A research group from the University of Bologna has succeeded in modifying the negative effect of a returning memory that triggers fear, and developed a new non-invasive experimental protocol.
The result of this study, published in the journal Current Biology, is an innovative protocol that combines fear conditioning – a stimulus associated with something unpleasant that induces a negative memory – and the neurostimulation of a specific site of the prefrontal cortex.
This process alters the perception of an unpleasant (aversive) event so that it will no longer induce fear.
“This experimental protocol combining transcranial stimulation and memory reconsolidation allowed us to modify an aversive memory that the participants had learned the day before,” explains Sara Borgomaneri, a researcher at the University of Bologna and first author of the study.
“This result has relevant repercussions for understanding how memory works. It might even lead to the development of new therapies to deal with traumatic memories.”
Can memories be altered?
The primary focus of the research group is the process of reconsolidation. This process maintains, strengthens and alters those events that are already stored in long-term memory.
“Every time an event is recalled in our memory, there is a limited period of time in which it can be altered,” explains Simone Battaglia, researcher and co-author of this study.
“The protocol we developed exploits this short time window and can, therefore, interfere with the reconsolidation process of learned aversive memories.”
Researchers used TMS (Transcranial Magnetic Stimulation) to “erase” the fear induced by a negative memory.
With an electromagnetic coil placed on the head of the participant, TMS creates magnetic fields that can alter the neural activity of specific brain areas.
TMS is a non-invasive procedure that does not require surgery or any action on the participant and for this reason, is widespread in research as well as in clinic and rehabilitation programs.
“With TMS, we could alter the functioning of the prefrontal cortex, which proved to be fundamental in the reconsolidation process of aversive memories,” says Sara Borgomaneri. “Thanks to this procedure, we obtained results that, until now, were only possible by delivering drugs to patients.”
The research group developed this protocol through a trial involving 98 healthy people. Every participant had learned an aversive memory and the next day underwent a TMS session over the prefrontal cortex.
“First, we created the aversive memory by combining an unpleasant stimulation with some images,” explains Borgomaneri. “The day after, we presented a group of participants with the same stimulus, which, in their memory, was recorded as aversive.
Using TMS immediately afterwards, we interfered with their prefrontal cortex activity.”
To test the effectiveness of the protocol, other groups of participants underwent TMS without their aversive memory to be recalled (no reconsolidation was triggered), and some other groups were stimulated with TMS in control brain areas, not involved in memory reconsolidation.
At that point, the only thing left to do for researchers was to evaluate the effectiveness of TMS. They waited for another day and once again tested how the participants reacted when the aversive memory was recalled.
And they obtained encouraging results. Participants who had their prefrontal cortex activity inhibited by TMS showed a reduced psychophysiological response to the unpleasant stimulus.
They remembered the event (explicit memory) but its negative effect was substantially reduced.
“This trial showed that it is feasible to alter the persistence of potentially traumatic memories. This may have crucial repercussions in the fields of rehabilitation and clinical medicine,” says Professor Giuseppe di Pellegrino, who coordinated the study.
“We’re dealing with a new technique that can be employed in different contexts and can assume a variety of functions, starting from treating PTSD, which will be the focus of our next study.”
The experiment was carried out by the center for studies and research in Cognitive Neuroscience at the Department of Psychology in the Cesena Campus of the University of Bologna.
The journal Current Biology published the results of this experiment in a paper called “State-dependent TMS over prefrontal cortex disrupts fear memory reconsolidation and prevents the return of fear.”
Pain is the most frequent reason why people seek medical attention worldwide.1-3
Chronic pain is present in 28% to 50% of the general population and is responsible for a large amount of health-related costs.4-7
Despite the availability of a large number of therapeutic options, up to 30% of patients with chronic pain remain symp- tomatic despite best medical treatment.8
For example, up to 40% of patients with neuropathic pain (NeP) are pharmacoresistant.9 In fibromyalgia, relief after the use of first-line treatments rarely
achieves ->35% to 45% pain reduction.10 Recently, different new treatment approaches have emerged to try to fill in these gaps, including drugs and interventions with novel mechanisms of ac- tion. Among them, neuromodulatory techniques have been the most broadly explored in patients with chronic pain.
Neuromodulation is defined as a treatment (drug or procedure) that potentiates or inhibits the transmission of nerve signals, but it is not the actual means of transmission itself.11
Under this broad defi- nition, many medical and nonmedical interventions can be catego- rized as neuromodulatory, and the classification of the different neuromodulatory techniques varies. One frequently used approach is to name the nervous structure that is targeted (eg, peripheral nerves, spinal cord, cortex) and then sort the techniques into invasive and noninvasive.
Therefore, noninvasive cortical stimulation refers to the transcranial stimulation of cortical structures, which can be achieved by different methods.
Transcranial magnetic stimulation (TMS) is the technique most frequently studied in chronic pain.
It is a noninvasive method that enables the stimulation of specific cortical areas by an electric current induced by a coil placed on the scalp: a rapidly varying electric current (1ms) flows through a wiring system (inside a coil) and creates an electromagnetic field, which creates an induced electric current a few centimeters away from the coil inside the brain parenchyma.
This focused (affects approximately 5mm3 of the brain cortex) electric current may depolarize neurons and create evoked responses (ie, muscle twitches, phosphenes) or change neuronal plasticity (even when performed in intensities below the neuronal depolarization threshold).
Barker et al12 first described TMS in 1985 as a method to noninvasively obtain motor-evoked potentials. In the early 1990s, technical improvements allowed for the performance of repetitive pulses of TMS, called repetitive transcranial magnetic stimulation (rTMS).
The first studies on rTMS showed that repetitive pulses of stimulation to the cortical areas were able to produce local changes that outlasted the stimulation period.13,14 These first experiments were followed by the first clinical trials on the use of rTMS on the dorsolateral prefrontal cortex (DLPFC) to treat major depression.15,16 Currently, rTMS is approved for this indication in several countries.
The effects of rTMS have been examined in the treatment of other neuropsychiatric conditions (eg, chronic pain, tinnitus, obsessive compulsive disorder, movement disorders).17
The idea of using rTMS to treat chronic pain derived from the efficacy of implanted electrical stimulation of the motor cortex to treat re-fractory NeP, which was reported by Tsubokawa et al18 in 1991.
Accordingly, the first studies using rTMS in patients with NeP tested the value of this technique in predicting the effects of the implanted surgical stimulation of the precentral gyrus.19,20
From these seminal studies, it was demonstrated that a single session of rTMS can decrease the intensity of NeP for a few days after stimulation, suggesting that TMS could be a tool used not only to predict the long-term effects of surgery but also to relieve chronic pain per se.21
Mechanisms of action of cortical stimulation in pain
Studies on the mechanisms of action of rTMS on pain in animals and patients are scarce, and most of the available data involve experimental pain studies in healthy volunteers.63-66 Another rich source of information comes from studies on implanted epidural precentral gyrus stimulation in patients and animals under experimental pain models.
Implanted epidural stimulation is a different technique from rTMS. However, the available evidence suggests that both techniques may share common analgesic mechanisms under certain stimulation parameters.63-65,67-72
In healthy subjects, high-frequency unilateral rTMS of the hand area of the M1 induces a bilateral increase in pain thresh- olds,69 and its analgesic effects depend on endogenous opioid systems, as indicated by the fact that they are significantly reduced after the blockade of m-opioid receptors by naloxone.63
Similar analgesic effects have been reported after stimulation of the DLPFC,63,65,73 but these effects most likely depend, at least in part, on different mechanisms because they were not changed after the administration of naloxone.63
There is a large body of evidence suggesting that the stimu- lation of the M1 and prefrontal cortex activates distant brain areas that are implicated in the integration of painful information and its modulation.74
Electrophysiological studies have shown that motor cortex stimulation has inhibitory effects on thalamic and spinal nociceptive neurons.71 Neuroimaging studies in patients with NeP75 under epidural electrical stimulation of the motor cortex showed that stimulation of the M1 induced an increase in cerebral blood flow in distant brain areas (eg, lateral and medial thalamus, anterior cingulate cortex, insula, brain stem).65,67,68,70
It has also been demonstrated that chronic M1 stimulation by epidurally implanted electrodes decreases the availability of opioid receptors in the anterior middle cingulate cortex and the periaqueductal gray (PAG) and that the magnitude of pain reduction correlated with changes in the availability of m-opioid receptors in these areas,65 further corroborating the idea that the analgesic effects of M1 stimulation depend on the release of endogenous opioids. Most animal studies have confirmed these observations.
Rats receiving electrical transdural M1 stimulation showed homotopic analgesia (ie, in the body region topographically related to the cortical target stimulated in the M1). These anal- gesic effects were also dependent on the availability of m-opioid receptors because they were blocked by naloxone.69
In a recent study, it was shown that motor cortex stimulation decreased thalamic activity bilaterally, affecting both the ipsilateral lateral thalamus and medial thalamic nuclei in naıve rats. It was also shown that increased PAG activity induced by motor cortex stimulation was associated with a local decrease in GABA activity.76,77
The PAG has limited direct projections to the spinal cord and modulates nociceptive inputs through its connections with the rostral ventral medulla, which in turn projects to the dorsal horn of the spinal cord as part of the descending pain modulation system.78 Glutamate and specific N-methyl-D-aspar- tate (NMDA) receptor ligands produce analgesia when applied to the ventrolateral PAG.79,80
Therefore, both the activation of the PAG via glutamate/ NMDA agonists and the disinhibition produced by GABA blockade/opioid receptors activation may lead to antinociceptive modulation of spinal pain inputs.
Consistent with this hypothesis, it has been shown that the blockade of NMDA receptors by ketamine induces a significant decrease in the analgesic effects of both the prefrontal cortex/premotor cortex and M1 stimulation.66
This result suggests that the analgesic effects induced by the stimulation of the 2 cortical sites most likely depends on a common final pathway. Other cortical targets have been used less frequently in chronic pain studies, and their putative mechanisms of analgesia remain largely unknown.
In the last decade, the effects of rTMS on facilitatory and inhibitory cortical circuits have been assessed noninvasively in patients with chronic pain using TMS as a neurophysiological tool. It has been shown that chronic pain patients with fibromyalgia,48 NeP,45,81 and CRPS82 have altered cortical excitability.
There are several cortical excitability parameters that can be measured noninvasively with TMS. In general, these measurements are obtained by the stimulation of the motor cortex and are derived from motorevoked potentials elicited by single-, double-, or triple-stimulation paradigms.83
Interestingly, chronic pain is associated with changes in these parameters, which can be modulated and restored toward normalization after rTMS. For instance, short-interval intracortical inhibition is a paired-pulse measure that depends on the function of GABA A interneuronal networks in the motor cortex84 and has been shown to be defective in patients with fibromyalgia and NeP.48,81
The degree of correction of altered intracortical inhibition after therapeutic rTMS correlates with pain improvement during long-term main- tenance rTMS sessions.31 Despite positive reports, it is currently unknown how specific cortical excitability changes are to differ- entiate between chronic pain syndromes.85 However, these mea- surements may also have a potential use in patients with chronic pain, in whom biologic markers of the presence of pain, its severity, and it prognostication are often scarce.
Analgesic effects of rTMS according to stimulation parameters
The analgesic effects of rTMS depend on a large number of var- iables, called stimulation parameters, which differ between studies, and may explain part of the variability in efficacy found across trials. We subsequently provide a review of the available evidence for each stimulation parameter and its effect on pain relief.
The M1 has been the target most frequently assessed in nonin- vasive and implanted cortical stimulation studies in chronic pain. In patients with NeP, it has been suggested that the location of pain in the body may influence the analgesic efficacy of TMS. Additionally, the use of regular coils and targeting techniques has resulted in better accuracy in targeting certain cortical areas (eg, hand and face M1 area) compared with others (eg, foot M1 area).86,87
However, there is a solid rationale for targeting other cortical areas (eg, prefrontal cortex) for pain relief. The DLPFC is a frequent cortical target used in major depression studies because its use in the treatment of mood disorders is safe and effective.88
Studies in healthy volunteers have shown that high-frequency rTMS to the right DLPFC was able to trigger analgesic effects similar to M1 stimulation, despite differences in their mechanisms of action.63
The left prefrontal cortex has also been used in rTMS studies in patients with fibromyalgia, but it has shown a small analgesic effect.89 Despite these potential uses, only 1 study has directly compared the analgesic effects of the different cortical targets on clinical pain; however, the prefrontal cortex was not included in this report.90
It has been shown that 5Hz stimulation of the M1 (500 pulses) provided pain relief of 30% in half of patients with NeP for up to 3 hours after the end of stimulation, an effect that was not found after primary sensory and premotor cortex stimulation. To date, only 3 studies have targeted the prefrontal cortex.
They assessed pain relief in different populations and using different stimulation parameters. Although a single session of prefrontal cortex TMS decreased morphine use in the post- operative setting,37 10 daily stimulations had a minor effect on fibromyalgia pain and its associated clinical features89 and provided negative results in central poststroke pain.91
The secondary sensory cortex was also targeted in a study on visceral pain and was shown to have a significant analgesic effect.32
Neuronavigation-guided rTMS allows for the targeting of cortical areas and the detection of deviations from the target during stimulation sessions with high accuracy.
Two groups used neuronavigation-guided rTMS for pain relief by targeting the M1.90,92,93 The actual benefits of using neuronavigation for M1 stimulation has never been directly assessed in studies on chronic pain, but this technique is promising for targeting deeper cerebral structures93 and the prefrontal cortex in a systematic way.94
University of Bologna