Memory and Resting-State Connectivity in Acute Transient Global Amnesia: A Case-Control fMRI Study

Transient global amnesia (TGA) is a striking model of isolated amnesia. While hippocampal lesions are well described, the network-level mechanisms and the precise neuropsychological profile remain debated. Our objective was thus to characterize functional and neuropsychological correlates of acute TGA and their longitudinal evolution.

Prospective, single-center case-control study of 20 patients with acute TGA and 20 age- and sex-matched healthy controls. All participants completed neuropsychological testing and underwent structural and functional MRI at three time points: acute phase (< 24 h from onset), day 3, and 3 months. Primary outcomes were neuropsychological performance across episodic, semantic, and metamemory domains and resting-state fMRI connectivity within the episodic memory network. Secondary outcomes were functional connectivity within the Default Mode (DMN), Executive (ECN), and Salience (SN) networks.

A total of 40 participants were included (20 patients with TGA, mean age 65.5 years, 45% women; 20 controls, mean age 64.3 years, 45% women). In patients, median delay from symptoms' onset to MRI was 6.67 h. Neuropsychologically, patients showed profound multimodal anterograde amnesia during the acute phase, resolving by 3 months. This deficit was largely isolated, sparing semantic memory and metamemory. Structurally, small bilateral lesions were present in most patients. Functionally, acute hypoconnectivity was observed within the extended hippocampal system, particularly between parahippocampal and cingulate cortices, normalizing by 3 months. No consistent disruption was found in large-scale networks (default mode, executive control, salience).

TGA is associated with transient, selective hypoconnectivity within the mesiotemporal-cingulate episodic memory network, aligning with previous reports and further precising the functional anatomy. The finding of a profound anterograde amnesia was replicated and its recovery timecourse was elucidated. Semantic memory and metamemory remain preserved, clarifying inconsistencies in prior reports. These findings suggest that TGA reflects a transient limbic dysconnectivity syndrome rather than a diffuse network disorder, reconciling structural lesions with clinical and functional data.