Also, there was a difference in frontal beta power for No-Think trials without intrusions vs. Yet we warrant that the relation to forgetting is indirect here and future research is needed to better flesh out whether the right frontal signature relates to this.
A second explanation for how the putative prefrontal stopping process relates to forgetting is that it reflects a prefrontal shut-down of the medial temporal lobe, reviewed by Anderson et al. On this view, whereas action-stopping putatively requires a right lateral PFC-basal-ganglia-M1 network, a memory-stopping system putatively requires a right lateral PFC-MTL network; different modes, but a common frontal signature. This account may be testable by showing that changes in the prefrontal beta signature perhaps induced by brain stimulation triggers changes in medial temporal lobe activity recorded with fMRI or LFPs.
A final possibility is that the prefrontally-mediated stop process controls the entrance of retrieved contents into working memory c. Badre and Wagner Scimeca and Badre For example, during No-Think trials, this process may operate via the basal ganglia in a way that impacts a thalamocortical retrieval process see, e.
On this view, when the cue occurs on No-Think trials, pattern completion via the medial temporal lobe begins for the target, but this has to then trigger reinstatement in neocortex to achieve recollection. The stopping process may interfere with this latter reinstatement aspect of retrieval. We note that whereas this explains how intrusions might be prevented, it is not clear how this would explain SIF.
These accounts of how stopping processes may prevent recall are not mutually exclusive, and successful control of retrieval may entail stopping at various points in the retrieval process. Whereas the study confirmed most of our pre-registered predictions, some findings were not expected. First, on the behavioral level, whereas several studies have found a relationship between the ability to reduce intrusions over repeated suppression attempts and later suppression-induced forgetting Levy and Anderson ; Hellerstedt et al.
It is unclear why this relationship was not found. As noted in the preceding discussion, however, recall can be stopped by interrupting mechanisms at any stage of the retrieval process, only some of which, when stopped, may give rise to forgetting.
One speculation is that if intrusions are sometimes controlled in ways that do not require hippocampal suppression, this relationship between intrusion control and forgetting may not emerge.
This possibility may also account for why the ability to reduce intrusions over blocks was not correlated with the frontal beta component. On the Same Probe test, there was no facilitation for Think items, and on the independent probe test, recall performance for Think items was actually below baseline. One factor likely to have contributed to the lack of facilitation on the Same Probe test is the near ceiling level performance observed on that test, and the consequent reduction in sensitivity to the benefits of retrieval during Think trials.
The reduced recall for Think items on the Independent Probe test has also been observed in other studies with this paradigm e. This effect has been attributed to encoding specificity effects driven by the repeated retrieval of No-Think items in response to studied cues see, e.
Finally, we note that, as in previous studies of action-stopping Wagner et al. We suppose this owes to differences in cortical folding which is known to affect the detection of the local field potential Luck In any event, our pre-registered study plan had anticipated such attrition, and adjusted for it, and we here analyzed 41 participants with a right frontal component, very close to our planned sample size of In conclusion, we show that the requirement to prevent a thought from coming to mind quickly recruits a similar EEG signature as stopping action.
This EEG signature — a right frontal beta band increase that occurs within ms — could be a specific neural marker of stopping via right lateral prefrontal recruitment perhaps specifically the rIFC , and also from basal ganglia Aron et al.
Building this link to action-stopping opens the prospect of leveraging the substantial across-species knowledge of the neural basis of stopping Schall and Godlove ; Bari and Robbins ; Jahanshahi et al. National Center for Biotechnology Information , U. Cereb Cortex. Published online Feb Author information Article notes Copyright and License information Disclaimer.
Address correspondence to Dr Adam R. Email: ude. Published by Oxford University Press. This article has been cited by other articles in PMC. Abstract In the stop-signal task, an electrophysiological signature of action-stopping is increased early right frontal beta band power for successful vs. Introduction The stop signal paradigm has been used to isolate the cognitive and neural mechanisms that enable people to cancel action Logan and Cowan ; Verbruggen and Logan Methods Participants Our pre-registered study plan aimed for a sample size of 42 participants.
Open in a separate window. Figure 1. Learning Phase 1 Participants learned 66 weakly related word-pairs that were taken from the University of South Florida word association norms Nelson et al.
EEG Analysis The specific planned analyses described below were pre-registered. Preparing the Independent Components Analysis We adhere to the exact approach intended in the pre-registered document, and which has been described in detail in our earlier publication, and for which we here provide scripts Wagner et al.
Figure 2. For the IC cluster with the dorsomedial topography 2 analyses were run: The stop signal task. Other Planned Analyses We planned to test whether the change in intrusion ratings across time in phase 2 related to the stopping process.
Figure 3. Stop Signal Task The metrics were typical for healthy young participants. Figure 4. Figure 5. Discussion Prior work has established a distinctive right frontal beta signature that relates to successful action stopping. We warrant, however, that further research is needed to confirm this — for example, using causal approaches such as Transcranial Magnetic Stimulation The logic of the 2-task ICA approach we used here is as follows and see Wessel Footnotes Conflict of Interest : None declared.
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Thus, innovation and creativity involve forward thinking. The regular critical thinking involves identifying and explaining the effect whereas forward thinking is concerned with bringing about an effect. Suspended judgement is a prerequiste for forward thinking. One has to suspend all judgment of ideas and concepts. One is allowed to be wrong on the way even though one must be right in the end. In lateral thinking judgment is delayed during the generative state of thinking in order to be applied during the selective stage.
The purpose of thinking is not to be right but to be effective. Being effective does eventually involve being right but there is a very important difference between the two. Being right means being right all the time. Being effective means being right only at the end As a process, lateral thinking is concerned with change not with proof.
The emphasis is shifted from the validity of a particular pattern to the usefulness of that pattern in generating new patterns. Design is used as practice for lateral thinking. In so far as it is not just a matter of copying, design requires a good deal of innovation. The emphasis is on the different ways of doing things, the different ways of looking at things and the escape from clich concepts, the challenging of assumptions.
Unlike analysis, with the help of we break down a complex and unknown situation into small pieces and synthesis, through which we creates a new combination of these elements, the design puts forward a key requirement, and then, when executed, establishes new necessary relationships between the elements. In military terms, in the first case we advance evenly on all fronts, and in the second we deal a concentrated blow and then throw troops into the breakthrough.
Unless one can convert a vague awareness to a definite pattern it is extremely difficult to generate alternative patterns, alternative ways of looking at the situation. One can more easily escape from something definite than from something vague. Liberation from rigid patterns and the generation of alternative patterns are the aims of lateral thinking.
Both processes are made much easier if one can pick out the dominant idea. If one cannot pick out the dominant idea then any alternatives one generates are likely to be imprisoned within that vague general idea. It is only when one becomes aware of the framework that one can generate an alternative point of view outside of it.
The crucial factor restricts the way the problem is looked at. Again, each individual with a different perspective may come up with a different crucial factor. The aim of lateral thinking is to look at things in different ways, to restructure patterns, to generate alternatives. The mere intention of generating alternatives is sometimes sufficient. This technique is very similar to analysis. Fractionation deals with completely breaking down of the situation into its components.
However, lateral thinking uses this fractionation to provide material, which can be used to stimulate restructuring of the original situation. Wherever a direction is indicated then the opposite direction is equally well defined.
Whenever there is a one way relationship between two parties, the situation can be reversed by changing the direction of this relationship. In the reversal method one takes things as they are and then turns them round, inside out, upside down, back to front. Then one sees what happens. It is a provocative rearrangement of information. You make water run uphill instead of downhill.
Instead of driving a car the car leads you. Therefore, the reversal method allows one to escape from looking at at the situation in the standard way. Also, by disrupting the original way of looking at a situation one frees information that can come together in a new way. Finally, the main purpose is provocative. By making the reversal one moves to a new position. Brainstorming is a formal setting for the use of lateral thinking. The main features of brainstorming are: 1.
Cross stimulation. Deferred judgment. Formality of the situation. Analogies are used to provide movement. In itself an analogy is a simple story or situation. It becomes an analogy only when it is compared to something else.
The problem under consideration is related to the analogy and then the analogy is developed along its own lines of development. At each stage the development is transferred back to the original problem. Thus the problem is carried along with the analogy. What is happening in the analogy is transferred as a process or relationship to the actual problem.
Unlike its use in argument, analogy in lateral thinking is not to prove anything. They are simply used like all other lateral thinking techniques; to generate further ideas.
Analogies are used as a method for generating further ideas. Instead of tryting to work form within the idea one can deliberately generate external stimulation, which then acts on the idea from outside. This is called random stimulation. With random stimulation, one uses any information whatsoever. No matter how unrelated it may be no information is rejected as useless. The more irrelevant the information the more useful it may be.
The following points may serve to illustrate the way random stimulation can be used. Accepting and even welcoming random inputs. Instead of shutting out something which does not appear relevant one regards it as a random input and pays it attention. Exposure to the ideas of others. We simply do not know enough about the basic underlying causes of these terrible diseases or how to predict and monitor their progression, to have all of the tools we need to develop treatments to fight, or better yet, cure them.
While these challenges are significant and cannot be ignored, they have not stopped FDA, and they do not mean progress is impossible. I would like to emphasize two points. First, making progress on expanding our basic, scientific understanding of neurodegenerative diseases is absolutely critical to making progress on developing treatments.
Comparisons are often made to the amazing advancements that we have made in treatments for cancer and HIV. While these advancements are stunning, these were made possible by a deep understanding of the underlying disease processes. For example, the discovery of specific molecular defects in different types of cancer has led to drugs specifically targeting these defects — and has resulted in numerous, targeted novel drugs approved — drugs which have prolonged the lives of patients and even offered cures to many.
Without that, I have no doubt that we would not be where we are today in the treatment of cancer. Second, I can assure you that FDA is not simply standing by while waiting for science to advance. We are using every tool at our disposal to help facilitate the development of treatments for neurodegenerative diseases, as I will lay out for you.
I can tell you from experience that drug development is not linear, and instead consists of many stops and starts along the way. In many cases, what may have been thought of as a promising compound on the lab bench does not bear out in early trials. Sometimes, these disappointments happen later, during late-stage clinical trials. I believe the challenges to developing meaningful therapies to target neurodegenerative diseases are serious but not insurmountable.
In oncology, we can objectively measure whether a tumor shrinks or its growth is arrested. We do not have those same parameters for many neurodegenerative diseases because the origin and disease course of many of these conditions are not known, and we have not yet identified sensitive biological markers to monitor the progression of these diseases. However, I remain optimistic about our prospects for future breakthroughs for neurodegenerative conditions. We are committed to doing all we can to ensure the development of treatments, and go beyond the drugs currently approved for neurogenerative diseases.
I am eager to discuss ways in which FDA can further our efforts in this area. Each disease or condition comes with its own unique presentation and diagnosis.
FDA has long stressed the appropriateness of exercising regulatory flexibility in applying the statutory standards to medical products for serious diseases with unmet medical needs, while preserving appropriate assurance that they are effective and have a favorable benefit to risk profile. We stand ready to thoroughly evaluate and act on applications for products that treat serious and life-threatening diseases. An example of the Agency working proactively to advance the development of new therapies is the approval of Radicava edaravone.
FDA participates in multiple patient engagement opportunities to learn from patients through listening sessions, external engagement, patient-focused drug development meetings and collaboration in the pre-competitive space. For example, this past January , we convened a meeting with the Duke-Robert J.
This meeting discussed topics on basic research, clinical trial infrastructure, and community engagement needed to advance and support drug development for treatment of ALS.
As an outcome of this meeting, a framework on how to approach these needs is under development. Although our prior experiences in trials for some neurodegenerative diseases have led to useful, standard trial endpoints and study designs, we are open to and supportive of efforts to further improve the approaches to study drugs to treat other neurodegenerative diseases.
Innovative clinical trial designs may be helpful in accelerating therapeutic development for neurodegenerative diseases. Drug developers— in many instances aided by FDA guidance—are exploring and implementing innovative approaches to clinical trial design, including platform and adaptive designs to maximize the statistical power of trials and to minimize study duration, risk to participants, and the overall number of participants required for trial conduct.
They also continue to seek out more innovative approaches to capture and incorporate patient-reported outcomes in trials and to maintain and utilize shared data.
Drug developers are also undertaking approaches to improve access to clinical trials across the spectrum of the patient and volunteer community, including ethnic and racial minorities and patients living in rural areas.
These approaches include: decentralized trials, which are designs that essentially bring the trial to the participant, to increase access and enrollment for individuals who are not located near a research center, or for whom travel to an investigational site can be very burdensome; remote monitoring used alongside digital tools to reduce the need for travel for those with limited mobility; the design of trial randomization schemes to increase the number of participants able to access an investigational treatment during the trial; and open-label extension studies to provide expedited access to the trial drug for those randomized to a placebo comparator in the placebo-controlled phase of a clinical trial.
We fully recognize the concerns that clinical trial participants share with us about the use of placebo-controlled studies, and understand their frustration with such designs.
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