TMS-evoked EEG responses in symptomatic and recovered patients with mild traumatic brain injury Jussi Tallus 1, Pantelis Lioumis 2, Heikki Hämäläinen 3, Seppo Kähkönen 2, Olli Tenovuo* 1 1 Department of Neurology, University of Turku, Finland, 2 Biomag Laboratory, Finland, 3 Department of Psychology, University of Turku, Finland *presenting author

Background Most patients recover from mild traumatic brain injury (mTBI) within 3 months Most patients recover from mild traumatic brain injury (mTBI) within 3 months About 15% develop persistent symptoms About 15% develop persistent symptoms Diffuse neuronal damage and anterior brain tract dysfunction are probably involved in at least some mTBI cases with chronic sequels (according to diffusion tensor imaging and fMRI studies) Diffuse neuronal damage and anterior brain tract dysfunction are probably involved in at least some mTBI cases with chronic sequels (according to diffusion tensor imaging and fMRI studies)

TMS-EEG Transcranial magnetic stimulation (TMS): A rapidly changing magnetic field induces a brief, focal electric field in the brain Transcranial magnetic stimulation (TMS): A rapidly changing magnetic field induces a brief, focal electric field in the brain TMS with EEG enables real-time measurement of brain responses to standardized stimulation TMS with EEG enables real-time measurement of brain responses to standardized stimulation Excitation occurs on cortical gray matter, but cortico-cortical and thalamo-cortical connections modify the activity of the stimulated circuits Excitation occurs on cortical gray matter, but cortico-cortical and thalamo-cortical connections modify the activity of the stimulated circuits

Participants 19 mTBI (GCS 13-15) patients, 11 with persistent symptoms and 8 fully recovered 19 mTBI (GCS 13-15) patients, 11 with persistent symptoms and 8 fully recovered 9 healthy controls 9 healthy controls No signs of injury in MRI in visual inspection No signs of injury in MRI in visual inspection No CNS affecting medications No CNS affecting medications

Experimental procedure Single pulse TMS on left dorsolateral prefrontal cortex (DLPFC) and left primary motor cortex (M1) in trains of 100 pulses (at 0.3Hz) Single pulse TMS on left dorsolateral prefrontal cortex (DLPFC) and left primary motor cortex (M1) in trains of 100 pulses (at 0.3Hz) Motor thresholds (MTs) measured using EMG, stimulus trains applied with intensities 90%, 100%, and 110% MT in randomized order Motor thresholds (MTs) measured using EMG, stimulus trains applied with intensities 90%, 100%, and 110% MT in randomized order

Data analysis Responses averaged for every stimulation condition Responses averaged for every stimulation condition Pools of 4-6 electrodes created for 8 regions of interest: Pools of 4-6 electrodes created for 8 regions of interest: left and right hemisphere prefrontal cortex (LPFC & RPFC), motor cortex (LMC & RMC), temporal cortex (LTC & RTC), and parietal cortex (LPC & RPC)

Results In all groups, the same peaks were identified in the TMS–evoked EEG responses. In all groups, the same peaks were identified in the TMS–evoked EEG responses. Statistically significant differences between the groups in peak amplitudes and latencies were observed in all time ranges, especially P30 and N100 deflections, and later in P200, P300, and the ms time range mean amplitude. Statistically significant differences between the groups in peak amplitudes and latencies were observed in all time ranges, especially P30 and N100 deflections, and later in P200, P300, and the ms time range mean amplitude.

Controls vs patients, 90% MT

Results Differences in the earlier deflections were mostly seen in the frontal areas. Differences in the earlier deflections were mostly seen in the frontal areas.

Recovered vs symptomatic P30-N100

Results Differences in the late (P300, ms mean amplitude) time range were most pronounced in the temporal and parietal electrodes. Differences in the late (P300, ms mean amplitude) time range were most pronounced in the temporal and parietal electrodes.

Controls vs patients ms

Results Patients in the symptomatic group were found to miss one or more of the normally appearing peaks more often than controls (p = 0.024). Patients in the symptomatic group were found to miss one or more of the normally appearing peaks more often than controls (p = 0.024). Control Symptomatic mTBI

Recovered vs symptomatic, 90% MT

Recovered vs symptomatic N100-P200 deflection

1 symptomatic 1 2 recovered 2 3 control 3 Group centroid Function 1 Function 2 Stepwise linear discriminant analysis of all three groups: 85.7% correctly grouped. Variables included: DLPFC 90% MT right parietal and right prefrontal P30 amplitudes, M1 90% MT left temporal P300 amplitude, and DLPFC 110% MT right prefrontal N100 amplitude.

Conclusions Based on current knowledge, interpretation of the observed changes seen is uncertain: – P30: may be related to an early spreading of activation to functionally connected areas (longer latencies in the symptomatic subjects) – N100: thought to reflect a cortical inhibitory process triggered by TMS (more negative in the symptomatic group on prefrontal areas) – P300 and later: current knowledge very limited, higher cognitive processes? (consistently lowest in the symptomatic subjects)

Conclusions A validated combination of TMS-evoked EEG responses could be valuable in separating mTBI subjects from controls and recovered mTBI subjects from those with chronic sequels (LDA of the two patient groups with three best variables grouped correctly 100% of cases) A validated combination of TMS-evoked EEG responses could be valuable in separating mTBI subjects from controls and recovered mTBI subjects from those with chronic sequels (LDA of the two patient groups with three best variables grouped correctly 100% of cases)