TMS can assess and modulate different physiologic processes in the brain. Specifically, TMS can measure cortical excitability, intracortical inhibitory and excitatory mechanisms, and local and network cortical plasticity. Furthermore, if coupled with functional and electrophysiological modalities, TMS can provide valuable insights into the processes of the brain in health and disease. In particular, TMS may elucidate the mechanisms underlying healthy neurodevelopment and aging, as well as neuropsychiatric pathology.
If one builds on a conceptual paradigm in which changes in E/I balance and brain plasticity are the ultimate result of the interaction between genes and environment, then measuring those changes may provide extraordinary insight into how the brain may initiate and compensate for pathology. If so, defining and measuring characteristic ‘TMS-related endophenotypes’ for distinct neuropsychiatric disorders may thus provide valuable biomarkers of disease. For instance, if the specific pattern of findings from Pascual-Leone's lab and others [e.g., (59
)] prove to be specific to schizophrenia, diminished cortical plasticity might be a biological marker for schizophrenia, and a progressive reduction of plasticity during developmental years may even be a predictor of disease, as those results were obtained in first-episode, early-onset, unmedicated schizophrenia patients. Moreover, early-life deficits in the mechanisms of LTP/LTD, which are considered molecular correlates of learning and memory (and can be induced by TBS), may originate and underlie the impairments in higher cognitive functioning observed in schizophrenia patients not only at the time of first episode (77
) but even long before illness onset (78
). Ultimately, abnormal changes in plasticity mechanisms may be the proximal cause of schizophrenia.
Furthermore, TMS—using TBS protocols coupled with EEG, for instance—can measure the efficiency of plasticity mechanisms in a given cortical region and network dynamics in functionally connected regions (16
). Of critical interest is the assessment of plasticity dynamics of the prefrontal circuitry for its involvement in working memory and abstraction abilities, profoundly disrupted in schizophrenia [e.g., (79
)], and of the prefrontal-temporal limbic network, involved in verbal episodic memory and disrupted in both schizophrenia patients and their relatives [e.g., (80
)]. Thus, defining biomarkers and predictors of schizophrenia, and other neuropsychiatric disorders, based on this TMS methodology appears to be a promising strategy for future research and diagnostics in schizophrenia, and ultimately for novel plasticity-based interventions.
In a broader perspective, it seems possible to define novel or support existent endophenotypes of schizophrenia using sophisticated investigations with TMS. Neurophysiologic and neurocognitive endophenotypes selected by the Consortium on the Genetics of Schizophrenia (COGS) (82
) included measures of inhibitory deficits (P50 suppression, prepulse inhibition, and oculomotor, saccadic control) and of various cognitive impairments (e.g., continuous performance tests for sustained attention, letter-number span for working memory). All of these have shown significant associations with functional status and outcome. It is easily envisioned how TMS measures of cortical excitability and plasticity are potential candidates to add to such list. Importantly, and consistent with criteria emphasized by Braff et al. (82
), measures of TMS can be (a) “state-independent” (i.e., impairments in cortical inhibition and plasticity do not seem to be due to medications, as they were found in drug-naïve patients; such impairments are observed regardless of illness state, as deficits seem to be present already at first-episode), and might be (b) altered also in “close non-affected biological relatives” (e.g., cortical inhibition deficits in non-psychotic first-degree relatives of schizophrenia patients have been reported). To date, no TMS studies on affected first-degree relatives (e.g., affected twins or affected offspring of schizophrenia parents) have been reported, and would certainly be desirable. Unquestionably, in order to apply a TMS-driven “endophenotype strategy” to schizophrenia, objectively and reliably, large samples of patients and genetic high-risk subjects are crucial, and multisite collaborations would be most advantageous.