间的连接表现出明显的方向不对称。与LPFC的其他区域相比，IFG强烈投射到大多数脑网络，与腹侧注意网络的连接最强（0.26±0.01，而LPFC其他区域的值在0.15至0.21之间）。与DLPFC前侧区域相比，DLPFC后侧与脑网络的连接更强（例如，与腹侧注意网络的连接为0.21±0.01对0.15±0.01），边缘皮层除外。LPFC的所有亚区域都强烈投射到额顶叶（大于0.17）和腹侧注意（大于0.15）网络，与默认网络有中等连接（在0.1至0.15之间，最大值对应于DLPFC上部）。最后，潜伏期分析表明，左侧LPFC对同侧情绪相关区域的影响主要是多突触的，从IFG到杏仁核（0.16±0.02）和海马体（0.12±0.01）的通路尤为强大。综上所述，这些全面的连接图谱为理解LPFC的功能解剖和指导靶向脑刺激方案提供了新的详细电生理基础。
