The intrahippocampal kainic acid (IHKA) mouse model is an extensively used in vivo model to investigate the pathophysiology of mesial temporal lobe epilepsy (mTLE) and to develop novel therapies for drug-resistant epilepsy. It is characterized by profound hippocampal sclerosis and spontaneously occurring seizures with a major role for the injected damaged hippocampus, but little is known about the excitability of specific subregions. The purpose of this study was to electrophysiologically characterize the excitability of hippocampal subregions in the chronic phase of the induced epilepsy in the IHKA mouse model. We recorded field postsynaptic potentials (fPSPs) after electrical stimulation in the CA1 region and in the dentate gyrus (DG) of hippocampal slices of IHKA and healthy mice using a multielectrode array (MEA). In the DG, a significantly steeper fPSP slope was found, reflecting higher synaptic strength. Population spikes were more prevalent with a larger spatial distribution in the IHKA group, reflecting a higher degree of granule cell output. Only minor differences were found in the CA1 region. These results point to increased neuronal excitability in the DG but not in the CA1 region of the hippocampus of IHKA mice. This method, in which the excitability of hippocampal slices from IHKA mice is investigated using a MEA, can now be further explored as a potential new model to screen for new interventions that can restore DG function and potentially lead to novel therapies for mTLE.

Transcranial temporal interference stimulation (tTIS) has recently emerged as a non-invasive neuromodulation method aimed at reaching deeper brain regions than conventional techniques. However, many questions about its effects remain, requiring further experimental studies. This review consolidates the experimental literature on tTIS’s effects in the human brain, clarifies existing evidence, identifies knowledge gaps, and proposes future research directions to evaluate its potential. A systematic literature search was performed in PubMed, Web of Science, and Scopus for studies published up to 27 January 2025. Eligible studies applied tTIS to the human brain and examined its effects on neural, behavioral, and clinical outcomes. Of 127 publications screened, 18 met the inclusion criteria. Studies were analyzed for design, stimulation target, parameters, control conditions, and outcome measures. Included studies exhibited low bias or minor concerns using the Cochrane RoB2 and ROBINS-I tools. Ten studies targeted cortical regions (motor, occipito-parietal, fronto-parietal), and eight probed subcortical sites (striatum, hippocampus, globus pallidus, caudate). Motor-cortex tTIS enhanced motor-network connectivity, though the effect was similar to that of transcranial direct current stimulation. Beta-band stimulation envelopes (20 Hz) promoted learning-related plasticity, while gamma-band envelopes (70 Hz) yielded immediate performance improvements. Occipito-parietal tTIS did not modulate alpha power. Preliminary deep-target findings are promising: 5 Hz hippocampal tTIS improved episodic recall, 100 Hz striatal tTIS enhanced motor learning in older adults, and 100 Hz hippocampal-entorhinal tTIS aided spatial navigation. Two fMRI studies confirmed network-specific modulation, although one raised concerns about using a fixed montage between individuals. Clinical evidence remains limited, with two Parkinson’s pilots and one epilepsy study showing short-term benefits. Overall, tTIS shows potential to modulate human brain activity and behavior. However, current evidence is preliminary and predominantly focused on cortical rather than deep targets. Larger, well-controlled studies are needed to reliably determine whether tTIS can effectively engage subcortical structures and provide meaningful clinical benefits.

Recent experiments in rats have demonstrated significant effects of VNS on hippocampal excitability but were partially attributed to hypothermia, induced by the applied VNS parameters. To allow meaningful preclinical research on the mechanisms of VNS and translation of rodent results to clinical VNS trials, we aimed to identify non-hypothermia inducing VNS parameters that significantly affect hippocampal excitability. VNS was administered in cycles of 30 s including either 0.1, 0.16, 0.25, 0.5, 1.5, 3 or 7 s of VNS ON time (biphasic pulses, 250μs/phase, 1 mA, 30 Hz) and the effect of different VNS ON times on brain temperature was evaluated. VNS paradigms with and without hypothermia were compared for their effects on hippocampal neurophysiology in freely moving rats. Using VNS parameters with an ON time/OFF time of up to 0.5 s/30 s did not cause hypothermia, while clear hypothermia was detected with ON times of 1.5, 3 and 7 s/30 s. Relative to SHAM VNS, the normothermic 0.5 s VNS condition significantly decreased hippocampal EEG power and changed dentate gyrus evoked potentials with an increased field excitatory postsynaptic potential slope and a decreased population spike amplitude. VNS can be administered in freely moving rats without causing hypothermia, while profoundly affecting hippocampal neurophysiology suggestive of reduced excitability of hippocampal neurons despite increased synaptic transmission efficiency.