The efficacy of Deep Brain Stimulation (DBS) for an expanding array of neurological and psychiatric disorders demonstrates directly that DBS affects the basic electroneurophysiological mechanisms of the brain. The increasing array of active electrode configurations, stimulation currents, pulse widths, frequencies, and pulse patterns provides valuable tools to probe electroneurophysiological mechanisms. The extension of basic electroneurophysiological and anatomical concepts using sophisticated computational modeling and simulation has provided relatively straightforward explanations of all the DBS parameters except frequency. This article summarizes current thought about frequency and relevant observations. Current methodological and conceptual errors are critically examined in the hope that future work will not replicate these errors. One possible alternative theory is presented to provide a contrast to many current theories. DBS, conceptually, is a noisy discrete oscillator interacting with the basal ganglia–thalamic–cortical system of multiple re-entrant, discrete oscillators. Implications for positive and negative resonance, stochastic resonance and coherence, noisy synchronization, and holographic memory (related to movement generation) are presented. The time course of DBS neuronal responses demonstrates evolution of the DBS response consistent with the dynamics of re-entrant mechanisms. Finally, computational modeling demonstrates identical dynamics as seen by neuronal activities recorded from human and nonhuman primates, illustrating the differences of discrete from continuous harmonic oscillators and the power of conceptualizing the nervous system as composed on interacting discrete nonlinear oscillators. The effects of specific electrode configurations, the set of active cathodes and anodes, can be understood to relate to the regional anatomy and the volume of tissue activation. While the effects of stimulation parameters, such as stimulation current (voltage) and pulse width, can be understood as related to activation of neuronal axonal elements mediated by the presence or absence of myelin, axonal diameter, and chronaxie, how DBS frequency controls the response is much more problematic . From thThe neurophysiology of the DBS frequency effect is an enigma and likely will require novel attempts to explicate. This article takes on this challenge, proceeding from the hypothesis that DBS can be considered a nonlinear discrete noise oscillator that is interjected into the nonlinear polysynaptic re-entrant discrete oscillators that comprise the basal ganglia–thalamic–cortical system. Whether this will illuminate the issue of DBS frequency effects requires the test of time. However, the theory requires the introduction of novel or, at the very least, unfamiliar concepts—hence the review-like nature of the article; these will be in addition to novel observations, hence the presentation of experiments. The format provides a significant advantage in the opportunity to make a full proposal with the mutual reinforcement or consilience of the many parts not typically available in most journals.The first effort is to demonstrate just how complex the effect of varying DBS frequencies is, in this case the effect of various DBS frequencies in the vicinity of the subthalamic nucleus on bradykinesia in patients with Parkinson’s disease, and to account for the failure of such complexity to be appreciated previously. There is considerable experience that demonstrates benefits from low-frequency DBS, for example of the STN for gait disturbances and for dystonia. Further, there may be differences in the frequency-dependent responses for different symptoms and signs of Parkinson’s disease. The failure to appreciate this complexity, although it has long been suspected by astute clinicians, is both methodological and due to conceptual presuppositions. Thus, the review aspects of this article necessarily have an epistemological and historical bent. Also, it will be necessary to provide evidence of highly complex neural oscillators intrinsic to the basal ganglia–thalamic–cortical systems. Further, these oscillations are tied to the orchestration of motor unit behaviors that necessarily mediate the motoric effects of DBS. Next, the power of DBS to induce oscillations is discussed. Finally, preliminary evidence of complex interactions between the DBS oscillator and intrinsic oscillators in the subthalamic nucleus is presented.The authors ask the indulgence of the reader. This is not a systematic review of all the publications that address the issue of DBS frequency. Such an effort is far beyond the opportunity reasonably offered by the editors. Thus, it is impossible to acknowledge the individual contributions made by many clinicians and scientists. This should not be taken as a judgment of their contributions or as a slight of any kind, rather a practical necessity. Second, this is a critique in the robust sense of the term. The critique recognizes that the issue of DBS frequency-based mechanisms is far from a complete understanding. Rather, considerable more research and scholarly efforts will be necessary. The strong critique is not a matter of fault-finding but more an effort so that future scientists and clinicians do not make the same mistakes that these authors and others have made. The term “error” as applied to any finding, inference, or conclusion is not a pejorative term. It is a wise person who learns from their mistakes; it a wiser person who learns from the mistakes of others. If one wants to change the future then one must see the present and the best way to see the present is to clearly see the past.No theory or hypothesis arises spontaneously but rather is the consequence of a long history of reasoning. Reasoning laboriously worked through, perhaps centuries ago—for example by Aristotle (384–322 B.C.E.), now may be forgotten or taken for granted as a presupposition but is no less relevant. This fact was not lost on some of the greatest neuroscientists, such as Sir Charles Sherrington. Any competent critique must trace the conceptual antecedents as far back as is necessary to fully inform the review. It would be naïve, at best, or petulant, at worse, to discount analyses and wisdom from any age.Historically, the study of the effects of DBS frequencies has dichotomized the frequencies into high and low. This article demonstrates that such dichotomization is the result of a methodological error reinforced by highly intuitive conceptual appeal, also probably in error. This is not to say that clinicians did not see a difference when they stimulated at high frequencies compared to low frequencies. Rather, one error lies in undersampling in the frequency domain, resulting in aliasing. This is not a matter of opinion but rather a direct consequence of the Nyquist theorem. Another error lies in the pooling of results across subjects when the intersubject variability is high. The result is information loss according to the Second Law of Thermodynamics. The study by Huang et al.  demonstrResults of the study by Huang et al.  demonstrThe implications of the study by Huang et al.  go beyonPerhaps the need to study the range of frequencies systematically did not raise sufficient concern. However, this could only be the case if the prior concept of a dichotomous effect of DBS frequency was thought to be sufficient. Further, there is nothing in past observations that would be evidence that such a dichotomous effect is sufficient. At the very least, it could demonstrate the Fallacy of Limited Alternatives, where one explanation is considered more certain  when some alternatives are eliminated or not considered. However, for the one explanation to be certain, all reasonable alternatives would have to be considered and excluded, which, in the case of the effects of DBS frequencies, was not done.Perhaps it was that the dichotomization of the effects of DBS frequencies seemed valid because of the analogy between pallidotomy and DBS in the vicinity of the globus pallidus interna. The logical fallacy of this analogy has been discussed elsewhere . InteresThe concerns raised here are more than historical. Successor theories likely share the same fatal flaw as the GPi Rate theory and therefore are at risk of delaying better theories. Current theories that posit excessive oscillations in the beta frequency range or excessive synchronization, along with the GPi Rate theory, share one-dimensional push–pull dynamics. At the very least, alternative theories that do not share these dynamics should be considered, particularly in view of the risks associated with the Fallacy of Limited Alternatives.Given the lack of direct evidence, the presupposition of a dichotomous effect of DBS frequency then appears to be a default. Actually, dichotomization of phenomena and inferred causes marks human reasoning for millennia. Dichotomization is a consequence of the human epistemic condition. The inherent tendency to such a dichotomy, in appropriate circumstances, represents a pitfall only avoided if appreciated. Below the case is made for the ubiquity of dichotomization and, ultimately, its relevance to the consideration of DBS frequencies.contraries, where Aristotle wrote:excess and defect’ ”.“The physicists (…) have two modes of explanation. The first set make the underlying body one—either one of the three or something else which is denser than fire and rarer than air—then generate everything else from this, and obtain in multiplicity by condensation and rarefaction. Now these are contraries which may be generalized into ‘These dynamics were codified by Aristotle in his notion of Aristotle’s notion was extended by Galen  in his notion of one-dimensional push–pull dynamics of relative excess or deficiencies of the humors. Galen’s dynamics continue underlying neurological and psychiatric therapeutics . John HuScience and Nature 50 years after publication of TheStructure of Scientific Revolutions [Needed now is a Kuhnian paradigm shift  away froolutions , Kuhn’s N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that fail to demonstrate predictions of the GPi Rate theory [Thomas Kuhn (1922–1996) argued that a paradigm shift occurs when observations unexplainable by the dominant paradigm—anomalies—accumulate to some breaking point. Kuhn left unexplained what the dynamics of the breaking point were, but many critics of science argue that the breaking point is a polemical issue. At what point do editors of scientific journals and grant administrators stop being accepting of failed paradigms? For example, almost since the inception of the GPi Rate theory, there have been contrary observations and anomalies, including the production of Parkinsonism in nonhuman primates with e theory , as welle theory .This critique is written with an eye to the future in the hope that much better hypotheses and theories will arise that, when vindicated, will extend our knowledge. There are some generic principles that may be helpful. Any theory is more than a set of facts and includes hypotheses that bridge gaps (interpolate) and extrapolate from observations to predictions. Hypotheses invoke notions of necessity and causality that go beyond correlations. However, the generation and evaluation of hypotheses in themselves are poorly understood and have been explained as happenstance, psychological, or aesthetic. However, Aristotle and other ancient Greek philosophers offered an important requirement called the Principle of Causational Synonymy that imposes constraints on any hypothesis and theory that posits some causal mechanism, such as changes in neuronal activities that cause, denigrate, or restore normal behavior. The Principle of Causational Synonymy holds that the means by which a cause acts to generate an effect must match the means in the effect that generates an effect. For example, when one pushes an object, the electrons in the outer orbit of the atoms on the surface of the hand repel the electrons in the other orbit of the atoms on the surface of the object. In the case of understanding the motor effects of DBS, these effects are through the recruitment and de-recruitment of motor units, as is discussed latter. As per the Principle of Causational Synonymy, no theory of the mechanisms of action of DBS can be considered complete or satisfactory without full explication of motor unit activities. Indeed, the inability of any theory or explanation to do so is evidence of serious shortcomings.The Principle of Causational Synonymy can be extended to a Principle of Informational Synonymy. Considering information as nonrandom state changes, the nonrandom state changes, such as the frequency by which electrostatic charges are placed, reversed, and then stopped on the electrical contact of the DBS lead (the cause), must be synonymous with the neuronal changes in the vicinity of the DBS target that generate the DBS effect. Thus, both with the Principle of Causational Synonymy and the Principle of Informational Synonymy, there must be precise mapping of the dynamics of the causal agent with the effector agent.Consider the situation of a person pushing a child on a swing. In addition to the repulsive forces in the appropriate electrons in the person and the child, there also is informational content in terms of the movements of the person pushing and the child swing. This is evident in the fact that the person pushing cannot push at any random time. Rather, the person pushing must be in phase with the child’s swing. Further, the pushing and swinging must be at the same frequencies, consistent with the Principle of Information Synonymy.Applying these principles to the theories of DBS mechanisms of action, particularly as it relates to the stimulation pattern, in this case frequency, shows that current concepts are inadequate. Start with the effect, in this case the normalization of movement in the case of DBS for Parkinson’s disease. Ultimately, any changes in the movement must be implemented by orchestrating the recruitment and de-recruitment of motor units over a number of muscles. This orchestration is very complex and operates over multiple levels over varying time scales. This includes the recruitment of motor units by size. Reciprocal coordination exists between muscles agonistic and antagonistic to the intended joint rotation. Synergistic coordination of motor unit recruitments and de-recruitments in muscles spanning the same joint can be extended to motor unit orchestration simultaneously over multiple joints. Each of these operates at different time scales, and if related to oscillators in the nervous system (as will be demonstrated), then each time scale implies multiple oscillators at corresponding frequencies. Further, the operations at different frequencies are organized simultaneously. These issues are addressed in detail in Montgomery .The fact that DBS improves motor control at specific frequencies argues that the frequency of the DBS is interacting in a nonrandom oscillatory manner with analogous oscillators within the basal ganglia-thalamic-cortical system. Indeed, as will be argued for, DBS can be considered as introducing an additional oscillator into the network of oscillators that comprises the basal ganglia-thalamic-cortical system. As discussed later, these oscillators are a specific kind that endows them with very important and interesting properties. The fact that multiple DBS frequencies exist shows that there are multiple oscillators of corresponding frequencies within the basal ganglia-thalamic-cortical system.The basal ganglia–thalamic–cortical system is involved in the recruitment and de-recruitment of motor units through oscillators within the system that then drive the motor cortex and brainstem structures that project to the lower motor neurons of the spinal cord and brainstem.The basal ganglia-thalamic-cortical system is composed of multiple loosely coupled re-entrant, nonlinear polysynaptic discrete oscillators . Note thOscillatory states consist of oscillators representing different frequencies simultaneously and that oscillatory states can shift dynamically, in the manner of a bifurcation in Complex Systems.DBS acts as a noisy discrete oscillator when introduced into the basal ganglia-thalamic-cortical system, which interacts with oscillators inherent to the basal ganglia-thalamic-cortical system.Positive and negative stochastic resonanceNoisy synchronizationPhase control such as advancement and entrainmentInteraction of the DBS oscillator within the oscillatory network is a model of mechanisms inherent in the basal ganglia-thalamic-cortical system, both in normal and in pathological circumstances. These interactions include the following:A possible alternative theory is presented here. The purpose here is to highlight alternative conceptions and not necessarily to champion any one particular theory. This is consistent with the intent of providing a critique rather than a review. To the authors’ knowledge, the proposed theory is rather novel, at least in literature searches of various databases, thus providing a study of contrast. For example, there is no other publication searchable in PubMed that discusses motor unit recruitment abnormalities in Parkinson’s disease or the effects of DBS. Nor are there any publications on discrete neural oscillators. Understandably, research bearing on the alternative theory largely will be those pursued by the authors. The theory advanced here includes the following:Oscillator activities in motor unit behaviors have been known, and perhaps underappreciated, since described by Piper in 1907 . At highMotor unit recruitment normally is organized based on the muscular force at which a motor unit becomes active. The phenomenology of motor unit recruitment order is the recruitment of small motor units with low force requirements followed by a recruitment of larger motor units with a greater force requirement and is known as the Henneman Size Principle. Small motor units generated are thought to provide the small forces necessary for fine resolution of the forces generated, whereas large motor units supply the strength.Another important extrapolation from the phenomenology is to the underlying mechanisms. Initially, it was hypothesized that motor unit recruitment was determined by the local biophysical properties of the lower motor neuron with large lower motor neurons, corresponding to larger motor units, being harder to excite. Subsequently, differential synaptic inputs with respect to lower motor neuron size, particularly peripheral afferents, were postulated to play a role. Nevertheless, most studies have not discussed or have discounted the role of descending inputs. Indeed, Enoka writes, “The great advantage of a spinally based control scheme (recruitment order determined by motor neuron biophysics—authors), such as orderly recruitment, is that it relieves higher centers  of the responsibility to select the motor neurons that must be activated for a specific task” . Thus, iIn a study of motor unit recruitment , subjectThe EMG signals associated with individual motor units were extracted using a template-matching algorithm  to identAs can be seen in The question is what accounts for restoration of the normal motor unit recruitment profile with high-frequency therapeutic DBS and the dependence on frequency as shown in One possible explanation is that an action potential generated in the axon of the thalamic neuron passing in the vicinity of the DBS contact proceeds in an antidromic manner, as demonstrated in the recording of extracellular action potentials , as wellThese considerations suggest that one possible mechanism for motor improvements with DBS in the vicinity of both the subthalamic nucleus and the globus pallidus interna may reflect resonance interactions between the oscillator composed of the thalamic-cortical loop and the oscillator in the manner of DBS. The resonant interactions between the DBS oscillator and the thalamic-cortical oscillator are thought to improve the signal-to-noise ratio by stochastic resonance, thereby reducing the misinformation exiting from the motor cortex to the lower motor neurons and restoring the normal order of motor unit recruitment.The next question is whether the model described here could account for the improvement in bradykinesia at other DBS frequencies, as demonstrated in Improvement in motor control can be considered increased information in the effectors, which is in the orchestration of motor unit recruitments and de-recruitments. Recordings of extracellular action potentials were obtained as a nonhuman primate preformed an arm-reaching task. Peri-event rasters and histograms show neuronal activities before and after a behavioral event . As can If this model holds for DBS, then the observation that multiple but specific DBS frequencies improve hand opening-closing bradykinesia argues for multiple oscillators involved in the hand opening-closing behavior. Indeed, it is likely that there is an orchestration of motor unit recruitment and that de-recruitment operates over multiple time scales, each related to an oscillator within the basal ganglia-thalamic-cortical system .z-score difference from the same spike train where the interspike intervals (ISI) were randomized. A 2-s window of the spike train was sampled and the z-score change was calculated. The window was then moved over the entire spike train at 0.2-s steps.The Schuster periodogram  is an alAs can be seen, there are multiple and high-frequency oscillatory activities in the neuronal spike train simultaneously. This multiplicity of frequencies and changes in the sets of frequencies can be seen in the following: 24 neurons were recorded in the globus pallidus externa, 15 in the globus pallidus interna, 16 in the putamen, 49 in the sensory cortex, 9 in the subthalamic nucleus, and 25 in the motor cortex . The aveThe theory is offered that each oscillator of different frequencies affects different physiological mechanisms over different time scales, for example, the orchestration of motor unit recruitment and de-recruitment as described previously. Thus, it would not be unexpected that DBS at different frequencies would have multiple effects on motor behavior as shown previously in Studying the effects of DBS in the vicinity of the subthalamic nucleus in a nonhuman primate on neuronal action potentials provided an example where DBS could induce oscillations in the basal ganglia-thalamic-cortical system . An examThe basic concept is that if the basal ganglia-thalamic-cortical system represents a closed loop or feedback system of oscillators, then a single pulse might reverberate in an oscillatory manner through the loop. If a second pulse is timed precisely to the returning effect from the prior pulse, these effects should be additive . Thus, aMacaca mulatta) were trained using only positive reinforcement to sit quietly in a loosely restraining chair and to allow passive movement of their arms. After training, a recording chamber was implanted surgically over a craniotomy site such that microelectrodes could be passed through the intact dura into the basal ganglia as described previously [Two nonhuman primates  referenced to the most proximal contact (contact No. 3). The morphology of the pulses was such that, at contact No. 0, the cathodic phase preceded the anodic phase. The reverse was true at contact No. 3. A pulse width of 90 μs per phase was used. The amplitude selected was 80% of the current that produced tonic contraction, presumably from the current spread to the internal capsule.A reduced scale model of the human DBS lead  was placed such that the deepest contact was at the bottom of the subthalamic nucleus using stereotactic methods confirmed by microelectrode recordings of extracellular action potentials. Locations of the DBS-like leads, as well as other microelectrode recordings, were later confirmed by histological analyses. The leads had four contacts, each 0.525 mm in diameter, 0.5 mm long, and with a 0.5-mm space between contacts, giving a total surface area of 0.82 mmStandard methods of microelectrode recordings of neuronal extracellular action potentials were used. As is standard in electrophysiological studies, autocorrelograms for all neurons were inspected for the absence of a refractory period as evidenced by a high probability of a neuronal discharge within 3 ms of the index discharge. Lack of a refractory period would indicate that the waveforms isolated and attributed to a single neuron were an admixture of two or more neurons. Data from these neurons were discarded. Also, all pair-wise cross-correlograms for neurons isolated from a single microelectrode recording site were constructed. Any cross-correlograms showing a refractory period effect were interpreted as the two neurons actually represented a single neuron that was isolated incorrectly. If found, data for these pairs of neurons were pooled. Loss of signal related to the effects of the stimulator artifact was accounted for and corrected.Continuous recordings of neuronal activity before and during trains of paired-pulse stimuli were made. Resonance effects were demonstrated by constructing post-stimulus rasters, and histograms that were indexed to the second of the pulse pair, test pulse. Rasters and histograms were constructed by taking segments of data immediately after the second or test pulse for 20 ms . This coz score based on the mean and standard deviation of neuronal discharges during the baseline prior to stimulation. Because of the short interstimulus intervals, it was not possible to compare neuronal activities following the first pulse to activities following the second pulse. Sampling of the prestimulation period values was determined by creating virtual stimulation pulses so that neuronal activity during the prestimulation period could be analyzed exactly as the neuronal activity during the stimulation period  the z score normalizes data, thus allowing comparisons between different neurons in different structures; and (2) the z score accounts for the variability of neuronal discharge activity, thus allowing inferences as to statistical significance.Although the interstimulation pulse intervals were not random and therefore the virtual stimulation train was not random, neuronal activity in the prestimulation period is independent of the subsequent virtual stimulation pulse train and therefore can be considered random with respect to the time of neuronal discharge. The mean and standard deviation of the neuronal discharge probability in the time bins during the prestimulation baseline were calculated as described previously for the stimulation period. In this case, histograms were indexed to the second virtual pulse. The probability of neuronal discharge in each time bin in the post-actual stimulus histogram was converted to a One hundred and eighteen neurons were recorded in the basal ganglia-thalamic-cortical system in two nonhuman primates . Forty neurons were recorded in the motor cortex, 25 in the somatosensory cortex, 16 in the caudate and putamen, 14 in the globus pallidus internal segment, and 23 in the globus pallidus external segment. While the number of neurons analyzed within each structure was relatively small, the intent was to study the dynamics of the basal ganglia-thalamic-cortical system such that consistency of observations across different nuclei was the primary interest. As such, the number of neurons for the system studied is similar to other published studies. Analyses within each structure were secondary.z score equal to or greater than 1.96. As can be seen, the significant resonance effects for longer interstimulus intervals had different latencies than the response to the interstimulus interval of 1 ms. Consequently, it is not likely that these other responses were mediated by the same mechanism or that they represent a direct response to the second pulse. An example of a response in a motor cortex neuron is shown in n = 16); globus pallidus externa, 9 ; globus pallidus interna, 6 ; somatosensory cortex, 7 ; and motor cortex, 7 . Thus, most neurons had multiple resonance effects at different frequencies.Results shown in Recent studies demonstrate antidromic action potentials in the subthalamic nucleus neuronal in response to DBS in the vicinity of the contralateral STN . InteresSpike trains containing only antidromic action potentials (antidromic-only spike trains) were constructed from the original spike trains by retaining only those time stamps of antidromic action potentials. Fifty-two of the 58 neurons demonstrated antidromic action potentials. Randomized antidromic-only spike trains were created by shuffling the order of the antidromic action potentials in the antidromic-only spike trains. This was accomplished by dividing the antidromic-only spike trains into segments between successive stimulation pulses. Each interstimulus pulse interval may or may not have an antidromic action potential.The hypothesis to be addressed is that sequence of antidromic action potentials are not random. Thus, it is necessary to compare the actual sequence of antidromic action potentials to what would be a random sequence. The orders of the consecutive interstimulus pulse intervals were randomized (shuffled) in order to affect a breaking up of any periodicity in intervals containing an antidromic action potential, creating a randomized antidromic-only spike train. If the probability of an antidromic action potential is not random, the interspike interval histogram of the randomized antidromic-only spike train would differ from the ISI of the corresponding antidromic-only spike train.Periodicity in the antidromic-only spike train was examined by comparing the antidromic-only spike train to the randomized antidromic-only spike train using power spectral densities (PSDs). It is important to note that the antidromic action potentials are time-locked to the stimulation pulse. The frequencies of the antidromic action potentials thus stand in complex relation to the DBS frequencies.Power spectral densities (PSDs) were constructed on antidromic spike trains from antidromic-only spike train and randomized antidromic-only spike train data. The various peaks are listed in The relatively few neurons available for analyses mean that any conclusions are tentative, and the difficulty of these experiments makes it unlikely that significantly more data are forthcoming. As one awaits future confirmation or refutation, these remarkable findings—their implications in particular—warrant reporting, albeit with the appropriate caveats kept in mind.The study led to the following conclusions: For many neurons, occurrence of an antidromic action potential is not random. The probability of an antidromic action potential reflects the underlying state of the neuronal excitability, which means that the antidromic action potential can be used as a probe of the underlying neuronal dynamics. The probability of an antidromic action potential and the underlying neuronal state of excitability appear periodic or oscillatory. Not simple harmonics of the DBS frequency, the frequencies of the underlying oscillatory neuronal states are, rather, independent of the latter. One cannot exclude the possibility that the actual frequency of these oscillators is not some integer multiple of the 26- or 66-Hz oscillators. The beat frequencies of 3 and 92 Hz for some of the neurons suggest that 26 and 66 Hz are the fundamental frequencies for the involved oscillators. The key finding for the purpose of this article is that DBS can be considered a discrete nonlinear oscillator, which interacts with independent oscillators within the subthalamic nucleus, possibly arising from oscillators intrinsic to the basal ganglia-thalamic-cortical system.As a proof of concept, although not of biological fact, computational simulations were conducted using an architecture derived from the theory that the basal ganglia-thalamic-cortical system is organized as large, loosely coupled, nonlinear polysynaptic discrete re-entrant oscillators , detailsThe operations of neurons in the simulation are depicted in One instantiation of the computational modeling is shown in The physiological mechanism underlying the effect of DBS frequency remains an enigma, particularly as the complexities of the relationship between the DBS frequencies and motor effects are more fully recognized. However, addressing the enigma is a great opportunity because, typically, new knowledge is needed in order to solve it. New knowledge can only come from new hypotheses, which most often require new perspectives. New perspectives require letting go of old perspectives, at least those aspects that are counterproductive. This requires exercise in epistemological analysis as well as experiments.It is likely that the effects of DBS frequency have a great deal to say about the underlying dynamics of the pathophysiology and physiology of the basal ganglia-thalamic-cortical system. A better understanding of those dynamics could provide a metaphor for research that extends beyond the basal ganglia-thalamic-cortical system.


Craniocerebral gunshot injury refers to a wound caused by a bullet passing through or lodged in brain tissue, resulting in the loss of function of a certain area or other fatal damage to the human brain. Craniocerebral gunshot injury is usually life-threatening and is very common in modern warfare, accounting for the majority of battle casualties. Most of the patients suffer from acute cerebral infarction caused by vascular injury. Lack of early and solid battlefield emergency medical interference adds to the risk of death among the wounded.We present a 24-year-old man who was shot with a shotgun from a distance of 15 m in an accidental injury. Forty-seven grapeshots were found on his body surface by physical examination. A computed tomography (CT) scan demonstrated large areas of low-density shadows in his right parietal lobe and right temporal lobe with the midline shifting to the left side 2 days later. Afterwards, the patient was transferred to our emergency medical center at Changzheng Hospital in Shanghai. Cranial computed tomography angiography (CTA) showed a high-density shadow in the initial part of the right middle cerebral artery. The branches after the initial part were obliterated. Prompt medical attention and decompressive craniotomy (DC) surgery contributed to the final recovery from cerebral infarction of this patient.Bullets can penetrate or be lodged in the brain, causing intracranial hypertension. The bullets lodged in the brain can result in stenosis and embolism of a cerebral artery, causing acute cerebral infarction. Combining dura turning-over surgery with DC surgery can not only decrease intracranial pressure, which can increase the blood supply for hypertension-induced vessel stenosis, but also help vessels outside the dura mater grow into ischemic areas of the cerebral cortex. However, this new pattern of surgery needs further support from evidence-based medicine. Since the late 1950s, firearm deaths have increased dramatically in the United States. Every year, guns are responsible for more than 32,000 deaths in the country. Suicide accounted for 53% of the fatalities and 40% of homicides. Accidental shootings and those with undetermined causes made up the remainder. Gunshot injuries to the head are the most lethal of all the firearm injuries, ranking among the leading causes of head injury in many United States cities. Each year, close to 20,000 persons in the United States are involved in gunshot wounds to the head [Acute cerebral infarction after gunshot injuries is a very common complication that can be fatal and result in the loss of function of certain brain areas, which can last for a life time if it cannot be corrected in time. Early and accurate examinations and diagnosis are of significant importance to reduce the high rate of morbidity and disability. Today, the common treatments for gunshot injuries include therapies to relieve symptoms and DC or craniotomy surgery to release the intracranial hypertension. However, some research has shown that the rates of moderate disability and good recovery with surgery were similar to those with medical management .A 24-year-old man suffered from an accidental gunshot injury on December 15, 2015 Fig. . An emerAlalia, facial paralysis of the left side, reduction in myodynamia of left upper and lower limbs emerged the next day. A CT scan was performed immediately that revealed large areas of infarction in his right parietal lobe and right temporal lobe. Mannitol was used to relieve his symptoms but did not take a favorable turn. The patient was admitted to Changzheng Hospital in Shanghai on December 17, 2015. Physical examination of the nervous system showed myodynamia degree II of his left upper limb and degree III of his left lower limb, reduction in the left biceps reflex and triceps reflex, reduction in the left knee reflex and Achilles’ tendon reflex. Hoffmann’s sign, Babinski’s sign and Kernig’s sign were all negative.Cranial CTA and digital subtraction angiography (DSA) was performed immediately and it showed a high-density shadow in the initial part of the right middle cerebral artery Fig. . The braAlthough the formation of compensatory circulation had taken place, the ischemic situation of the patient’s brain tissue had not improved effectively according to the low-density areas in the CT scan examination Fig. . The patIn terms of the dangerous and urgent situation of this patient, he was taken into the operating room. A DC and dura turning-over surgery was conducted to help him from becoming worse under general anesthesia. We removed a part of the skull in the area of the frontal bone, temporal bone and parietal bone Fig. . We madeFive days after the surgery, the patient started to speak logically but was still in lethargy. Medical examination of the nervous system showed myodynamia degree I of his left upper limb, degree II of the proximal part of his left lower limb and degree II of the distal part of his left lower limb. Nine days after the surgery, the myodynamia degree of his left upper limb rose to degree II. Twelve days after the surgery, the patient turned became conscious without somnolence. Posterior-anterior picture of the patient 2 weeks after the surgery showed a decreased difference between two sides of the face Fig. . FifteenCraniocerebral penetrating gunshot injuries have a high potential to kill as wounds in action, even when treated aggressively and timely in the battlefield. The projectile will transmit the kinetic energy to the skull, fragmenting and fracturing bones, severing the brain parenchyma and generating secondary missiles that damage brain structures further –7.DC is widely used for wounds in wartime. It has been reported that patients who undergo DC had worse injuries than those receiving craniotomy and, while not achieving the same outcomes as those with a lesser injury, they did improve with time. Hemicraniectomy is recommended for damage control to protect patients from the effects of brain swelling during the long overseas transport to their definitive care , 4. WarfA CT scan in time is very necessary, because it can detect foreign bodies inside cranial tissue and the secondary injury condition. CTA has remarkable superiority in regard to the battlefield condition because it can reveal the position relationship between bullets and vessels and whether the continuity of the vessel has been blocked. However, DSA is irreplaceable in the assessment of the compensatory state of the blood supply of craniocerebral vessels in the ischemic tissue.Acute cerebral infarction is a contradiction for cranial artery by-pass operation. DC is effective in lowering intracranial pressure but there is not enough evidence to demonstrate that the surgery can improve blood supply for the ischemic tissue. There is no evidence to support the routine use of secondary DC to reduce unfavorable outcomes in adults with severe traumatic brain injury (TBI) and refractory high intracranial pressure (ICP). To date, there are no results from randomized trials to confirm or refute the effectiveness of DC in adults. However, the results of non-randomized trials and controlled trials with historical controls involving adults suggest that DC may be a useful option when maximal medical treatment has failed to control ICP , 9. A stThere are abundant vessels on the surface of the dura mater. Thus, we used a new way of surgery by turning over the dura mater above the ischemic brain tissue to increase the attachment of vessels to the cerebral cortex, which often lack blood supply in a brain infarction , 12, 13.A follow-up survey carried out later showed that this new pattern of surgery is effective in improving the blood supply and relieving symptoms and signs of damage to certain brain tissue. Combining dura turning-over surgery with DC can not only lower ICP, which can increase the blood supply for hypertension-induced vessel stenosis but also help vessels outside the dura mater to grow into ischemic areas of the cerebral cortex , 14–16. Combination of dura turning-over and decompressive craniectomy can be a safe and efficacious option in the treatment of cerebral infarction caused by gunshot injury on the battlefield.


The use of model-based propensity scores as matching tools opens the way to the indirect estimation of mode-related measurement effects and selection effects in web surveys, including a component of selection that cannot be traced back to observable characteristics. By matching and comparing respondents from real independent surveys that use the same questionnaire, but different administration modes, it becomes possible to isolate the selection effect induced by unobservable (or unobserved) respondent characteristics. This study applies a stratification matching algorithm to compare a web survey from a proprietary panel with a computer-assisted telephone survey based on random digit-dialing. The experiment is run in two countries  to check for consistencies across different cultures and different internet penetration rates. The application to the elicitation of support for healthy eating policies indicates large and significant measurement and selection effects. After controlling for differences in the observed characteristics of respondents and the intensity of internet use, findings suggest that web surveys record lower support and higher neutrality. Similarly, after controlling for administration mode and observed respondent characteristics, internet users are less likely to state support compared to non-users. This suggests that unobserved characteristics play a major role, and post-stratification weighting is not a sufficient countermeasure. As demonstrated by the cross-country comparison, rising internet penetration rates are not a guarantee against this type of error, as disparities in these unobserved characteristics are likely to increase at the same time. The exponential growth of web surveys over the last two decades has sparkled a large body of research aimed at providing taxonomies of the potential sources of bias they are subject to, and tools to assess the quality and reliability of the information they collect . DespiteThe focus of this study is on stated support to specific health-related public policies, and the selection and measurement effects which undermine its measurement through web surveys. Suggestive evidence on the difference between results from web surveys relative to other survey administration modes has been provided for health-related domains, including quality of healthcare , 6, healTo our knowledge no structured empirical analysis has evaluated the biases in on-line surveys exploring public support for specific health policy measures. Denscombe  providesAll of the aforementioned health-related and political studies found significant differences between surveys based on computer-assisted web interviewing (CAWI) and their computer-assisted telephone interviewing (CATI) or face-to-face counterpart. Furthermore, these disparities did not disappear after the application of demographically-related weights aimed at correcting observable unbalances in the composition of the two samples.Thus, this study provides ex-post empirical evidence on the magnitude and statistical significance of disparities in public support towards healthy eating policies as measured through a CAWI survey on a probabilistic stratified sample extracted from a proprietary panel, relative to a CATI survey based on a random digit-dial (RDD) sampling design.The challenge of this task lies in the combinations of effects arising from the adoption of different administration modes, sampling frames and sampling strategies. Hence, we propose a strategy based on propensity score matching (PSM), which should be distinguished from the common application of (inverse) propensity scores weighting (PSW) as a post-stratification tool. The latter procedure is effective in reducing the selection bias which can be traced back to the observed characteristics of the respondents, but it may not work for other selection effects driven by unobserved and possibly unobservable characteristics of the respondents . This isIn surveys whose focus is on opinions or attitudes there is no objective population benchmark against which one can compare the absolute performance of web-surveys or CATI surveys. In other words, while reference population estimates may exist for variables like age, gender, or other objective characteristics, this is extremely difficult for attitude items and self-reported behaviours, which in addition are strongly influenced by the interview mode , 22. As effects between two modes rather than absolute errors, where the selection effect is defined as the difference in the selection bias between two modes, the measurement effect is the difference in the measurement error, and the non-response effect is the difference between the non-response error.In the Methods section we illustrate our error decomposition strategy and the assumptions on which it rests, but first we provide a formal classification of web survey errors based on Couper , 3. The Both modes are potentially affected by different selection biases imputable to two main causes: (a) the two sampling frames and the consequent coverage errors are different; (b) non-response rates and errors also differ across the two modes.Coverage error is due to discrepancies between the target population and the sampling frame from which the sample is extracted . If the In this study we had no control or measurement of non-response errors, thus it is not possible to separate its contribution to the overall selection effect from coverage error.In order to correct for selection bias in surveys, the standard procedure is based on post-stratification, i.e. providing adjustment weights based on observed variables so that the weighted sample matches the target population in terms of these measurable characteristics. Various procedures exist to provide adjustment weights, but they do not lead to a complete elimination of selection biases , becauseIn a two-mode CAWI-CATI comparison, the measurement effect relates to the fact that the same respondent would give a different answer to the same question, depending on the administration mode. Measurement errors may also originate from choices on the questionnaire structure , but this has been shown to be unrelated to the interview mode .The remaining differences can be classified into three non-independent categories, interviewer impact, media-related effects, and information transmission , 25. TheThe expectation that web surveys are less exposed to social desirability and sensitivity biases is confirmed by experimental results . There iThe measurement of public support for healthy eating policy actions has received attention in the US and elsewhere, since the seminal study by Oliver and Lee , which eThe data for this specific two-country/two-mode study were collected as part of a wider international research project on the economic evaluation of healthy eating policies . The proThe two-mode survey (CAWI and CATI) was conducted in Italy and the UK with the main purpose of identifying and quantifying the measurement and selection biases associated with running a web survey using a proprietary panel, a common approach in this area of research. The choice of these two countries among the five of the larger scale survey , was driven by manifest differences in both food culture and internet penetration. The questionnaire was adapted from the one used in the larger scale web survey to meet the requirements of both administration modes and to reduce to the maximum possible extent any questionnaire-related measurement effect. The script for both surveys was written using a multi-modal data collection package. The English version of the script was checked by researchers to confirm that question wording and routing instructions were as required. For the Italian version, a back translation of both the questionnaire items and instructions ensured consistency of the contents. The sampling frame for the CAWI survey was provided by the GfK NOP e-panel, which–at the time of the survey–included about 236,000 contacts in the UK and 73,000 in Italy. The e-panel is built on a voluntary basis whereby panelists sign up online through ads, websites, social forums, etc. Selected respondents received an invitation with details of the research and an unique link to access the questionnaire.Field work was conducted between 7 and 22 February 2011. Ethical clearance was obtained from the project lead institution’s (University of Reading) ethics board. Informed consent by participants was obtained by the research agency running the field work, electronically for the CAWI survey and verbally for the RDD CATI survey. The final sample sizes were 249 for the UK CATI, 251 for the Italian CAWI, and 250 for the other two surveys. Sampling was based on probabilistic methods, through stratified sampling (by age and gender) on the list of e-panelists for the CAWI survey, and RDD for the CATI survey. Replacements for non-respondents in the CAWI surveys were made by extracting units from the same stratum, while the CATI survey proceeded until the desired number of respondents was achieved. No quotas were applied.The CATI sampling strategy followed a RDD approach along with the Rizzo Brick variant of the next birthday rule  for seleThe questionnaire included 27 questions, building on and extending the questionnaire by Oliver and Lee . The queAs shown in Beyond cultural and lifestyle differences, there is a major disparity in internet coverage rates, intended as the proportion of individuals who have accessed the internet at least once over the last 12 months, 87% in the UK and 59% in Italy according to 2011 Eurostat data. Estimates from the CATI samples are different and smaller , but together with the frequency of internet use they still reflect a substantially higher penetration in the UK.The heterogeneity found across observed respondent characteristics provides the rationale for this study. Clearly, estimates of support rates for healthy eating policies between the two administration modes are hardly comparable without some balancing of these variables.The study provides information on the following groups of respondents: (a) respondents from the CAWI survey, who are obviously internet users; (b) respondents from the CATI survey who are internet users (CATI_INT); (c) respondents from the CATI who are not internet users (CATI_NOINT). This design enables us to isolate selection and measurement effects, based on few assumptions and the application of propensity score matching techniques to make these groups comparable, conditional on a selected set of characteristics. The overall mode effect, intended as the different outcome between the CAWI and CATI surveys, is a combination of a measurement effect and a selection effect.X), and their frequency of internet use (INTERNET). For individuals who have similar characteristics, and similar frequency of internet use, we ascribe the average difference in outcomes to the gross measurement effect (GME), intended as the difference in measurement errors:First, we consider the measurement effect. An experimental estimate of the measurement effect would require the same respondents to answer to both the CATI and CAWI questionnaires. We approximate such ideal situation by comparing CAWI and CATI_INT respondents after conditioning on a set of observed respondent characteristics (U) that are not captured by the observed characteristics X and are relevant in explaining different responses across the two modes. An implicit assumption is that this measurement effect would not be different if we could measure it on non-internet users, so that information on internet users is sufficient to estimate the GME.This estimate of the measurement effect is gross of a residual selection effect, if there exists a set of unobservable respondent characteristics (SE). Consistently with the classification of survey errors adopted in this paper, we attribute this selection effect to a coverage component (differences in the sampling frames) and to non-response behaviors which differ across the two modes. We only refer to the CATI sample to isolate this effect, so that in a single mode there is no measurement effect. This means that we implicitly assume that the selection effect would not be different if we could measure it on the CAWI sample, which is impossible because it excludes non-internet users. Under this assumption, the selection effect is:Second, we explore the selection effect associated with internet use , and one generated by the fact that a further selection bias occurs on unobserved characteristics, for example attitudes towards technology which may lead two otherwise identical individuals to make different choices on whether to use the internet or not. If these unobserved characteristics are related to the outcome variable, then they will add to the selection bias. If we indicate with SEOBS and SEUNOBS these two components of selection effect, then SE = SEOBS + SEUNOBS and an estimate of SEUNOBS can be obtained by looking at the different outcomes between internet users and non-users conditional on the observed characteristics X and, as before, using only data from the CATI sample to exclude measurement effects:Consistently with our objectives and evidence from the literature, we make a further decomposition of the causes of X, as before). Their estimates are obtained as predicted probabilities from a binary regression model, where the selection variable is regressed upon these characteristics, using data from a reference survey which is assumed to be unaffected by selection errors, or simply more representative of the target population. There are several applications to adjust estimates from web surveys [X because of imperfect (or absent) randomization (PSM), as originally conceived by Rosenbaum and Rubin [X, but not necessarily the unobserved covariates U, unless they are correlated with X [X captures all covariate effects on the outcome other than the experimental effect being investigated, and there is no selection on unobservables. This is the conditional independence assumption (CIA), also known as ignorability, as it allows unobserved variables U to be ignored [X to be unaffected by the experimental effect (e.g. the interview mode or the use of internet). In other words, the variables on the right-hand side of the binary regression model must be exogenous to avoid introducing further biases. Hence, the availability and the choice of the variables to be included in X is crucial to perform a meaningful PSW or PSM to control for selection biases in internet surveys [GME) or which is affected by internet use (for SEUNOBS) should not be used as a covariate in the probit model. This generates a trade-off between considering as many covariates as possible, and including only those which can be safely assumed to be exogenous.A common post-stratification procedure to adjust for selection bias in web surveys consists in weighting observations using propensity scores (PSW). Propensity scores reflect the probabilities of being a web survey respondent conditional on a set of observed respondent characteristics  and on the matching criterion used , see  for an oX is needed to ensure the necessary condition for the BP. The algorithm might fail to find a stratification which meets the BP, in which a less parsimonious specification of the binary regression is needed.Stratification consists in grouping individuals in each sample into intervals (strata) based on their propensity score values, where the number and size of the strata is determined in a way to meet the so-called balancing property (BP). Meeting this property implies that within each stratum the average values of the covariates are not statistically different between the two surveys. Stratification was proposed as a method to control for selection bias well before PSM , and 5252 first GME when comparing outcomes from the CAWI (target) and CATI (benchmark) surveys, then to estimate the selection effects on unobservables (SEUNOBS) between internet users (target) and non-users (benchmark) from the CATI survey. The procedure we implement consists in three steps: (1) estimate a probit model to obtain propensity scores, where the dependent variable is D = 1 if the respondent belongs to the target group and D = 0 for the benchmark group; (2) apply the stratification matching algorithm to the estimated propensity scores; (3) estimate the average difference in outcomes, which consists in a weighted average of the differences for each stratum, where the weight is the relative frequency of target observations. The procedure to estimate GME and SEUNOBS is run separately for Italy and the UK, hence our PSM strategy involves the estimation of four probit models.For the purpose of our study, we adopt stratification matching first to isolate the GME, some of the covariates are potentially affected by the interview mode themselves, and including them could violate the CIA requirement. Thus, our probit estimates exclude those variables related to health status, weight, eating out habits, physical activity, and financial conditions based on the rationale that these self-reported measurements are themselves likely to be exposed to an interviewer effect. However, as a robustness check, we explored the effects of including all the covariates regardless of the risk of endogeneity, and the difference in the GME estimates was negligible.The set of potential covariates is the list of variables in The rates of support for each policy item are reported in For most items, there are also large country differences. For example, only 22% of UK CAWI respondents support regulations on workplace meals, against 70% in the Italian CAWI sample. These differences also vary by mode. The CAWI support rate for banning advertising to children is 71% in the UK and only 57% in Italy, whereas the difference is negligible (83% vs. 82%) in the CATI sample.GME to explore to what extent these differences can be explained by a measurement effect. We compare the CAWI sample with the CATI_INT subgroup of internet users from the CATI sample. While both groups include internet users only, diverging estimates of support rates are likely to stem from other differences in the characteristics of respondents. Our PSM strategy involves matching these two groups on the observed covariates, in order to mitigate the selection effect generated by the different sampling frames and non-response rates. The inclusion of covariates measuring internet behaviors  aims at balancing other unobserved variables that are relevant to entering an e-panel. We cannot rule out that residual selection effects on unobservable characteristics affect the comparison between the matched CAWI and CATI_INT samples, but this is the best possible approximation of the pure measurement effect.First, we estimate the SE) associated with internet use. Then, we isolate that component of SE which cannot be ascribed to differences in the observed covariates. PSM on the two CATI sub-samples balances the observed characteristics of internet users and internet non-users, so that any remaining difference in outcomes can be ascribed to differences in any unobserved respondent characteristic not captured by the observed covariates.Second, using CATI data only, we explore the selection effect associated with being an internet user by comparing the CATI_INT and CATI_NOINT sub-samples. The simple difference between the outcomes is a raw estimate of the overall selection effect . The second pair of probit models is functional to the estimation of SEUNOBS and propensity scores are expected to balance the characteristics of the CATI_INT and CATI_NOINT sub-samples. The goodness of fit is good  and the marginal effects confirm the role of age and education, while the financial condition variable is non-significant. Other significant covariates are related to risk perception and health , and to the BMI in Italy.Probit estimates are shown in Table A in A summary of the estimated differences is provided in GME estimate, hence what is left after matching on the observed covariates is ascribed to the mode-related measurement effect. The evidence is strong and consistent across the two countries and shows that CAWI respondents are less likely to state support and more likely to state neutrality than their CATI counterpart. As shown in Table B in The second column–where the CAWI-CATI comparison is restricted to internet users–confirms and reinforces these findings. The negative shift in those opposing the policy statements becomes larger  and significant. The third column is the SEUNOBS Estimates of support are highly dependent on the survey mode, and discrepancies between a CAWI probabilistic sample from a proprietary panel, and a CATI-RDD sample can be as large as 25% for some items(b)Our estimate of the mode-related measurement effect suggests that the CAWI mode systematically leads to higher neutrality rates relative to CATI;(c)The increase in CAWI neutrality rates stems from relatively lower support rates and–to a lower extent–lower opposition rates;(d)Our estimate of the selection effect associated to internet use also suggests that internet users are less likely to support policy interventions relative to non-users;(e)This selection effect is amplified in the UK, where the internet access rate is higher. As internet coverage increases, the gap between users and non-users is smaller in terms of observed characteristics, but the selection factor which depends on unobservable (or unobserved) characteristics may become more prominent.(f)In relation to the results reported in , our anaOur study is subject to various limitations intrinsic to its empirical nature, and requires some simplifying assumptions. First, our estimate of measurement effect is also gross of a selection effect which can be traced back to unobserved characteristics. Second, we are unable to isolate the non-response component of the selection effect. Furthermore, our CAWI sample is randomly extracted from a self-selected proprietary panel. The effectiveness of our matching procedure in mitigating the impact of self-selection into the sampling frame depends on the range of available covariates, but a purely probabilistic CAWI sample may return a lower measurement error.Our results might be refined by a variety of ad-hoc studies. More specifically, it would be valuable to obtain a more explicit assessment of the selection effect induced by the use of the internet as distinguished by the overall mode effect. For example, an experiment administering a web survey to non-internet users would allow to validate our estimates that are based on CATI respondents only. Similarly, it could be interesting to extend our analysis to consider face-to-face interviews, which would also allow to have a more explicit estimate of the interviewer effect as a separate source of bias from the medium and information effects. Other important extensions would be the collection of information to explore the relevance of the non-response dimension and the impact of extracting the CAWI sample from a proprietary panel. These analyses would shed further light on the overall representativeness of CAWI estimates relative to the target populations. While future research might address these limitations, the strength and consistency of our estimates across two countries and 20 different policy items provides a good degree of confidence in the above listed conclusions. The relevance of the measurement effect is hardly surprising or innovative, and our contribution is simply to suggest a procedure to estimate its magnitude. Instead, our results pinpoint the risks of ignoring the portion of selection error which does not depend on differences in the observed characteristics between internet users and non-users. One might wrongly assume that the potential biases associated with internet surveys fade out as internet coverage increases, especially after controlling for demographic and socio-economic differences. Instead, we claim that higher internet access is associated with larger differences in factors which are not necessarily measured, for example the attitude towards technology, information processing skills and opportunities associated with internet access, subjective health status or risk perception. When–as in our case–these factors are likely to impact on the variables of interest, web surveys not adopting countermeasures are subject to potentially serious biases even after post-stratification weighting.S1 AppendixProbit models for the propensity score models by country and PSM-based Gross Measurement Effects and Selection Effect on Unobservables.(DOCX)Click here for additional data file.S1 Dataset(SAV)Click here for additional data file.


This article comments on:Abu-Abied M, Belausov E, Hagay S, Peremyslov V, Dolja V, Sadot E. 2018. 69, 2869–2881Myosin XI-K is involved in root organogenesis, polar auxin transport and cell division. Journal of Experimental Botany . Plant myosin XI motors are renowned for their function in cytoplasmic streaming. But the cell biology of myosin XI has taken an unexpected turn as a study byet al. (2018)Abu-Abied suggests a role of the motor in auxin transport and cell division plane alignment.Chara and related algae . The establishment of further causal relationships needs careful experimental testing. Coming back to the myosin 3KO phenotypes presented by Abu-Abied and colleagues: could it be that the auxin effects are the basis for the cell division defects? Or is it rather the other way around?As exciting as these novel phenotypes may be, it is not that easy to put them into a simple coherent model. Are these phenotypes interrelated, and if yes, what is cause and what is effect? As humans we tend to infer causal relationships where sometimes there are just correlations. When speaking to my students I ask them initially to view the different phenotypes presented by a given mutant as entirely independent. I suggest comparing a set of phenotypes with the spokes of a wheel see : a priormyosin 3KO mutant has many described phenotypes, as indicated on the spokes of the wheel . It is tempting to speculate about causal relationships between these phenotypes, though this depiction emphasizes that we should initially view the different phenotypes presented by a given mutant as independent. However, one speculative interaction is indicated by the arrow.The et al. provide some evidence that myosin XI has a genuine function in cell division, suggesting that the cell division phenotypes observed may be independent from the defect in auxin signalling. Plant cell division involves the succession of three microtubule arrays, the preprophase band, the mitotic spindle and the cytokinetic phragmoplast. The phragmoplast expands centrifugally and assembles in its midline the cell plate, the nascent division wall. In wild-type cells, the phragmoplast and cell plate grow back to the position on the parental membrane that was occupied and marked by the preprophase band before mitosis  localizes to the parental plasma membrane  and to the edge of the cell plate.Research on the mechanism of cell division plane orientation and, specifically, cell plate guidance has produced a set of novel molecular players in recent years. Most of the proteins discovered point directly towards involvement of the microtubule cytoskeleton, perhaps because the respective plant mutants have strong phenotypes. However, imaging and inhibitor studies have previously shown that the actin cytoskeleton must have an important role in the process of cell plate guidance (Physcomitrella was shown to interact with both F-actin and microtubules. Knockout mutants of myosin VIII showed division-plane orientation defects in the protonema of Physcomitrella (et al. now shows that myosin XI of Arabidopsis associates with the cortical division zone and with the expanding cell plate. Because the 3KO mutants of myosin XI in Arabidopsis show skewed division planes in the stele the analyses provide important molecular genetic evidence that myosin is involved in the division plane alignment of higher plants.But the puzzle is incomplete as we know of only a handful of proteins involved and the mechanisms suggested to explain cell plate guidance are diverse (mitrella . InteresTogether, the new results show that the cortical division zone of plants contains a group of myosins and myosin-like sequences. This alone is curious, as the cortical division zone itself is thought be F-actin deficient (The paper by


The stricter legislation within the European Union for the regulation of herbicides that are prone to leaching causes a greater economic burden on the agricultural industry through taxation. Owing to the increased economic burden, research in reducing herbicide usage has been prompted. High-resolution images from digital cameras support the studying of plant characteristics. These images can also be utilized to analyze shape and texture characteristics for weed identification. Instead of detecting weed patches, weed density can be estimated at a sub-patch level, through which even the identification of a single plant is possible. The aim of this study is to adapt the monocot and dicot coverage ratio vision (MoDiCoVi) algorithm to estimate dicotyledon leaf cover, perform grid spraying in real time, and present initial results in terms of potential herbicide savings in maize. The authors designed and executed an automated, large-scale field trial supported by the Armadillo autonomous tool carrier robot. The field trial consisted of 299 maize plots. Half of the plots (parcels) were planned with additional seeded weeds; the other half were planned with naturally occurring weeds. The in-situ evaluation showed that, compared to conventional broadcast spraying, the proposed method can reduce herbicide usage by 65% without measurable loss in biological effect. The general practice of controlling emerged weeds in arable fields consists of the uniform application of a selective herbicide. This ensures a competitive advantage for the crop without severely damaging it. However, the extensive use of herbicides in the last few decades  has beeng points . This leEarly research in this area used mean weed infestation levels as a measure of weed control needs. In ,5, weedsCurrently used agricultural sprayers are built to uniformly apply herbicides across fields. However, new machinery with variable rate application technology has recently been developed, such as Amaspot from Amazon, which is based on the Weed-IT sensor developed by Rometron. Some scientific equipment  is now bSeveral tasks must be addressed to produce control signals for a sprayer system in this scenario. The first is to sense the weeds in the fields . Data anSeveral sensor-based approaches have been investigated in the past few years. With the aim of producing weed infestation maps, a remote sensing approach was used with some success ,10,12. RFor ground-based sensing, high-resolution image data is the prevailing approach taken by researchers. The sensor type varies from off-the-shelf RGB cameras to specialized spectral cameras that utilize the general absorption of light of wavelengths in the vicinity of 670 nm and reflection of approximately 800 nm for vegetation. High-resolution images enable the use of shape and texture characteristics in addition to spectral characteristics. Instead of the detection of weed patches, local weed cover or density can be estimated at a sub-patch level, and single plant identification has been made possible .To the best of the authors’ knowledge, no existing commercial system offers herbicide application on a single-plant basis, with the exception of systems for spot spraying large plants, such as volunteer potatoes in sugar beets ,14,15 inHandling the presence of crop plants means that the vegetation is a mixture of the crop and weeds. Several researchers have reported on systems that can distinguish crops from weeds with certain limitations ,17,18,19In past work , the autThis paper is divided into the following sections: (1) MoDiCoVi Dicotyledon weed quantifying algorithm briefly shows the principles of operation of the proposed method and modifications to the algorithm; (2) Evaluating experimental layout describes the in-situ plot trial that enables an efficient evaluation of the potential herbicide savings of the two algorithms; (3) Automated trial execution explains the technical details of the Armadillo robot and the grid-spraying tool. This section also describes the planning and control of the robot’s movement in an experiment; (4) Data pre-processing and visualization explains the data processing, filtering, and validation involved. Furthermore, the necessary visualizations that are needed to motivate the initial idea of potential herbicide savings through the two algorithms are described.R, and a blue pixel, B. Based on work by [Images were acquired with a Basler Ace aca2000-50gc RGB camera  equipped with a Bayer patterned color filter in front of a complementary metal–oxide–semiconductor (CMOS) sensor. An excess green index was computed for a pixel in the raw image by observing a 2 × 2 square placed above the pixel such that the center of the pixel coincided with the lower-right corner of the square. The square always contained two green pixels,  work by , but derAt this stage, the image was segmented using a fixed threshold; further, a binary vegetation/soil image was obtained. Pixels with values above the threshold were considered vegetation, whereas the other pixels were marked as soil. Examples of the images from the segmentation process can be seen in The Bayer pattern is segmented into a binary vegetation/soil image.Contours are located, and a subset of edge segments along the contours is chosen for further analysis.The relative locations of nearby edge segments are calculated.The probability distribution of coordinates of the nearby edge segments is calculated. Using this information, the number of weed pixels in the image is estimated.The proposed approach to quantifying dicotyledon weed plants in a monocotyledon crop such as maize is based on a close analysis of the contours of vegetation regions . By obseFurthermore, by analyzing edge segment positions relative to other edge segments, the algorithm is not affected by changes in the position and orientation of the analyzed objects. In the following sub-sections, the components of the algorithm are described in detail. The image processing steps are shown in From the binary image of the vegetation, the outline of the vegetation regions is located using an edge detection kernel. To obtain oriented edge segments, complex moments around every pixel in the input image are calculated using the following Equation :(2)Im,nσ is the bandwidth, and x and y describe the position relative to the windows’s center. The parameters m and n determine the shape to be searched for, and are set to 1 and 0, respectively, in order to locate edges. The computation was implemented as a convolution with a complex kernel. The result of the convolution with the edge detection kernel is an image where pixel values are represented by complex numbers. This is converted to a magnitude and phase response (see examples b and c in x and y) and orientations (θ). In the following, the n-th edge segment is denoted by In this equation, Given two edge segments d between the edge segments and a measure, k, of the curvature of the path through the two edge segments. The features are derived from the raw relative coordinates as follows:When the relative coordinates of the relevant edge segment pairs have been determined, their distribution is investigated. By projecting the density of the relative coordinates onto a two-dimensional (2D) surface spanned by a combination of two of the relative coordinates, a fingerprint of the edge structure is generated. This type of fingerprint is interesting because monocots and dicots appear very distinctly in it. This is shown in m, N is the total number of relative points. The estimation of the weed area ratio is then performed through a linear combination of the Gaussian features through a linear combination asm and n iterations. The regression model resulting from this process is the finished model.In order to estimate the distribution of the relative points, a framework inspired by Gaussian mixture models is applied. The concept is to measure the density of data near specific interest points. Nearness is determined by applying a Gaussian weight. The farther a point is from the point of interest, the smaller its weight. The density near these interest points is calculated using the following formula:Gm=e−∑ΔP−In the previous version of the MoDiCoVi algorithm  the densIn order to align the selection of the threshold value for spraying with the expected yield loss as described in , the regBrassica napus L.), Corn Marigold (Chrysanthemum segetum L.), and Fat Hen  were sown following the crop seeding in two strips, 200 mm apart and orthogonal to the crop rows for every eight meters corresponding to every second row of plots. The field was divided into 299 plots. Each plot was 3 m × 4 m . The herbicide MaisTer , seeded/unseeded weeds (2), and camera placements (2)), each with their respective number of variations in parentheses. The desired number of repetition plots (parcels) for each combination was ten, which resulted in a minimum number of 280 plots. Furthermore, two cameras with different short-pass filters were used, each controlling three sprayer valves. This resulted in plots that, in reality, were split between two neighboring 750-mm wide sub-plots. For further details, see the description of the grid-spraying chamber below. The seven instances of on/off spraying treatment decisions were split into two main groups: (1) Control where spraying was always on or always off for the entire plot; (2) MoDiCoVi on/off spraying algorithm with five threshold levels based on weed leaf coverage defined in the previous section. The weed variable defined whether two orthogonal rows of weeds within a plot had been seeded in order to guarantee a minimum weed population beyond what might occur naturally in the field. Two rows of unsprayed seeded weed rows are shown in A large-scale field experiment for fully automated execution was designed in order to obtain a high degree of consistency in the results. A total of 28 treatment combinations were randomly assigned to the 299 plots, and a fully autonomous robot sprayer performed all treatment combinations in a single pass. The robot sprayer consisted of three major components: (1) An autonomous tool carrier; (2) A grid-spraying implement; and (3) A trailer Hardi ATV spray tank .The automated tool carrier, Armadillo IV, was described in . It consThe grid-spraying tool consisted of two chambers, one for image acquisition and the other for spraying. The image acquisition chamber  was 1.8 n, as in . The griBased on the plot ID and velocity of the robot, the computers determined the treatment combination, especially with respect to the two on/off ground truths and the five threshold levels of the vision-based spraying algorithm. The vehicle velocity was used to set the delay between the image acquisition and potential valve actuation to compensate for the mounting distance between the camera and spraying nozzle. At the same time as the image-based spraying, raw images were stored and geo-tagged for post-data processing and visualization. The frame rates for image acquisition were set to 1 Hz or 4 Hz, depending on whether the laptops were required to run the spraying algorithms in real time or only acquire images, as was the case for the third sampling date. The Hardi ATV spray tank trailed behind the Armadillo tool carrier A. The loThe 4 m × 3 m plots used by the automated execution control system were reduced to the width of the six spray nozzles and by half a meter in length at either end of each plot. Hence, the net dimensions of each plot were 3 m × 1.5 m. This was conducted to avoid treatment in areas where the vehicle tracks would be driving. To remove outliers caused by the tool carrier, plots that involved too long or too brief a time interval for driving through them were removed. The plots to be removed were determined in accordance with the amount of time in the driving through: those in the 5% of the upper intervals and 5% in the lower intervals of drive-through times were excluded. This would typically be caused by becoming stuck in mud, a system crash, or similar non-spray/algorithm- related issues. To calculate the reference weed coverage in each plot, logged GPS tracks from the seeder were used to estimate the position of the maize rows. By combining these positions with the known position from the GPS log of the Armadillo robot, locations were projected into the image plane. Based on the projected GPS positions, the path was interpolated using bilinear splines. Morphological dilation was used along the spline to mark the area deemed part of the maize row. The radius of the dilation disc was set to 350 pixels ( 146 mm), thus ensuring that the majority of the crop leaves were covered across all three sampling dates. To enable the leaves of plants to extend beyond the marked area, the centroid of each plant (defined using blob labeling) was used to define whether each plant was considered maize or weed. The weed coverage area was estimated by counting the number of segmented pixels not classified as maize .MATLAB was used to estimate weed coverage in the images to establish the ground truth. Data was then exported for analysis in R (2012), which was used to pre-process the data and visualize the initial findings. Nozzle activity was estimated based on the recorded spraying log files as the ratio between the on/off nozzle times for the 3-m plots. The estimated weed coverage within a plot was based on the estimated inter-row band shown in The trial was performed for 299 plots, of which 241 were accepted for further data analysis; the remaining 58 were excluded. This section describes the method of exclusion for the remaining plots and the results from the 241 accepted plots. Pre-processing was performed on the data to exclude invalid instances. A plot was discarded if it did not meet the specifications of the experiment for any of the three sessions. These specifications defined the velocity of Armadillo, and stipulated that the initial area covered by weeds should be between the 0.5% and 99.5% of the data. Armadillo became stuck in muddy conditions due to heavy rain prior to the first day of spraying, resulting in several disturbed plots, which also had to be excluded from the trial. As the spray timing assumed a constant velocity, stopping would cause the spray to be incorrectly positioned. A crude filtration of plots yielding unusually low or high amounts of initial weed coverage at the first spraying session was considered an outlier and permanently excluded from the analysis. The log file from the third session to acquire images contained significantly more extremes with regard to the average time taken to pass a plot. Hence, the 90% quantile used for sessions 1 and 2 was narrowed by removing the additional 5% for the slowest pass times. The number of excluded plots from the trial was within the safety margin for the number of repetitions of the trial. These excluded plots from treatment combinations with only two or three replicates. The impact on treatment replicas should be kept in mind when studying nozzle activity and weed coverage in The seeding of the maize crop went as planned for all plots. In total, 64% of the planned weed strips were seeded because of a limited amount of available seeds. In this trial, weed seeding was carried out to guarantee weed growth in the plots. Prior to the execution of the actual spray procedure, it became clear that natural weed growth in the plots was sufficient even without the seeded weeds. No visual markers or poles were placed in the plot trial. This saved a significant amount of time in setting up the trial. However, when following the Armadillo tool carrier performing automated execution, it was difficult to determine which treatment combination was active at any given time, and to obtain an impression of the performance of the on/off spraying algorithm active at any given time. The route plan included two pit stops after 900 m of driving to enable the refilling of the Hardi ATV trailer. This turned out to be unnecessary because herbicide consumption was lower than anticipated, indicating a measurable reduction.By the time the first spraying date arrived, significant efforts had been invested in integrating the Armadillo tool carrier with the grid-spraying tool and its internal sub-components, and calibrating and trimming the dicotyledonous weed quantification algorithm (MoDiCoVi). The day prior had been rainy, and the window of time for the spraying session was restricted to an afternoon on account of forecasted showers the following day. It was therefore decided to use the features derived from training from the previous year, which had the added benefit of rendering overfitting less likely to influence the results. The dataset used was based on work by  on anothThis sub-section contains plots summarizing the performance of the proposed algorithms. In the field trials, the fraction of time for which the sprayers were active in each plot was logged. Sprayer activity is plotted for the different algorithms in For algorithms MoDiCoVi 1 to MoDiCoVi 4, nozzle activity seemed higher for the camera with the standard filter than one with the SP700 filter. With regard to nozzle activity in relation to whether weeds were seeded, there was no clear offset for MoDiCoVi. The area seeded with weeds within a plot covered less than 7% of the area. Hence, it might be difficult to perceive this in the nozzle activity. The camera location seemed not to have had an effect on nozzle activity for the MoDiCoVi algorithm. Nozzle activity seemed higher for the second spraying session, especially in plots with no seeded weeds. In plots with seeded weeds, nozzle activity tended to be identical for MoDiCoVi 1 and MoDiCoVi 2. However, for MoDiCoVi 3 and MoDiCoVi 4, nozzle activity seemed to be highest in the second spraying session. The weed density estimate for each of the runs and threshold levels is shown in Based on visual inspection of nozzle activity in The MoDiCoVi algorithm could obtain herbicide savings with no clear increase in weed coverage, which was surprising even when using the camera with poor segmentation. The fact that the authors had trained the algorithm on a dataset from an earlier season indicates that specific training may not be required each time a new field is reached. The authors of  showed tThis study implemented and tested in situ two vision-based algorithms for grid-based on/off spraying. The tests showed that, compared to conventional broadcast spraying, the potential reduction in herbicide usage through the proposed method is 75% while maintaining weed control effects. However, a statistical analysis is needed to confirm this finding. The most promising and robust algorithm in the experiments was the computer-intensive MoDiCoVi algorithm. Additional growth seasons are needed to confirm these findings.


An accurate representation of time-dimension in the neuronal circuits is required for a successful interaction of the brain with the four-dimensional physical world. Time-dimension, unlike other three dimensions of our physical universe, is never perceived as a novelty, but only reported as the flow of time. As there are no known neurological or psychiatric disorders that are associated with the loss of the sense of flow of time, this suggests that the functions of the brain involve processing of temporal information  in time-bins of specific size along the time-dimension  model and the new evidence that supports it. In contrast to other models, the SBF is more biologically plausible and implies the existence of cortical oscillators of various frequencies. At the onset of a timed interval, cortical oscillators are phase-reset and, at the offset of the interval, the state of these cortical oscillators is read by the medium spiny neurons of the striatum. Due to the fact that spiny neurons are coincidence detectors of the cortical input, the output of these striatal neurons could in principle tell time. Now, the authors suggest that the cortical input on the spiny neurons could be any stable neural pattern including neural avalanches  beta power was modulated by the unpredicted deviant pitches, suggesting that beta power is associated with predictive perceptual processing for the stimuli what (the pitch) and when (the tempo of the isochronous beat). The authors interpret these findings as the evidence that predictions for what and when are dynamically processed through attentional networks, and that beta oscillations in auditory cortex reflect the functional significance of sensory prediction and prediction error processes.The paper by Kumar et al. report findings from a study of the McGurk effect, in which semantically-incongruent visual information modulates auditory perception. Authors employed incongruent audio-visual (AV) pair (audio/pa/ superimposed on the video of the face articulating /ka/) to induce the cross-modal percept/ta/. They find that for asynchronous AV  stimuli, a broadband enhancement, in the global coherence at theta, alpha, beta, and gamma bands, aids the cross-modal perception (percept/ta/). Long-range oscillations  aid in the multidimensional processing of information of asynchronous AV stimuli by providing temporal window of integration, which is a specific phase of long-range oscillations  and wave shape parameters —characterizing the MMN waves produced by deviant sound. Their results revealed only one important correlation: a positive correlation between the MMN amplitude and the slope of decaying phase, also called downslope . The authors argue that this represents an efficient feedback process, which allows MMN to return to the baseline within a predefined time-window. This also suggests a coupling between the neuronal processes associated with deviant stimuli and a representation of the physical time-axis in the brain. This coupling may subserve the mechanism to input the physical time information into brain circuits, which would calibrate endogenous oscillators in a distributed modular clock model  wave, which reflects neuronal processes underlying the brain's automatic reaction to novel or deviant as well as unattended sensory stimuli  and a 600 ms (long) exemplar. In both emotional conditions, short or long exemplars were used as standard or deviant stimuli. When short exemplar served as the standard, long exemplar was used as the deviant stimulus, and the vice versa. Authors observed a MMN-like negativity—climbing negativity that plateaued. Greater negativity for deviants than standards emerged shortly after the deviant onset, before the standard or deviant duration had lapsed. This suggested that listeners implicitly tracked sound speed and detected speed changes . Continuous detection of the changes in the speed of unattended sounds would play a role in the calibration of endogenous oscillators in modular clock mechanisms  task is the most desirable. In this tasks subjects are asked to discriminate which of two pairs of stimuli presented consecutively was the most synchronous. They develop an appropriate signal detection theory model to analyze the 2xSJ data, and finally, they compare the data from the novel task with more conventional simultaneity tasks. Compared to classical tasks such as the temporal order judgment task, the 2 x SJ provides more constrained estimates of sensory noise, which indicates a more straightforward decision process. In fact, the 2 x SJ requires explicitly to decide which alternative timing relationship is most synchronous on any given trial, rather than revealing what range of relationships are perceived as synchronous. Consequently, 2 x SJ will serve as a crucial complement to existing methods for investigating subjective timing.The paper by García-Garibay et al. demonstrate the ability of the rhesus monkeys and humans to perceive and maintain rhythms of different pace in the absence of sensory cues or motor actions. They use a visuospatial task in which subjects observe and then internally track a visual stimulus that periodically changed its location along a circular path. The proportion of trials in which subjects correctly estimated the position of the stimulus, along with other variables were determined in this study. Both species showed variability, consistent with Weber Law, where time independent variability increased as a function of timed duration .Alústiza et al.). The overlapping regions, which are primarily in the right hemisphere, showed reduced rather than increased activity in schizophrenic patients relative to control subjects, not only by time perception tasks but also by an increase in the level of difficulty of non-temporal tasks . Reduced activity of various brain structures is consistent with the prevailing view that there is an impaired functional connectivity of brain regions in schizophrenia , as well as parietal regions and the basal ganglia , which suggests that beta oscillations play an important role in the functioning of brain networks serving the levels of cognitive effort and time perception that is likely affected in schizophrenia  Future studies should look more closely at the role of the representation of the time-dimension in the temporal processing of information in the brain, which may be affected in psychiatric illnesses.Various papers in this special issue describe that modulations of beta-range oscillations play an important role in the timing behavior. Beta power increased as working memory load increased in a temporal version of n-back working memory task (All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.