Objective assessment of the degree of improvement or deterioration with patients by means of Ipsative Trend Analysis of resting electroencephalograms

Accepted Manuscript Objective assessment of the degree of improvement or deterioration with patients by means of Ipsative Trend Analysis of resting electroencephalograms Gerald Ulrich, Georg Juckel, Willi Schlosser PII: DOI: Reference:

S0306-9877(17)30931-3 https://doi.org/10.1016/j.mehy.2018.02.002 YMEHY 8784

To appear in:

Medical Hypotheses

Received Date: Accepted Date:

3 September 2017 6 February 2018

Please cite this article as: G. Ulrich, G. Juckel, W. Schlosser, Objective assessment of the degree of improvement or deterioration with patients by means of Ipsative Trend Analysis of resting electroencephalograms, Medical Hypotheses (2018), doi: https://doi.org/10.1016/j.mehy.2018.02.002

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Objective assessment of the degree of improvement or deterioration with patients by means of Ipsative Trend Analysis of resting electroencephalograms Gerald Ulrich(a), Georg Juckel (b), Willi Schlosser.(c) Professor Dr. med.Gerald Ulrich (a) Dept.of Psychiatry, Charité Benjamin Franklin, Berlin, Germany T:+49-030-43324011 Professor Dr. med. Georg Juckel Corresponding author Dept of Psychiatry, Psychotherapy and Preventive Medicine, Ruhr-University Bochum, LWL University Hospital of the Ruhr University Bochum Alexandrinenstrasse 1D-44791 Bochum, Germany, T: + 49-(0)234 5077 E-Mail: [email protected] Willi Schlosser (c) D-6521, Heidenrod T: +49 06120-978021 Wischsoft software engineering Schulstrasse 3 D-6531 Heidenrod Sources of Support: none Abstract We report on a new quantitative EEG-approach, called Ipsative Trend Assessment which is based on the spatio-temporally defined patterns which are generated by the global interaction of cortical neurons. Methods The data were acquired from EEGs being recorded under resting conditions. Target variables are not the usually employed absolute values of the spectral parameters but rather their change being calculated from successive recordings with a single subjects design. Rationale Since the resting-EEG does not provide specific information, we had to decide what else might be addressed by that method. Conclusions Our hypothesis according to which the SR-EEG indicates Selye’s behaviorally non-specific General Adaptation Syndrome is based on good evidence. Main findings Dynamic pattern comparison between subsequent EEGs on the single case level is a hitherto neglected method, which may be utilize, for instance, with regard to objective therapeutic outcome assessment.

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Significance In order to substantiate the clinical meaningfulness of our new approach we report two case vignettes of psychiatric impairments. Apart from that, our procedure should provide the desperately needed objective assessment of the therapeutic effect with any disease displaying a certain proportion of unspecific symptoms. Keywords: Cerebral Global Function; Ipsative Trend Assessment; General Adaptation Syndrome; Dynamic Pattern Approach Highlights 

The hierarchically structured intermediary stages, being due to the global top-down integration, i.e. Global Cerebral Function (GCF) of the neuronal tissue constituting the spontaneous resting EEG (SR-EEG) are the objective of a new quantification procedure which involves the dynamic information.

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To that end we made use of the sequence of patterns being described to characterize the timecourse of the SR-EEG.

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GCF was treated as the macroindicator of the non-specific General Adaptation Syndrome (GAS) being the common denominator of the non-specific features of any disease, whatsoever.

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As physiologic measure of the ever changing brain-electrical function, the EEG indicates the related psychological level of performance/behavior, thus allowing an objective assessment of clinical improvement/deterioration.

Please insert the following graphics: Fig. 1 , p.4 (colored) Fig. 2 ,p. 7 Fig. 3, p. 13 Fig. 4, p. 14 (colored) Fig. 5, p. 15 Fig. 6, p. 17

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1. Introduction 1.1

Quantification of the actual level of Global Cerebral Function (GCF)

About three decades ago we had begun to conceptualize a quantification procedure based on the Spontaneous Resting EEG (SR-EEG). The underlying idea was to objectify clinical improvement or deterioration at the single case level [1, 2, 3, 25, 26]. The data were acquired from EEGs being recorded under resting conditions. The underlying idea was due to Jackson’s Global Cerebral Function (GCF) or the principle of hierarchically organized functional levels and its dynamics. The latter were calculated from spatio-temporally defined EEG-patterns according to the staging by Loomis et al. [4]. Attendant on Bente et al. [9, 10] we defined the spatio-temporally defined patterns as intermediary - or transitory stages of brain-electrical integration. This designation was less ambiguous than vigilance stages because it did not restrict the term to alertness/drowsiness. The target variables were not absolute spectral values but rather the difference values between successive recordings. Our algorithm, was based upon the FFT analysis of 300 consecutive 2-second epochs. In contrast to the common proceeding, target variables were not the absolute spectral values from each single recording but rather the differences between subsequent recordings. Repeated attempts to get the manuscript [1] published failed with the recurring rationale of “idiosyncratic with mainstream research”. We eventually found a journal without the unsurmountable hurdle of peer-review. Even though its idiosyncrasy with mainstream, our approach proved repeatedly its clinical usefulness without becoming prevalent [11, 12, 13, 14, 15, 16, 17].

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Fig.1 Jackson’s Global Cerebral Function (GCF) as an Electroencephalographic Macroindicator of Selye’s General Adaptation Syndrome (GAS)

Tracing back to J.H. Jackson [5], the lowest level of the pyramid is the molecular one and the highest level is deemed to the brain or its cortex. According to Jackson’s principle of hierarchically structured levels, the cortical level corresponds to a maximum of degrees of freedom or of functional non-specificity. Each level controls the next lower level and will be controlled by the next higher. The Jacksonian pyramid may be understood as a precursor of more recent comprehensive theories of the statistical mechanics of neocortical interactions and may complement other

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modern phenomenological theories. In addition, the proposed emphasis on global dynamics provides a new conceptual framework for brain studies [51]. The higher degree of integration in neural tissue motivated renowned neuroscientists as W. Freeman [6] to base his experimental research rather on the neural mass top-down paradigm than on the bottom-up paradigm of studying single neurons. Inspired by H. Ey [7], who himself declared as a neoJacksonian psychiatrist, several other followers of Jackson’s ideas considered the intermediate EEG patterns distinguished by Loomis et al. [4] as the expression of the actual level of GCF and its dynamics. The interaction of local and global dynamic systems,may be regarded as the current state of the art [51 ] A first move towards a psychophysiologic or psychiatric EEG, we owe to the French psychiatrists Lairy & Dell [18] as well as some years later to Bente et al. [9, 10]. The updated second version [2] following the first quantification approach [1] was called Quantitative Electroencephalographic Ipsative Difference Assessment, QUEIDA [2]. In 2003 we introduced the hitherto last version, called Ipsative Trend Assessment, ITA [3, 25]. Since SREEG indicates brain’s structure and dynamics, it delivers the data for quantification of the actual level of GCF. But this will not work without an appropriate theory. Such a theory is provided by Head’s concept of “Vigilance” [8, 26, 54] which was published several years before Berger’s first article on the human EEG [19]. Unfortunately the epistemic underpinning by Head does not always become lucid along with his writings. As an inescapable result Head was to a great extent misunderstood, for example in the sense of “sustained attention” or even of “arousal” [20, 21, 22, 23]. Thus, for instance Dongier [21] wrote in his handbook contribution: ”this vigilance appears to be only an absolute dispensible, superfluous name for alertness, vigility, wakefulness, attention etc.” But if one troubles oneself about reading Head’s original paper diligently one will learn that his Vigilance has a different meaning compared to Arousal or Attention. The decisive flaw consists in the misunderstanding of Head’s Vigilance as an empirical term instead of a theoretical one. 1.2

HEAD’s concept of Vigilance

“Vigilance” was indispensable to Head for explaining both the clinical observation of spontaneous recovery following damage of the brain and the characteristic fluctuations of impaired performances accompanying that process. Furthermore, Vigilance was neither a physiological nor a psychological term to him but rather a theoretical term, strictly speaking

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an “explanatory principle” [24]. As a creation of the human mind it is needed to bridge the gap between the methodically incommensurable domains of physiology and psychology. Both types of data cannot be reduced to each other. They rather exist in complementarity and coincidence. Vigilance was coined in order to overcome the seemingly insolvable “hard problem” of mind-body interaction [26]. For neuropsychiatry it was anticipated by Jackson’s “doctrine of concomitance” [5]. Neither the macroscopic properties nor the interactions between neural masses can be understood at the level of the individual neurons alone. Accordingly, the common idiom of “psycho-physic interactions” has to be regarded as an unscientific facon de parler of colloquial speech. This is tantamount to the all too often heard statement that the “power of thoughts may steer physiological processes”. Rather, the psychological state appears coincident with a distinct physiological process. What is badly needed is an Integrative Theory in order to overcome the epistemological gap between the incommensurable categories/domains of mind and brain. Head’s Vigilance is needed as a term which enables a unification of both categories. Given the extreme complexity of neocortical interactions, a linear description is probably inadequate, as was stated by Nunez [51]. The theoretical impact of Head’s concept essentially remained unrecognized in the following decades. It rather was equated with “Arousal” in the wake of an article of Oken et al. [22, 23]. The main problem with “Vigilance” as introduced by Head is due to its misleading limitation to the sleep-wake cycle. Thus the stages according to Loomis et al. [4] were equate do be stages of lowered vigility, The unique one-to-one correlation of the hierarchically organized functional levels with different degrees of drowsiness represents a typical “categorical fallacy”. An empirical proof for that is the surprising low correlation coefficient of rs =0.20 or less, which is impressing at first glance between self-assessed fatigue and SR-EEG parameters indicating a waking state. Such a paradox owing to semantics would be avoided by speaking about a decrease/increase of GCF and of intermediary instead of subvigil or drowsiness stages/patterns.

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Fig. 2

The mediating between Physiology (Global Cerebral Function) and

Psychology (Perception/Behavior) by means of Head’s construct of Vigilance

The bridging between Physiology and Psychology is illustrated by two vertical arrows

Apart from rare exceptions, Jackson’s “doctrine of concomitance” was discounted as being enigmatic and obscure without importance for psychiatry. The same applied to the development of the psychophysiological EEG based on Head’s Vigilance in the following decades. Though Head established a new horizon for research as well as for making use of the SR-EEG for clinical purposes, the main reason that prevented psychiatry to take advantage of his epochal inspiration was the undue use of his central term. Only Lairy & Dell [18] pointed to certain passages of Head’s article from which one could follow that “Vigilance” did not intend an empiric issue, e.g. a particular psychic state (alertness/drowsiness) but that it rather had “une signification très générale”. Furthermore, they stressed that the equation between Vigilance and alertness is amiss. Last, but not least, Head’s vigilance anticipated modern nonlinear systems’ dynamics. In contrast to linear systems, non-linear systems do not allow for a prediction of the output in spite of an exact physical characterization of the input. Without the

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notion of “Vigilance” one could not account for the incessantly changing of the actual levels of GCF. Credit has to be given to Dieter Bente for elaborating the neglected idea of Lairy & Dell concerning a relationship between Head’s Vigilance on the one side and the patterns being defined by Loomis et al. on the other. It is important to make strictly sure that Head’s Vigilance is not another word for GCF but rather acts as a mediator between the quantitative GCF and a qualitative performance/behavior. 1.3

General preconditions for a quantification of SR-EEG.

Bente [9, 10] was the first who repeatedly pointed out that the SR-EEG reflects both the structure of cortical mass activity (55) and its dynamics. The first step of any quantification procedure which has to be theory-guided is the selection of appropriate variables. The crucial question has to be answered if or to what extent, clinical deterioration/improvement may be objectified. Till now only one quantification software with a single case design exists, - called “Ipsative Trend Assessment” (ITA) - in order to quantify both the structure of as well as its dynamics [3, 25, 26]. In trying to accomplish a sufficient exhaustion of the targeted information, different constraints are imperative. A major source of adulteration concerns inappropriate artefact-editing. The naturally given time-structure of the SR-EEG is tantamount to its dynamic information. Even if the common visual artefact editing should be regarded as the gold standard, it has to be challenged if an uninterrupted SR-EEG is required. Thus, viable alternatives have to be searched for. The chronological dependence on the recording time has to be regarded rather as a rule of thumb than as an invariant succession. Alpha activity representing the A-stages and low voltage desynchronized activity with only a few Alpha waves, if at all represents the stage B1 which shows a preponderance over time. minute thenceforward, one may observe an alternating between A- and B-stages with a preponderance of the latter. With healthy adults the initial stages A1 and A2 are maintained for about 4-6 minutes, as a rule. During the last third of a 10 minutes recording, stage B2 pattern prevails. The proper relevance of such regularities, as well as the methodological importance of Head’s Vigilance for assessing SR-EEG dynamics remained obscure for decades. As already stated, the most disturbing problem therewith consisted in the labelling of the patterns as subvigil- or drowsiness-patterns. A terminological clarification may be arranged with the various kinds of complex psychological behaviors, for instance alertness/fatigue, but just as well, attention/inattention, adaptivity/non-adaptivity, reactivity/non-reactivity etc. (see Fig. 2). Additional confusion was created by Nagata [27], who claimed that the EEG has to be regarded above all as a paraphenomenon of integrated

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brain metabolic processes being superimposed by a process of wake-sleep control. From that a tacit agreement of the mainstream opinion has been deduced to “stabilize EEG-Vigilance” by acoustical alerting tasks along with the recording [28, 29, 30 31, 32]. For instance Thatcher et al. [32] persuaded the users of NeuroGuide software to treat the patterns which corresponded to intermediary stages as artefactual drowsiness patterns: “The simple truth is that drowsiness which is an artefact that can and must be eliminated has never been established to be a problem with the Thatcher et al. technique”. He who aims at a “stabilization” of the SR-EEG by “alerting tasks” overlooks that therewith the spontaneous SR-EEG will be deprived of its constitutive property which consists in its genuine spontaneity. In this context, it shall be pointed out that Berger’s early assumptions about the relationships between 

Alpha amount and psychomotor relaxation



Beta amount and activation



Theta/Delta amount and drowsiness

have never been verified by modern digital technique. In his thesis, Bente [32] followed the French psychiatrist Henri Ey [33] when he referred that psychopathology in its entirety may be arranged on a continuum between the poles of neurasthenia and loss of consciousness. Moreover, Ey postulated a common time-structure between the psychological destruction of the field of consciousness and the physiological dynamics of the GCF. This model might serve as methodological premise for EEG-quantification in case of any psychiatric disturbances, whatsoever. 1.4

How to avoid artifacts with preservation of dynamic information

The only safe method to avoid adulteration of the time-course of SR-EEG, or of the dynamic information, consists in the exclusion of the slow spectral range from 0.5-2.0 Hz from the quantification procedure [34]. It is this very spectral range which contains the vast majority of artifacts, irrespective of their origin. Becoming aware of the deleterious impact of a hitherto unknown “virtual” artifact upon the test-retest reliability, we generally restricted our quantification calculations to the frequencies above 2.0 Hz and below 15.0 Hz. Due to its origin we called this artifact Arterial Pulse Impedance Artifact, APIA. It presumably went unnoticed on account of its invisibility in the raw EEG, becoming evident by means of FFT analysis. If one takes into consideration that the spectral range for EEG quantification is arbitrarily chosen, there is no sound reason why the exclusion of the frequencies below 2.0 Hz

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(as well as the frequencies above 15.0 Hz in order to exclude the slow proportion of muscular potentials) should have any negative impact on GCF-information.

2. Methods and Implications 2.1

The Cerebral Global Function (GCF) as an Indicator of the General Adaptation Syndrome (GAS)

It is generally accepted that the SR-EEG and its intermediary stages are nosologically nonspecific. According to Selye [35], chronic diseases have in common a syndrome consisting of non-specific symptoms, which he designed as General Adaptation Syndrome (GAS). Deviations of the GCF may be considered as a macroindicator of the non-specific GAS that is responsible for general malaise and the impulse to see a doctor. As underlying mechanism of GAS a disturbance of the so-called HPA-axis was detected by means of animal experiments. The HPA-axis is a complicated set of relationships that exist between the hypothalamus, the pituitary gland and the adrenals. The axis controls reactions to stress and regulates many body processes. Selye conceived GAS in his days as an unexploited field of scientific insights. It was his very theory of the non-specific impact that laid the foundations for an end to the unproductive dispute of the brain-mind relation, nevertheless considered as an insoluble conundrum. It stands to reason that the GCF is an indicator of the sum of the non-specific features. Since successively recorded GCF may be compared by means of the ITA-algorithm, the latter may be attributed to a behaviorally-based physiology. In order to determine the amount of clinical change, two staggered recordings at least, are needed. As already stated, the exclusive target variables with ITA are therefore not absolute power values but rather the differences between the patterns characterizing the intermediary stages of GCF. A psychopathological decompensation goes along with a systems’s imbalance. This may be either an “overshooting control” (Dynamic Lability = DL) or a “delayed control” (Dynamic Rigidity = DR). A well ”balanced” control to be observed with healthy adults may also be denoted as “metastabilization” (or Physiomorphic Dynamics, PD). By introducing the GAS as the main concept for his famous neuroendocrinological discovery, Selye’s mindset becomes obvious from the following citation: “ the adaptation syndrome could have been discovered during the Middle Ages, if not earlier; its recognition did not depend upon the development of any complicated pieces of devices, new techniques of observation, nor even upon much ingenuity or intelligence, as far as that goes, but merely upon an unbiased state of mind, a fresh point of view [35].

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The notion of GAS deserves attention on account of its semantic status as a macroindicator characterizing medicine as an “inverse science”. Inverse sciences deal with circumstantial evidence and thus with so-called ill-posed problems occupying broad areas of medicine. Compared to sciences with well-posed forward problems, for instance physics, one has to make conclusions from particular symptoms to the underlying causes being not directly observable. With respect to indicator problem, one has to distinguish between microindicators representing specific phenomerna, (for instance Koplik spots indicating measles) on the one hand and macroindicators, representing the full range of non-specific causes of chronic diseases, on the other. 2.2

Definition of the ITA–variables

Variable 1:

Alpha-Rhythm (8-13 Hz), to be designed as posteriorly accentuated; calculated for O1-A1 and O2-A2); ideally prevailing for the first 5 minutes of an unimpaired SR-EEG [36, 40].

Variable 2:

Barycentric Frequency (BF), defined as “geometrical descriptor of the frequency power spectrum” or the “frequency median” across the spectral power range from 2.0 to 15.0 Hz [37, 38]. It has been shown to correlate well with the oxygen intake. Moreover, it is the most valid indicator of the restitution of brain infarctions, remarkably not only over the lesioned but also the unaffected hemisphere

Variable 3:

Anterior spreading out of the Alpha-Activity, indicates a moderate decrease in the level of CGF [39, 40, 41, corresponding to the intermediary stage A1-A2 which is quantitatively expressed by a quotient, both for the left and the right hemisphere (AQl and AQr). The AQ is calculated from absolute Alpha-power values (8-13 Hz) for successive 2-second epochs due to the anterior-posterior relationship: and

Variable 4:

Number of non-A segments, ideally Alpha background activity shows a certain degree of continuity. This feature is expressed by a number of non-A segments within successive recording minutes [1, 2, 3, 12, 13, 14, 15, 16, 25, 26 ]. A non-A segment is referred to, when the absolute Alpha-power (8.0-13.0 Hz) does not exceed more than 50% of the total power (2.0-15.0 Hz). A greater number of non-A segments corresponds to more Alpha-discontinuity. A comparison between the diagrams of the time course of the AQ measures and the numbers of the non-epochs, shows up as nearly congruent. This may be

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replicated ad libitum. The finding of a mutual validation of two indicators of the actual GCF-level deserves interest because Alpha-topography and Alphacontinuity are seemingly quite disparate as well independent parameters. The distinctness of the mutual validation of the two indicators of the EEGVigilance level could not be expected since Alpha-topography and Alphacontinuity are to be viewed as quite disparate aspects of the EEG signal. Variable 5:

Absolute power of the slow frequencies (2.0-7-5 Hz), calculated for F3, F4, O1, O2, referenced to the ipsilateral earlobes; conventionally regarded as an indicator of a more or less pronounced impaired CGF [1, 2, 3, 13, 25, 26, 40, 41] but also to be observed without any psychiatric impairment in about 1 % of a sample.

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Fig. 3 The five ITA Variables

An increase of the Variables 1 and 2 and a decrease of the Variables 3, 4, and 5 compared to the initial EEG reveal improvement of the CGF. The left column indicates “Sensitivity level I”, the right one “Sensitivity level II”. With Variables 1, 3, 4, and 5 changes are to be related to the initial value (100 %). With Variable 2 (BF) the scoring follows on grounds of a fixed bandwidth of change. The choice of the non-A criterion 70, 60, 50, 40, or 20 absolute AlphaPower complies with initial SR-EEG. The chosen criterion has to be maintained in the analysis of all subsequent calculations. Within the pilot stage it had turned out, that test-retest reliability could be improved by logarithmical transformation of the original measures. Furthermore, with the lower sensitivity level (Sensitivity I) differences are treated more conservatively, than with the higher sensitivity level (Sensitivity II). The Difference-TotalScore, resulting from adding up of the single difference-scores indicates the degree of clinical improvement or deterioration. Paradoxical effects have to be considered according to Wilder’s Law of Initial Value [43, 44]. For instance, one has to take into account that with an initially distinct amount of DR, a decrease of Alpha-continuity indicated an improvement of the GCF or of the clinical condition. The same applied in contrast with an initially distinct DL where an increase into the direction of DR or Alpha-continuity indicated clinical improvement. To make things even more complicated, one will have to attend those 10 % (at

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least) of subjects with the occurrence of outlasting, state-independent patterns in the sense of a trait with doubtful dynamical information content. With those subjects it will be of particular importance to pay special attention to the single case information [44] by using a Longitudinal Single Subjects Design (LSD). Fig. 4 Glossary for weighing the ITA-Score Differences. Point allocation table for Score Differences

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3. Results 3.1

Vignette 1: Alcoholism, in-patient, detoxification Pat. H.A.: Male 59 y; excessive intake of alcoholic beverages since his early twenties; numerous in-patient treatments related to attempted suicides; withdrawal treatments and abstinence ravings; hospital admission for detoxification as precondition for a subsequent abstinence therapy.

Fig. 5 ITA-Score Differences due to detoxification with a male in-patient aged 59 years, suffering from a severe longstanding alcoholism

Visual assessment: First snippet (001), the second snippet (002) was recorded 14 days later, at same day-time; both recordings taken from the 10th to the 19th seconds from start (F3, F4, C3, C4, P3, P4, O1, O2) referenced to the ipsilateral earlobes: (I) Low voltage desynchronized pattern, corresponding to stage B1; (II) distinct increase of posteriorly accentuated Alpha-Activity, corresponding to stage A1.

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Distinct improvement of GCF. From a total recording time of 12-15 minutes, two uninterrupted sequences of 10 minutes - comparable both with respect to technical conditions, starting within the 2nd minute of recording - were chosen. Distinct improvement of GCF due to an increase of the Alpha Power, the BF and a decrease of desynchronized Slow-WavePower. For some decades the EEG has nourished the view of a genetic predisposition to alcohol abuse [45; 46]. A majority of patients admitted for detoxification showed the distinct picture of Dynamic Lability (DL), i.e. a Low voltage SR-EEG with frequent transitions into segments with stage B1 - morphology, along with restlessness, anxiety and tenseness. Alcoholic beverages induced as a rule pleasant psychological effects accompanied by an increase of Alpha-continuity. Sobriety, in contrast affected the well-known DL of EEG along with adverse feelings. Thus, the most probable interpretation of the conspicuous EEG dynamics is that of a state-dependent decrease of GCF due to chronic alcohol ingestion. This is confirmed by a simultaneous change of the cortical tissue volume to be demonstrated by brain imaging (MRI). A disturbance of cerebral metabolism may be considered as a common cause. Within two weeks of sobriety state-dependent DL generally changes into metastable physiomorphic dynamics. This interpretation was fully supported by our ITA findings. It was additionally confirmed by the typical psychophysiological pathology due to subsequent relapses in the course of his addictive behavior.

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3.2

Vignette: Experimental therapy with 20 mg Methylphenidate to an in-patient suffering from Acute Mania Pat. H.W.: Male 62y; with Acute Mania, suffering from a Bipolar Affective Psychosis since about 35 years, predominantly manic episodes; Therapeutic effect of a single dose of 20 mg Methylphenidate, as shown by ITA, two hours after oral intake. Fig. 6 ITA-Score Differences due to a single oral dose of Methylphenidate suffering from Acute Mania

Visual assessment: First snipped (001) pre-drug, EEG from 10th to 19th seconds. Two hours later a second SREEG (snipped 002) was recorded (electrode placement identical to the first case). Together with begin of the first EEG-recording (001) 20 mg of Methylphenidate were orally administered. Low voltage activity with transitions into 4-7 Hz groups and interspersed rapid Beta-waves of about 20 Hz, corresponding to stage B1-B2. Distinct increase of posteriorly accentuated spindle-like 10 Hz Alpha-Activity corresponding to stage A1-A2. As with the previous case vignette an uninterrupted sequence of 10 minutes – from the 10th to the 19th min - was chosen for the quantification.

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The two snippets of SR-EEG were completely comparable both with respect to the conditions, being only different with respect to medication of 20 mg Methylphenidate. The comparison showed a distinct improvement of GCF which was due to an increase of the total power of Alpha-Activity along with a posterior accentuation and a clinical improvement of the manic symptoms. ITA confirmed the finding according to which it is justified to start an experimental antimanic drug therapy with methylphenidate, provided the manic condition corresponds to patterns showing late B-stages up to the C-stage [16, 48]. Though the stimulant-therapy was continued with daily doses of 20 mg Methylphenidate, the drug effect faded away within 14 days. Therefore, the therapy was continued with neuroleptics as usual until complete remission. ITA seems to be the ideal procedure to support the conventional anti-manic drug therapy by new experimental attempts. It offers the possibility of a temporally overlapping therapy, i.e. starting with the stimulant in order to obtain the patient’s cooperation, which often cannot be achieved in manic patients.

4. Outlook 4.1

Neurophysiology and/or Psychophysiology

With introducing Head’s “Vigilance” the complementary notion of “Functional Maturation” is implied [26, 40]. This methodically sound requirement may be used to guard Head’s theoretical term of Vigilance against the common misconceiving by the empirical term of “Arousal”. The latter is defined as a physiological activation of psychological performances through the reticular formation up to a certain level and afterwards a decrease, following an inverted U. Arousal states have no traffic with “functional maturation”, of course. With psychiatric issues, the inter-subjects variance is about three times bigger with a sample of psychiatric patients compared to mentally sound controls (40). From that reason alone follows that a mutual reduction of physiological and psychological data is impossible. Therefore any psychophysiologically grounded research needs a theory as a basis which allows to bridge the epistemic gap between the two incommensurable languages of description. It is the basic intention of Head’s theory of vigilance to create such a conceptual basis or framework by bridging of the epistemic gap. Since the vigilance theory only applies to individuals and not to groups of individuals, primary group-statistical comparisons between different groups, for example mentally impaired and mentally sound subjects have to be replaced by the single subjects design whereby each person functions as

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its own control. Our demand challenges the popular normative data based statistical group comparisons, of course. 4.2

Dynamic Pattern Approach (DPA), a promising perspective for future research

According to the currently prevailing research strategy, psychiatric research should be done mainly data-driven. It has to be solved by means of the DPA [51]. The central assignment of DPA is to answer the laconic question by the title of an article of Kosslyn [53: “If neuroimaging is the answer, what is the question? ...and he continues: “To ask questions we must rely on theories … we must devise theories, test them, revise and test again, keeping our eyes open for the unexpected… Simply finding that certain areas are active when someone performs a task is not enough”. DPA is incompatible both with the SR-EEG as a random process as well as with the trendy pseudoscience of “Neophrenology” [49]. The latter culminates in the assertion that brains worked as a “mosaic of rigidly encapsulated modules” [50]. In contrast to Fodor’s theory, brains are working by highly integrated, hierarchically ordered levels consisting of neural mass activity (see above). We are fully d’accord with Nunez’ rather gloomy depiction of the current status of clinical EEG when he called for new pattern recognition methods being based on theoretical considerations and sufficiently sophisticated to deal with the complexity of cortical dynamics. To our opinion this demand represents a decisive perspective for future research: “The clinical EEG is a genuine global measure of neocortical dynamic function. It is currently dominated by experimental studies having minimal theoretical basis in the underlying dynamics. Though ever-increasing mathematical and engineering expertise there is disproportional little progress achieved both with respect to scientific interest and clinical application. Quantification methods are mainly ad hoc approaches. One major flaw consists in general disregarding of the behavioral meaning of the target variables [6]]. and “ Clinicians and psychologists may perform EEG-experiments with little or no theoretical framework [51, page 70 ], and further on Many popular algorithmsare readily available to estimate correlation dimension and formally implementing the cookbook procedures.

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However much more knowledge of the underlying theory is required to produce good science As a result many published EEG works are canditates for the “Journal of Irreproducible Results”[page 468 ]. 4.3 Methodological Reflections We are aware that a thorough understanding of the problems dealt with, requires an amount of epistemic knowledge beyond the usual basics. Since the purpose of our work consists more in the utility and convenience of the methods than in its modernity and prestige we still prefer allegedly outdated procedures of signal analysis as for instance spectral analysis (FFT), compared to the much more modern sounding Detrended Fluctuation Analysis (52). By the way, it may be shown that both methods (FFT and DFA) reveal the same three predilection types of dynamics shown by the spontaneous resting EEG [25, 26] – (see chapter 2.1). Though not belonging to the current vocabulary of present neurosciences, the constitutive terms of Dynamic Pattern Approach (DPA) are to be viewed as seminal in favor of the future development of neurosciences. The Jacksonian pyramid (see Figure1) outlines the importance of the terms being constitutive of the DPA-framework. Its epistemological foundation goes back to JH Jackson [5]. The thought content was promoted by outstanding neuropsychiatrists up to now [9, 54, 55, 56, 57]. The idea behind such a metaphoric paradigm is not to provide an accurate view how brain works. It represents rather an overarching model reflecting the mass action of hierarchically ordered levels due to the interacting elements. If one deals with biosignals, the assessment of structure and dynamics of ongoing activity delivers a measure of global cerebral function (GCF). The theory-guided GCF is both a core term for a global integrative theory and a top down macroindicator of cerebral functioning. As a macroindicator it encompasses the multitude of subordinated datadriven bottom-up research being geared to lose perspective for that reason alone. Therewith, the decisive question of the meaning of the research falls behind. To regain the lost sight of the big picture it may be recommended to refer to the writings of allegedly long-lost authors but in fact highly contemporary authors. This applies especially to John Hughlings Jackson, but also to the largely forgotten Janos Selye whose notion of GAS has to be considered as the key to the treasure chest of modern endocrinology. There exist abundantly examples that a science depends on bearing in rememberance those persons who have decisively contributed to progress. In an article “Hughlings Jackson’s Hirnpathologie” O. Sittig [57] wrote:

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“It can be taken for granted that nobody except Jackson has thought more profoundly about the theoretical foundations of our discipline. It is wise to follow his traces. Jackson’s teachings are not the teachings of today but the teachings of tomorrow”.

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Captions to illustrations Fig. 1 (p. 4)

Ipsative Trend Assessment (ITA) as Indicator of the General Adaptation Syndrome

Fig. 2 (p. 6)

The Theoretical Construct of Head’s Vigilance as mediating between Physiology (Function) and Psychology (Perception/Behavior). The bridging between both is denoted by the two bold vertical arrows

Fig. 3 (p. 11) The five ITA Variables Fig. 4 (p. 12) Glossary for weighing the ITA Score-Differences. Point allocation table for Score-Differences Fig. 5 (p.13) ITA-Score Differences due to the detoxification with an in-patient suffering from severe longstanding alcoholism Fig. 6 (p. 15) ITA-Score Differences due to a single oral dose of Methylphenidate with a patient suffering from acute Mania

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Funding None Availability of data and material All data can be shared. To verify originality our article may be checked by the originality detection Cross Check Competing Interests The authors ensure that the work described has been carried out in accordance with the Code of Ethics of the World Medical Association Conflicts of interests: None