Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: a systematic review

To summarize the results, we can state that high-frequency rTMS (10–20 Hz) is most likely to cause significant cognitive improvement when applied over the left (dorsolateral) prefrontal cortex, within a range of 10–15 successive sessions and an individual motor threshold between 80 and 110%. Regarding the analyses of clinical status and stimulation condition concerning the efficacy of rTMS, the clinical group is superior to the non-clinical group and verum stimulation is in general superior to sham stimulation. All in all, many studies failed to demonstrate significant cognitive effects, but they could show trends toward selective cognitive improvements. In comparison with studies using 1-Hz stimulation, high-frequency studies seem to be superior concerning the cognitive outcome. However, the evaluation is limited due to partly methodological differences between and within studies or to the marginal number of low-frequency studies. General limitations concern the absence of healthy control groups as well as sham conditions to some extent. Important to note is the marginal number of studies using functional imaging and integrating follow-up measures for the exploration of long-term effects. The relative high number of studies giving evidence of placebo or practice effects requires future amendment of control conditions. There are discrepancies concerning the onsets of cognitive testing after rTMS administration being substantially relevant for the outcome. Therefore, results seem to be inconsistent throughout the literature and the particular biological mechanism of rTMS for cognitive improvement seems to be questionable until the underlying pathophysiology remains unclear. We do not know how long the effects of rTMS on cognitive function will persist. Studies investigating systematically the duration of the induced cognitive effects are lacking, but one can assume, based on the remaining effects on psychopathology (e.g. improvement of mood), that also the cognitive improvement will persist for a certain period of time. Future work is needed to systematically investigate the impact of different test onsets after rTMS application.

It should also be further addressed that the correct positioning of the coil is important for the effects of rTMS. Most of the studies used the method of Pascual-Leone (placing the coil 5 cm rostrally from the hot spot of primary motor cortex) to identify the DLPCF or localized the left DLPFC by the 10-20 EEG-system. While recent studies on neuronavigation for TMS have shown that stereotactically neuronavigated TMS results in stronger and more robust TMS effects, neuronavigation may be important for inducing long-lasting cognitive improvement. For example, one study demonstrated a systematic difference in the behavioral effect size due to the way of localization. Individual fMRI-guided TMS neuronavigation yielded the strongest and the 10-20 EEG-system stimulation approach the smallest behavioral effect size (Sack et al. 2009). There was a nearly tenfold increase in the needed number of probands to induce the same behavioral effect when using the 10-20 system compared to fMRI-guided neuronavigation. In addition, a previous study demonstrated clearly that in most cases the DLPFC was not targeted correctly when compared to the commonly used method of Pascual-Leone with neuronavigated coil positioning (Herwig et al. 2001).

To discuss the effect of rTMS on attention, one has to consider the different elements that build attentional processes. A basal part of attention is the alertness, which is generally separated in tonic alertness, representing the enduring alert state over the day, and phasic alertness, implying the temporary enhancement of this state due to an internal or external stimulus (Posner 1975). The maintenance of concentration over a longer period of time under monotonous stimulus conditions is called sustained attention (Davies et al. 1984), whereas divided attention is commonly characterized by keeping on line two or more currently relevant (classes of) stimuli or mental operations at the same time. Therefore, divided attention requires the simultaneous monitoring of different information channels to quickly detect relevant events and to execute actions according to the actual demand (Posner and Boies 1971). The essential function of selective or focused attention is the selection of a particular subset of the available stimuli for preferential processing and, consequently, the simultaneous suppression of currently irrelevant information (Kinchla 1992). Important to note is that the concept of divided and selective attention is closely connected to the concept of executive functions. The studies reviewed in our work mainly found improvements in selective and sustained attention, not in alertness. The concept of executive function describes higher cognitive processes like problem solving, mental planning, initiation and inhibition of behavior as well as action control. The main function of the executive system is monitoring cognitive (sub-) processes and their flexible dynamic regulation due to changing environments. Such adaptive behavior necessitates a flexible mind, which maintains and updates currently relevant information and exerts top–down control over the perception of incoming information and execution of outgoing behavior. This control is most commonly associated with the anterior pole of the brain, the prefrontal cortex (PFC) (Fuster 1987; Miller and Cohen 2001; Chao and Knight 1995). For successfully using executive control the ability of dynamic attentional shifting is necessary. Working memory consists of the short-term storage of incoming information and a set of executive processes. Short-term storage involves the active maintenance of a limited amount of information for a matter of seconds and is a necessary component of many higher cognitive functions mediated in part by the prefrontal cortex (PFC). The executive component implies the mental manipulation of maintained information (Carpenter et al. 1990; Fuster 1987; Goldmann-Rakic (1997); Stuss and Benson 1986). Therefore, working memory is often operationalized by continuous performance tasks requiring the permanent maintenance and manipulation of incoming information. As executive function and working memory were attributed to prefrontal cortex, one could expect a significant influence of rTMS on these cognitive domains. Nevertheless, the presented studies do not exhibit high significances. They mainly report on improvements in “working memory”, “cognitive flexibility” or “verbal fluency”, but there are no effects in problem solving, planning or reasoning. Maybe such higher cognitions require too specific modulations of activity than they could be effectively modified by rTMS. We do not know whether executive improvements underlie alterations in basic functions like attention or concentration.

Concerning the learning and memory section, memory refers to intermediate- and long-term storage of information and has to be distinguished from short-term storage or working memory described above. It contains the encoding, consolidation and retention of verbal and nonverbal material. Therefore, tasks used are requiring the immediate and delayed free recall or cued recognition of information. With regard to the well known memory complaints after electroconvulsive therapy (ECT), it is important to note that no marked memory deficits have been found after rTMS. In addition to this outcome beneficial therapeutic (e.g. antidepressant) effects have been the consequence. RTMS (compared to ECT) seems to be a more sensitive technique while exhibiting therapeutic and even improving cognitive effects.

Psychomotor speed/processing speed describes the time a person needs to process incoming stimuli and to adequately react to them or initiate behavior, e. g. connecting numbers as fast as possible in ascending order. Only a few studies indicate significant increase in processing/motor speed when measured solely.

All in all, there are inconsistencies between results that may be attributed to differences in methodology (e.g. stimulation protocols, number of sessions, for details see, Table 1) or sample constitution. Missing statistical power in some cases may be due to marginal psychometric test properties. The evaluation of results is difficult on account of the sometimes overlapping contents of cognitive domains.

Regarding the differential rTMS effects throughout the literature, evidence is growing about the modification of cerebral blood flow, glucose metabolism and neuronal excitability in the stimulated area as well as in interconnected brain regions (Conca et al. 2002; Fox et al. 1997). Moreover, short-/long-term potentiation of synapses and rapid dynamic alterations in gray matter (GM) density are reported (Esser et al. 2006; May et al. 2007). The latter result resembles structural changes in normal learning mechanisms that could be triggered by high-frequency rTMS pulses. The reported dynamic shift of gray matter density after about 5 days of stimulation is attended by clinical ameliorations within the same time. The occurrence of structural alterations mirrored by changes in functional processing exemplifies structural neuroplasticity as a counterpart of function. Furthermore, there is a large body of literature suggesting an association of hypofrontality in schizophrenia with negative symptoms and cognitive deficits (Dolan et al. 1993; George and Belmaker 2000; Weinberger et al. 1988). High-frequency rTMS (especially at 10 Hz) seems to be a promising technique to improve such negative symptoms (Hajak et al. 2004; Cordes et al. 2005; Jin et al. 2006). Consequently, high-frequency rTMS can be suggested to be able to evoke improvements in both negative symptoms and cognition. The herein reviewed rTMS studies assessing cognition in schizophrenia did not show convincing effects toward a cognitive improvement. Additionally, it remains unclear whether structural changes, alterations in metabolism or neurotransmission under the stimulated area or in the connected neuronal network (or the combination of all) may produce behavioral outcomes (e.g. May et al. 2007; Strafella et al. 2001). Regarding the stimulation location (PFC) one could expect improvements in most of the abovementioned cognitive functions, because they all underlie (at least in part) this area. Nevertheless, the results of the studies do not exhibit such consistent pattern.

The mechanism how rTMS may lead to an improvement of cognitive function is rather complex and raises some difficulties in interpretation. TMS-induced enhancement of performance might be the result of the excitation of a functionally relevant task-supporting activation, the excitation of an area that inhibits competing functions, the inhibition of an area that suppresses the execution of the task, or the inhibition of an area that promotes competing functions (Sack and Linden 2003). This is complicated by the fact that the same stimulation pattern (e.g. suprathreshold rTMS with 10 Hz) could lead to different effects on cerebral blood flow depending on the stimulation site (e.g. increase when stimulating the frontal eye field and decrease during rTMS of the primary motor cortex) (Sack and Linden 2003). The effects of rTMS also depend on the history of synaptic activity in the stimulated region. For example, if 6-Hz rTMS is applied for a short period (below the threshold for any lasting after-effects), then the suppressive effect of a subsequent period of 1-Hz rTMS is enhanced (Ridding and Rothwell 2007). Generally, a prior history of increased activity seems to increase the effectiveness of rTMS protocols that decrease excitability, whereas a prior history of reduced activity increases the effect of facilitatory rTMS.

Further differential investigations are necessary to expand knowledge of rTMS functioning and the underlying biological mechanisms by linking structural and functional imaging data (including spectroscopy data) with behavioral outcome variables. For a detailed analysis of functional cerebral alterations, the rTMS procedure could be conducted during fMRI-scanning. Such a simultaneous approach provides the opportunity to investigate the local response to TMS at a neurophysiological level with high spatial resolution, thus helping to determine in vivo the brain areas that are directly or transsynaptically affected by TMS. Nevertheless using fMRI tends to create also problems with interpretation; for example, whether changes in perfusion or BOLD signal reflect changes in excitatory, inhibitory or combined neural activity.

An interesting topic in this context could also be to evaluate and compare the contrast of brain alterations and differences in activated neuronal networks in diseased and healthy people to explore different coping strategies. All in all, investigations have to prove the efficacy of rTMS in randomized sham-controlled trials with higher statistical power using larger sample sizes and improved methodology. This may even become more interesting while stimulation protocols inducing longer-lasting effects like theta-burst stimulation (TBS) have been developed. Currently studies are underway to test these TBS in terms of affecting not only motor response, but also cognition.