Neuroscience and Biobehavioral Reviews 104 (2019) 11–25

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review article

“Average is good, extremes are bad” – Non-linear inverted U-shaped T

relationship between neural mechanisms and functionality of mental
features
⁎
Georg Northoffa,b,c, , Shankar Tumatib
a
Hangzhou Normal University, Department of Psychology, Hangzhou, Zhejiang, China
b
Mind, Brain Imaging and Neuroethics, Institute of Mental Health Research, University of Ottawa, Ottawa, Canada
c
Centre for Research Ethics & Bioethics, University of Uppsala, Uppsala, Sweden

A R T I C LE I N FO A B S T R A C T

Keywords: Traditionally, studies emphasize differences in neural measures between pathological and healthy groups, as-
Optimal suming a binary distinction between the groups, and a linear relationship between neural measures and
Neuro-mental relationship symptoms. Here, we present four examples that show a continuous relation across the divide of normal and
Inverted-U shape model pathological states between neural measures and mental functions. This relation can be characterized by a non-
Psychiatric diagnosis
linear inverted-U shaped curve. Along this curve, mid-range or average expression of a neural measure is as-
RDoC
sociated with optimal function of a mental feature (in healthy states), whereas extreme expression, either high or
low, is associated with sub-optimal function, and occurs in different neural disorders. Neural expression between
the optimal or intermediate and pathological or extreme values is associated with sub-optimal function and at-
risk mental states. Thus, this model of neuro-mental relationship can be summarized as “average is good, ex-
tremes are bad”. By focussing on neuro-mental relationships, this model can facilitate the transition of psychiatry
from a categorical to a dimensional and individualized approach needed in the era of precision medicine.

1. Introduction how a mental function is affected. A linear regression model (which is

1.1. Background and general aim
Studies in neuroscience and neural disorders typically investigate
mean differences in a neural measure between healthy subjects and
patients. It is assumed that the normal and pathological population
form two distinct groups, between which such a measure differs by a
large extent. For example, the amygdala is a key region in emotion
regulation and its response (evoked activation) to stimuli are altered in
different disorders (Ochsner et al., 2012). In schizophrenia, hypoacti-
vation of the amygdala is observed in response to emotional faces
(Sugranyes et al., 2011). Statistically, this approach relies on detecting
non-overlapping areas of two Gaussian or normal distributions
(Fig. 1A). It also assumes that the normal and pathological populations
are sampled from two different groups with significantly different mean
values (Fig. 1B). From such models, one can only infer that the groups
differ from each other in that particular measure but it does not indicate
commonly used) can extend this approach but would lead to the in-
ference that higher values of the neural measure would occur in the
healthy state and therefore, indicate much better mental function.
However, the accuracy of linear models depends upon measuring
the entire range of values of the independent variable (neural measure,
in this case), and can be used to predict the group (a binary distinction).
However, studies typically assess a healthy group and patient group,
which does not ensure that the entire range of the neural measure in
question is included. In Fig. 1B, a linear model is positioned over the
group differences. If higher values of the neural measure were to occur,
then what would be the status or functioning of this group? Going back
to our example where low and high activation in the amygdala in re-
sponse to emotional faces occurs in schizophrenia and healthy groups,
respectively, a traditional approach would suggest that an even higher
activation in the amygdala would also predict a healthy group. How-
ever, this is not the case empirically, where higher activation than in
the healthy group is seen in post-traumatic stress disorder (PTSD)

⁎
Corresponding author at: Hangzhou Normal University, Department of Psychology, Hangzhou, Zhejiang Province, 310013, China; Mind, Brain Imaging and
Neuroethics, Institute of Mental Health Research, Royal Ottawa Healthcare Group and University of Ottawa, 1145 Carling Avenue, Room 6467, Ottawa, ON K1Z 7K4,
Canada www.georgnorthoff.com.
E-mail address: georg.northoff@theroyal.ca (G. Northoff).

https://doi.org/10.1016/j.neubiorev.2019.06.030
Received 18 March 2019; Received in revised form 18 June 2019; Accepted 20 June 2019
Available online 25 June 2019
0149-7634/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
G. Northoff and S. Tumati Neuroscience and Biobehavioral Reviews 104 (2019) 11–25

Fig. 1. Linearity assumption in analyzing neural changes in patients, its limitation, and comparison to a non-linear model.
In a typical study, a neural measure in a patient group is compared to a matched control group (A, B). A significant difference in the group means is assumed to reflect
an abnormality in the region or measure. However, in this approach, the focus is on the difference in the neural measure between the groups, rather than on the
continuum with possible degrees of the neural measure across groups. The linear model only considers the consequence of one extreme in expression of the neural
measure (inadequate expression in B). In case of overexpression of the neural measure, the functional status of the group (indicated by ‘?’ in B) remains unclear. We
suggest that there exists a continuum of different degrees in the neural measure with an optimal range that is associated with ‘normal’ mental function. Outside this
optimal range shifting to either extreme, i.e., too much or not enough expression, mental function is disrupted and leads to ‘pathological’ states (C). When plotted as a
relation between a neural measure and functionality of mental features like, for instance, self or consciousness, an inverted U-shaped model is revealed (C).

(Etkin and Wager, 2007; Stein et al., 2007). It becomes apparent that
inadequate as well as excess activation of the amygdala is associated
with pathological states, though in different disorders.
Thus, a binary approach comparing a single patient group to a
healthy control group only reveals group differences, and a corre-
sponding mental function can only be considered either present or
absent. Furthermore, this binary approach does not reveal how ex-
pression of a neural measure over its entire range modulates the man-
ifestation of a corresponding mental feature, which is affected in a
disorder. Although implicit, the consequences of different degrees of
neural measures, encompassing its average and extreme values, on
mental features is left in the shadows by such a binary approach.
Another drawback of this binary approach is that between-subject
differences are often regarded as errors of measurement (indicated by
the whiskers of the boxplots in Fig. 1B, or as outliers). This approach
does not account for between-subject differences even within the group,
let alone that of individual differences across the entire study cohort. It
can be seen in Fig. 1B that such between-subject differences show an
underlying continuity from the patient group to the control group in the
neural measure. While the difference in a neural measure between
groups can be discerned, it is not immediately apparent how the neural
measure may be related to a mental feature or function.
Going back to our example, the degree of activation in the amygdala
can indicate three possible states – too low in schizophrenia, adequate
in healthy, and too high in PTSD groups. This leads to an alternate
interpretation of the data – considering the entire range of possible
values of activation in the amygdala, the intermediate range is asso-
ciated with a normal or healthy state, whereas low and high values are
associated with pathological states of schizophrenia and PTSD.
Therefore, amygdala activation in the intermediate range is linked to an
optimal functional state, even though the underlying mental feature of
this association is ignored (Fig. 1C).
How can we then approach the neural basis of specific mental fea-
tures? In this opinion paper, we aim to show that there is a continuous
relation on a functional level between the possible range of neural ex-
pression and an associated mental feature that is non-linear and forms
an inverted U-shaped curve. We review studies in healthy and patient
populations that investigated mental features and synthesize the results
that suggests a new approach – instead of determining differences be-
tween healthy and patient groups, quantifying the continuous re-
lationship between a neural measure and the functionality of a mental
feature can provide a better understanding of the brain and its dis-
orders. A crucial aspect of this neuro-mental approach is to first de-
termine a mental correlate of a neural measure and to recast the
quantification of this mental feature in terms of its ‘functionality’. In
other words, a mental feature is not merely measured in an absolute
manner but also viewed in terms of whether it serves its intended be-
havioral purpose.
We also shed light on healthy brain function by utilizing studies in
various disorders to describe this approach. In doing so, we bridge the
divide between healthy and patient populations. The neuro-mental re-
lationship, in terms of functionality, follows a non-linear inverted-U
shaped curve that is applicable across normal and pathological states,
which can be indexed according to the degree of neural expression.
1.1.1. Relating neural mechanisms to mental features - linear versus non-
linear relationships
Traditionally, a linear relationship between neural and mental fea-
tures is presumed - the higher the degree to which a neural mechanism
is expressed, the better the respective mental feature is expressed.
Consequently, higher values are inferred to be optimal for mental
functions (see also (Holmes and Patrick, 2018) for an evolutionary view
on what is optimal). In the same vein, low degree of expression of the
neural mechanism is considered to be suboptimal, and pathological for
the respective mental feature in psychiatric disorders. For instance,
imaging studies demonstrated reduced neural variability in the sen-
sorimotor network in the depressive stage of bipolar disorder, which
was further associated with psychomotor retardation in these patients
(Martino et al., 2016a,b; Northoff et al., 2018). In this example, one
may infer that a low degree of neural variability impedes psychomotor
function, and that a high degree of neural variability may be required.
This line of reasoning thus assumes a linear relationship between neural
variability and psychomotor function. This relation can be described as
“high is good, low is bad”.
However, data do not conform to the “high is good, low is bad”
model. Martino et al. (2016a,b) and Northoff et al. (2018) demon-
strated that neural variability in the sensorimotor network is higher
than normal in the manic state of bipolar disorder, and is associated
with psychomotor hyperactivity. Thus, amygdala activation as well as
neural variability in the sensorimotor network across disorders show
that high levels of neural expression are not conducive for normal
function.
The implicit presumption of such a linear model of neuro-mental
relationships in neurology and psychiatry stands in stark contrast to
models in medicine (Canguilhem, 1991) and biology (Jonas and Jonas,
2001; Schiff and Fins, 2016) where non-linear models are dominant.
The linear model assumes that only low degrees or values in the ex-
pression of a specific mechanism leads to suboptimal or pathological

12
G. Northoff and S. Tumati
manifestation of the respective behavioral or mental features. This re-
lationship stands in contrast to non-linear models, where the expression
of both low and high degrees of a specific mechanism leads to sub-
optimal and ultimately pathological functioning. Here, each mechanism
has a characteristic range of expression that is associated with optimal
functioning. The optimal values typically fall in the middle of an in-
verted U-shaped curve. Therefore, considering the physiologically
possible range of expression of a neural mechanism, a non-linear model
shows that “average is good, extremes are bad”.
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Neuroscience and Biobehavioral Reviews 104 (2019) 11–25
Fig. 2. Example of a biological model.
(A) Homeostatic regulation by insulin maintains blood glucose
level (in simple terms) in a narrow range (in green) that is
optimal for metabolic and mental functioning. Outside this
range on both ends (in yellow), the functional state remains
normal but the biological state is abnormal and represents a
suboptimal or risk state. Further deviations on either end (in
red) lead to a dysfunctional states, e.g., clouding of con-
sciousness. Thus, the biological mechanism consists of a con-
tinuum with a range of insulin expression that maintains
blood glucose homeostasis, which is necessary for optimal
metabolic and mental functioning (i.e. consciousness) as
manifested in normal behavior.
(B): An inverted U-shaped model relating neural mechanisms
to the functionality of mental features. In this model, the focus
lies on measuring the expression of a neural mechanism (re-
presented on the x-axis) over a continuous range. A corre-
sponding mental feature that is linked to the said neural me-
chanism would also show a range of expression. Importantly,
the y-axis represents ‘functionality’, i.e. the degree to which
the individual is able to function given various degrees of
expression of the mental feature. Hence, the degree of func-
tionality associated with the expression of the mental feature
corresponds to the degree of the neural measure. The ex-
pression of the neural mechanism in the intermediate range
(in green) is expected to lead to an expression of the mental
feature in a manner that is optimal for mental order or func-
tioning. Expression of the neural measure outside the optimal
intermediate range, is expected to be associated with changes
in the functionality of the mental feature that are ‘normal’ but
fall in a suboptimal zone (in yellow), representing a state of
increased risk for mental disorder. Further extremes in the
neural measure (in red) are associated with an expression of
the mental feature that is dysfunctional and occurs in a ‘pa-
thological state’ as it leads to impairments in behavior.
A classic example that highlights a non-linear model while also
bridging biology and mental features is the relationship between glu-
cose, insulin, and the level of consciousness. Both, extremely low and
high levels of glucose and insulin lead to suboptimal or abnormal
mental states, i.e., lost or clouded consciousness. In contrast, inter-
mediate or average values of glucose and insulin are necessary for an
optimal mental state, i.e., normal consciousness. This relationship be-
tween glucose/insulin and consciousness can thus be described as non-
linear and demonstrated graphically as an inverted U-shape
G. Northoff and S. Tumati
relationship (Fig. 2A). Instead, if a linear model were to be assumed, it
would predict increasing levels of consciousness with increasing levels
of blood glucose. This is clearly not the case.
Inverted U-shaped models have recently been introduced in neu-
roscience. For instance, such models have been shown to characterize
the relationship between the concentration of neurotransmitters (like
dopamine, acetylcholine, and noradrenaline) and the degree of neu-
ronal activity (at the cellular level) (Aston-Jones and Cohen, 2005;
Bentley et al., 2011; Cools and D’Esposito, 2011; Luksys et al., 2009;
Vijayraghavan et al., 2007). Recent data suggest that such an inverted
U-shaped relationship also extends to the mesoscopic scale - inter-
mediate degrees of neural activity measured with local field potentials
(reflecting activity in a neuronal populations) were associated with
optimal behavior in the form of high hit rates and reaction times (He
and Zempel, 2013). Based on this result, the authors concluded that
medium or average values of neural activity is best or sufficient for
“optimal behavioral performance” (He and Zempel, 2013). This ex-
ample shows that the inverted-U shaped model not only holds on the
molecular level of neurotransmitters but also on the systemic level of
behavior and with regional neural measures like local field potentials.
1.1.2. Function versus functionality
In our approach, the functionality of a mental feature or behavioral
measure is considered to be crucial. Here, the degree of expression of a
particular measure is not the primary outcome of interest; rather
whether the function serves its intended purpose is important. For ex-
ample, in the regulation of blood levels of glucose, the biological pur-
pose, in simple terms, is to provide adequate energy for metabolism and
not to increase glucose levels to the maximum extent. Similarly, local
field potentials are not simply elevated in response to stimuli but in-
crease to the extent necessary for executing the response. In the same
way, it is likely that neural variability in the somatomotor cortex occurs
to the degree necessary to facilitate motor movements, and amygdala
activation occurs to the degree needed to signify emotional salience.
Let us consider the consequence of excessive expression of the
measured variables on functionality in the above examples. Blood levels
of glucose beyond the optimum range adversely affect the biochemical
milieu, and are associated with hyperosmolarity and loss of con-
sciousness; increased amplitude and frequency of LFP are seen in sei-
zure states; increased neural variability in the somatomotor cortex was
found to be associated with psychomotor excitation in the manic phases
of bipolar disorder; excess amygdala activation is seen with excess re-
activity to stimuli in PTSD.
Thus, an optimum level of expression of a neural measure is re-
quired for normal functionality. The central thesis of this paper is to
show that such an inverted U-shaped model also holds for the re-
lationship between neural mechanisms and mental features. We present
four examples of mental features that include perceptual synchroniza-
tion, consciousness, sense of self, and time speed perception where
current evidence supports a non-linear neuro-mental relationship.
Results across the divide of normal and pathological studies in neu-
roscience and neurology/psychiatry show that only intermediate de-
grees of expression of a specific neural mechanism lead to an optimal
manifestation of the respective mental features. In contrast, low and
high extremes of expression of the same neural mechanism is associated
with suboptimal or pathological manifestation of the mental feature
(Fig. 2B).
2. Inverted U-shaped relationship between neural mechanisms
and mental (dys)functioning
2.1. Inverted U-shape relationship I - excitation-inhibition balance,
perceptual synchronization, and schizotypy personality
2.1.1. Background
We are bombarded with a multitude of stimuli from different
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Neuroscience and Biobehavioral Reviews 104 (2019) 11–25
sensory modalities. These stimuli may occur at slightly different time
points. Despite the asynchronous occurrence of these multisensory sti-
muli, we are nevertheless able to integrate them into our perception in
the form of a temporally unified event. The temporal range over which
asynchronous multisensory stimuli can be integrated is called the
temporal binding window (TBW) (Wallace and Stevenson, 2014).
The TBW is prolonged in individuals with autism (Stevenson et al.,
2014) and schizophrenia (Stevenson et al., 2017). These individuals
show increased temporal integration and decreased temporal resolution
in multisensory perception (see (Northoff and Duncan, 2016) for a
detailed discussion). Prolongation of the TBW is also observed in sub-
clinical subjects with increased degrees of schizotypy personality,
which indicates proneness to psychosis (or schizophrenia) (Ferri et al.,
2017).
Ferri et al. (2017) investigated the neural, biochemical, and genetic
correlates of TBW and schizotypy in healthy subjects. The TBW of
subjects was determined as the duration of asynchronous audio-tactile
stimuli that were reported as a unified event. The authors hypothesized
that the frequencies of the brain’s spontaneous (or resting state) activity
mediate the neural link to the TBW. Long-range temporal correlations
(LRTC), indexed by the power law exponent (PLE), were expected to be
related to the TBW. The equation P∝ 1/f β (where P is power, f is fre-
quency, and β is the PLE) describes the relation between power and
frequencies in the brain’s spontaneous activity (He, 2014, 2011). A high
PLE value indicates stronger power in slow frequencies relative to
power in high frequencies (Chialvo, 2010; Hardstone et al., 2012;
Linkenkaer-Hansen et al., 2001; Manning et al., 2009; Miller et al.,
2009; Palva et al., 2013).
Further, it was hypothesized that, because LRTC are linked to ex-
citation-inhibition balance (EIB), the TBW may also be related to bio-
chemical and genetic indices of EIB. Glutamate and GABA, which are
the principal mediators of EIB, were measured in the auditory cortex
using magnetic resonance spectroscopy (MRS). A genetic EIB score
calculated on the basis of polymorphisms in the expression of glutamate
and GABA in these subjects. This score indicated the relative balance in
excitation or inhibition in each subject.
2.1.2. Neural data
As hypothesized, a higher PLE in the auditory cortex on fMRI, in-
dicating stronger power in slower frequencies relative to faster ones,
predicted a shorter TBW. Moreover, biochemical and genetic measures
of EIB were also related to the TBW. Subjects with a low biochemical
concentration of glutamate in the auditory cortex and low genetic EIB
scores also exhibited a low PLE and a long TBW.
A crucial finding of this study was that high genetic and biochemical
EIB scores were also associated with a longer TBW and low PLE
(Fig. 3A). Notably, these subjects also scored high on schizotypy. In
contrast, a short TBW was only present in subjects with low schizotypy,
intermediate or averages values of glutamate concentration and genetic
EIB scores, and exhibited a high PLE. (See Fig. 3A for an overview of the
results).
2.1.3. Neuro-mental relationship
The TBW is a mental feature of multisensory integration. Ferri et al.
(2017) show that this mental feature is negatively affected by extreme
values on either end of the range of biochemical and genetic expression
of EIB. By also linking the extremes of EIB to schizotypy, the authors
show that extreme neural values even in otherwise normal individuals
impair their functionality, while intermediate values favor optimum
functioning. These findings are in accordance with the model of an
inverted U-shaped relationship between genetic/biochemical measures
on the one hand and mental features (i.e., schizotypy and TBW) on the
other. As this study was conducted only in healthy subjects, the results
show that the inverted U-shaped relationship is also applicable within
the ‘normal’ range. Extreme biological values in the healthy or ‘normal’
range can distinguish between optimal and sub-optimal mental
G. Northoff and S. Tumati
functioning (Fig. 3B).
As schizotypy is a risk factor for psychosis, extreme values on either
end of the spectrum of the ‘normal’ range can also be seen as a tran-
sition zone towards a pathological state of manifestation of mental
features such as in autism or schizophrenia. The TBW in schizophrenia
patients is also altered in audiovisual perception and linked to hallu-
cinations (Capa et al., 2014; Foucher et al., 2007; Martin et al., 2013;
Stevenson et al., 2017; Zhou et al., 2018). Moreover, the TBW is also
altered in autism (Foss-Feig et al., 2010) and epilepsy (Noel et al., 2017)
indicating that a common neuro-mental feature may be affected across
these states. Neural correlates of TBW in these disorders are lacking at
present, and could extend the proposed model to the pathological
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Neuroscience and Biobehavioral Reviews 104 (2019) 11–25
Fig. 3. A: Relationship between excitation-inhibition bal-
ance (EIB), temporal binding window (TBW) in multisensory
perception, and schizotypy personality.
The figure summarizes the results from Ferri et al. (2017).
Multisensory perceptual synchrony was measured by the
TBW (see main text) in healthy subjects along with their
schizotypy personality score. EIB was measured in each
subject with two measures – a genetic score based on poly-
morphisms in the glutamatergic and GABA-ergic genes, and
glutamate and GABA in the auditory cortex by magnetic
resonance spectroscopy. In addition, subjects underwent
resting state fMRI. Subjects with low schizotypy showed in-
termediate values of TBW, power law exponent (PLE, from
fMRI data), and EIB. Subjects with a prolonged (or shor-
tened) TBW (in multisensory perception) showed a corre-
sponding increase (or decrease) in PLE and EIB; in both cases
schizotypy, and hence, risk for psychosis/autism was high.
B: Inverted U-shaped relationship between EIB and psy-
chosis. Recasting the data from Fig. 3A in terms of func-
tionality yields an inverted U-shaped curve where optimal
TBW (multisensory perceptual synchronization) occurs in
the intermediate range (in green) of EIB and PLE. A shift in
the degree of EIB and PLE (in yellow) is associated with an
apparently ‘normal’ TBW, which however implies a risk for
psychosis. Individuals with schizophrenia show a prolonged
TBW (in red) but neural data (about PLE and EIB) in this
cohort are still lacking. As suggested by the figure, EIB and
PLE may be shifted further to the right in schizophrenic
patients, potentially exhibiting low PLE and increased EIB.
range. Accordingly, although more findings are needed, the data indeed
suggest a continuum from schizotypy to schizophrenia that is in line
with the current model of an inverted U-shape.
To summarize, the mental feature of TBW was optimal (as indicated
by their schizotypy score) only when the EIB scores (genetic and bio-
chemical) were optimal. At the functional level, a shift in EIB to either
extreme is associated with reduced temporal multisensory perception
and high schizotypy. On a more mechanistic level, these findings sug-
gest that the temporo-spatial dynamics of the resting state, e.g., scale-
free activity, is transformed into the temporal features of the TBW on
the mental level. Temporo-spatial dynamics may, at least in this and
possibly in other instances, thus seem to provide a “common currency”
G. Northoff and S. Tumati
of neuronal and mental features: the temporo-spatial features on the
neuronal level are manifest and thus transformed into the subjectively
perceived temporal features of the TBW (see also (Northoff et al., 2019)
for the concept of “common currency”).
2.2. Inverted U-shape relationship II – long range temporal correlation
(LRTC) and the richness of consciousness
2.2.1. Background
In the second example, we focus on the relationship between con-
sciousness and neural frequencies. Consciousness is considered as the
ability to experience specific contents, i.e., objects or events, in a sub-
jective way as featured by a specific quality, and/or to access the
contents of that experience (Block, 2005; Changeux, 2017; Dehaene
et al., 2017). It is classically expressed by the rhetorical question –
‘what it is like’ (Koch, 2018; Koch et al., 2016; Nagel, 1974; Northoff,
2013a; Tononi et al., 2016).
The neural mechanisms of the contents of consciousness remain
unclear. Various neuroscientific theories of consciousness have been
proposed such as the Integrated Information Theory (Tononi et al.,
2016), the Global Neuronal Workspace Theory (Changeux, 2017;
Dehaene et al., 2014), entropic brain hypothesis (Carhart-Harris, 2018;
Carhart-Harris et al., 2014), and the Temporo-spatial theory of con-
sciousness (TTC) (Northoff, 2013b; Northoff and Huang, 2017). As it is
not central to the purpose of this article, we will not go into the details
of these theories, which have been discussed elsewhere (see (Northoff,
2013a, 2018) for overviews). Here, we focus on LRTC (long-range
temporal correlations) in neural activity, which has been investigated in
various states of consciousness.
Consciousness is commonly described in terms of contents or rich-
ness and in levels. Richness refers to number of events or objects that
are perceived, and level refers to the degree of consciousness, such as in
minimally conscious state (MCS), sleep, and wakefulness. The contents
of consciousness can become increased to an abnormal extent. Such
extremes occur in states induced by drugs (psilocybin, lysergic acid
diethylamide (LSD), or ketamine) (Atasoy et al., 2018, 2017; Carhart-
Harris et al., 2016; Schartner et al., 2017; Tagliazucchi et al., 2016; Viol
et al., 2017).
Drug-induced states can therefore be considered an extreme in-
stance where the contents of consciousness are experienced in an ab-
normally rich manner in quantitative and qualitative terms (Carhart-
Harris, 2018). It can be said that richness of consciousness is extended
beyond its “normal” or average range. The opposite occurs if the rich-
ness of the contents of consciousness is reduced. This state is observed
in sedation, early sleep stages (N1 and N2), and MCS where con-
sciousness becomes clouded and restricted (Laureys, 2005; Tononi
et al., 2016).
2.2.2. Neural data
Recent studies (fMRI and E/MEG) on drug-induced psychosis (using
ketamine, psilocybin, LSD, and/or ayahuasca demonstrated increased
power in the faster frequencies (Atasoy et al., 2018, 2018; Carhart-
Harris, 2018; Carhart-Harris et al., 2016; Schartner et al., 2017; Viol
et al., 2017). In contrast, power in the slower frequencies was pre-
served. The relative power balance was thus shifted toward the faster
frequencies, which results in a lower PLE (Fig. 4A).
Interestingly, sleep deprivation shares a commonality of increased
arousal with drug-induced psychosis, which manifests as increased
vigilance and sensitivity to stimuli. Similar to drug-induced states, sleep
deprived subjects also show lower PLE values (on EEG) (Meisel et al.,
2017). Although it is not clear whether common behavioral and neural
changes extend to an increased level of consciousness, the finding
suggests that neural and behavioral changes similar to the drug-induced
state can occur in the absence of the drug. Hence, the behavioral state
(and presumably level of consciousness) is tied to the neural state rather
than the drug.
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Neuroscience and Biobehavioral Reviews 104 (2019) 11–25
The opposite state of sparse contents of consciousness occurs during
early sleep stages (N1 and N2), sedation, and loss of consciousness. In
these states, opposite changes occur in the power spectrum. Power in
the faster frequencies is reduced while power in the slow frequencies
(0.01 to 0.1 Hz) is preserved or abnormally increased as demonstrated
in both fMRI and EEG/MEG (Fingelkurts et al., 2012; He et al., 2010,
2008; Huang et al., 2018; Lewis et al., 2012; Sitt et al., 2014; Zhang
et al., 2018)
As measured in the respective frequency ranges of fMRI (0.01 to
0.1 Hz) and EEG/MEG (0.1–100 Hz), the balance between the fre-
quencies is thus shifted towards the slower ones, which as the data
suggest, is associated with diminished content-richness of conscious-
ness. Reflecting the relative power increase in slower frequencies, stu-
dies reported increased PLE during sleep (N1, N2, and N3 stages), se-
dation, MCS, and anesthesia (Huang et al., 2018; Meisel et al., 2017;
Tagliazucchi et al., 2016, 2013; Zhang et al., 2018) (note – Huang et al.,
2018 used autocorrelation function).
2.2.3. Neuro-mental relationship
Taken together, PLE provides an index of neural activity and shows
a linear relation to the contents of consciousness – high in states of
increased richness of consciousness and low in states of sparse contents
of consciousness. It is important to note that both these states with
increased or decreased contents of consciousness are sub-optimal.
Individuals in either extreme state are unable to function in day-to-day
life. In contrast, PLE values in healthy awake subjects fall in the in-
termediate range between the two extremes, reflecting an appropriate
balance of power between the slower and faster frequencies. Here too,
an inverted U-shaped relationship is demonstrated between the neural
measures (PLE) and functionality of content-richness of consciousness
(Fig. 4B).
This inverted-U shaped relationship is reinforced by moving to-
wards one extreme - complete breakdown of consciousness seen in
coma or deep surgical anesthesia. In these states, the LRTC of sponta-
neous activity and thus of its scale-free operation completely break-
down (Huang et al., 2018; Tagliazucchi et al., 2013; Zhang et al., 2018).
Accordingly, the neural measure also moves towards the extreme end
with very low values of PLE. One may speculate that at the opposite
extreme, for instance, during states induced by abnormally high doses
of the above-mentioned drugs, the PLE value will be very high. How-
ever, no studies to our knowledge have reported such results. (see also
(Carhart-Harris, 2018)).
Finally, it shall be noted that, on a more mechanistic view, the
observed relationship of PLE and contents of consciousness supports
those theories of consciousness that emphasize the central role of the
brain’s temporo-spatial dynamics; these include especially the temporo-
spatial theory of consciousness (TTC) (Northoff, 2018, 2016, 2014,b;
Northoff et al., 2019; Northoff and Huang, 2017) as well as others like
the entropy hypothesis (Carhart-Harris, 2018) and the Operational
time-space theory (OST) (Fingelkurts et al., 2010). Assumption of in-
formation integration, like in the Integrated information theory (IIT)
(Tononi et al., 2016), and access to global workspace, as in the Global
Neuronal Workspace theory (GNWT) (Dehaene et al., 2017, 2014), may
then need to be related to the brain’s temporo-spatial dynamics.
2.3. Inverted U-shape relationship III – medial prefrontal cortex (MPFC)
resting state/task-evoked activity and the sense of self
2.3.1. Background
A sense of self is a central feature of our inner mental life. What do
we mean by self? Psychological investigations describe a self-reference
effect (Northoff et al., 2006; Rogers et al., 1977; Sui et al., 2012; Sui and
Humphreys, 2015). Contents related to oneself in various psychological
functions including memory, perception, emotions, and decision-
making show higher degrees of accuracy and faster reactions (Nakao
et al., 2013; Northoff, 2016; Sui and Humphreys, 2015). In addition to
G. Northoff and S. Tumati
self-reference, other cognitive functions related to the self include self-
experience, self-awareness, self-reflection, self-attribution, and self-
monitoring (Philippi and Koenigs, 2014). For the sake of simplicity, we
refer to these functions as sense of self, self-consciousness, or self-focus.
The sense of self is related to neural activity in specific regions of the
brain. When participants are asked to judge trait adjectives (own vs
other) or other stimuli (like auto- vs hetero-biographical events, or own
vs other names), the resulting task-evoked activity strongly recruits the
ventro- and dorso-medial prefrontal cortex (MPFC), ventral anterior
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Fig. 4. A: Scale-free activity, as measured by the power law
exponent (PLE), and content-richness of consciousness.
Temporal correlations in neural activity are scale-free, as seen
in the schematic power spectrum. The PLE, which is the slope
of the power spectrum, provides a measure of the relative
distribution of power in slow and fast frequencies. The green
line represents the power spectrum in the conscious awake
state in normal individuals. A shift in the power spectrum in
either direction, towards slow or fast frequencies, is associated
with an altered state of consciousness. Specifically, a shift in
the power spectrum towards faster frequencies is seen in drug-
induced psychosis where the contents of consciousness are
increased. The opposite case is seen in sedation where con-
tents of consciousness are reduced and power is shifted to-
wards slow frequencies. In the extreme case of anesthesia, the
relation between slow and fast frequencies, and thus the
power-law relationship itself, break down altogether.
B: Inverted U-shaped relationship between scale-free activity
and the content-richness of consciousness.
The figure shows the relation between power-law scaling in
neural activity and the functionality of contents of con-
sciousness. The balance between slow and fast frequencies is
measured by the PLE. The optimal state (conscious and
awake) is associated with a degree of PLE in the intermediate
or average range (green). In contrast, a change in the PLE (in
yellow) indicating a shift towards either slower or faster fre-
quencies occurs in the sleep and sleep-deprived states, re-
spectively. A further shift towards either slower or faster fre-
quencies (in red) is associated with pathological states such as
sedation and anesthesia (towards slow), and drug-induced
psychosis (towards fast). States indicated in the yellow and red
zones indicate poor functionality on the mental level of con-
sciousness either due to too few or too many contents of
consciousness.
cingulate and posterior cingulate cortex, which together form the so-
called cortical midline structures (CMS) (Huang et al., 2014; Murray
et al., 2015, 2012; Northoff and Bermpohl, 2004; Northoff et al., 2006;
van der Meer et al., 2010). It should be noted that the CMS are not
specific to the self as they have been implicated in other internal pro-
cesses like emotion regulation, mind wandering, and social interaction
(Christoff et al., 2016, 2009; Schilbach et al., 2012).
Spontaneous neural activity organizes the brain into networks, of
which the default mode network (DMN) closely overlaps with the CMS
G. Northoff and S. Tumati
(D’Argembeau et al., 2005; Davey et al., 2016; Qin and Northoff, 2011;
Schneider et al., 2008; Whitfield-Gabrieli et al., 2011). Moreover, re-
cent studies show that the temporal structure of spontaneous activity
(measured by PLE), autocorrelation window, and cross-frequency cou-
pling) in the MPFC predicts the degree of self-consciousness (Huang
et al., 2016; Wolff et al., 2018). This “rest-self overlap” (Bai et al., 2016)
not only shows the convergence between the self and the spontaneous
activity of the brain but also allows for inferring changes in the resting
state to changes in the sense of self.
The sense of self is affected in major depressive disorder (MDD) and
in the depressive phase of bipolar disorder (dBD). In these cases, the
sense of self is abnormally increased - thoughts revolve around oneself,
and are associated with negative emotions like sadness and guilt
(Hamilton et al., 2015). This is described as increased self- or internal-
focus as a typical psychopathological hallmark of depression in general
(Northoff, 2014; Northoff and Sibille, 2014; Northoff, 2007; Northoff
et al., 2011). In contrast, the focus of depressive patients towards the
external environment is strongly reduced. Thus, there is an imbalance
between increased self-focus and decreased environment-focus.
2.3.2. Neural data
Various studies show that task-evoked activity in the dorsal MPFC
during self-reference is abnormally elevated in depressed MDD patients
(Lemogne et al., 2012, 2010; Li et al., 2017; Nejad et al., 2013; Renner
et al., 2015; Sarsam et al., 2013; Wagner et al., 2015). At the same time,
task-evoked activity in the ventral MPFC exhibits reduced deactivation,
i.e., the magnitude of the negative BOLD response during is lower
(Grimm et al., 2011, 2009; Lemogne et al., 2012). Because the degree of
deactivation or negative BOLD response in VMPFC reflects the degree of
cognitive involvement with externally-directed attention (Raichle et al.,
2001; Shulman et al., 1997), reduced deactivation in this region can be
considered to indicate increased internal self-focus and internally-di-
rected attention (Fig. 5A).
Increased task-evoked activity during self-reference in MDD is
complemented by studies that consistently find increased resting state
activity in the dorsal and ventral MPFC in MDD (Fingelkurts and
Fingelkurts, 2017; Hamilton et al., 2015; Kaiser et al., 2015). Analogous
findings are also observed in dBD where the same regions show ab-
normally increased neural activity in the resting state (Martino et al.,
2016a,b).
Mania forms the opposite clinical picture of depression and as stu-
dies show, it also has the opposite mental and neural features. In mania,
internal or self-focus is decreased, and external- or environment-focus is
increased (Martino et al., 2016a,b; Northoff, 2007). As expected, manic
patients show reduced task-evoked activity in the MPFC during self-
referential stimuli (Herold et al., 2017) and posterior cingulate cortex
(Zhang et al., 2015). Moreover, resting state activity in MPFC is de-
creased in mania as measured by functional connectivity and neural
variability (Martino et al., 2016a,b).
2.3.3. Neuro-mental relationship
These results show that extremes of self-focus are associated with
abnormal behavioral states of depression and mania, and these extreme
states are related to extremes in neural activity in the MPFC in the
resting and task-evoked states. Thus, activity in the MPFC is associated
with balance between self- and environment-focus (Fig. 5B).
Accordingly, opposite extremes on the neural level lead to opposite
extremes on the mental level with both ends of this spectrum being
suboptimal and even pathological, favoring an inverted U-shaped
model between neural mechanisms (MPFC activity) and mental func-
tion (self-focus). Intermediate degrees of MPFC resting state and MPFC
task-evoked activity are thus optimal for a sense of self where the in-
ternal self-focus is balanced with external environment-focus. In con-
trast, too high or too low neural activity in the MPFC leads to sub-
optimal manifestation of the sense of self.
On a more mechanistic level, this suggests that the self may allow
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for integrating internal and external contents and thus exert what has
recently been described as ‘integrative function of self’ (Sui and
Humphreys, 2015). For instance, the self may allow integrating the
external contents of perception of objects in the environment with the
more internal contents of our inner thoughts. That integration of in-
ternal and external contents seems to be abnormally tilted towards ei-
ther the internal or external contents which, importantly, also goes
along with different degrees in the expression of self. This suggests that
the degree of expression of self is closely coupled to the balance of
internal-external contents.
2.4. Inverted U-shape relationship IV – neural variability and time speed
perception
2.4.1. Background
A central element of consciousness is the perception of time – this is
reflected in William James’ (1890) description of “stream of con-
sciousness”. In addition to projecting ourselves into the past and future
(Schacter et al., 2012), perception of the speed of time is central to our
“stream of consciousness”. Even if an event unfolds at an objectively
slow speed, we may nevertheless perceive it as fast if we are fascinated
by or drawn into the event – afterwards, we will say “time flies” en-
tailing that our subjective time speed perception was faster (with a
perceived shorter duration of the event) than the objective physical
time duration of the event itself. The opposite is the case if we are
bored; in that case, time does not move at all in our subjective per-
ception so that we will perceive the duration of the event much slower
and longer than it actually was.
Psychiatrists like Thomas Fuchs (2013) distinguish between inner
and outer time speed perception. Inner time speed perception describes
our own personal time, that is, how one perceives the speed of the own
self as either slow or fast. While outer time speed perception is about
how the subject perceives the speed of events or objects in the outer
world.
In healthy subjects, inner and outer time speed perception are
synchronized. In depression and mania, time speed perception is highly
abnormal, albeit in opposite ways. Depressed patients show abnormally
slow inner time speed perception – “nothing changes for them”, which
ultimately results in the perception of a complete “standstill of time”
(Fuchs, 2013; Jaspers, 2014; Northoff et al., 2018; Stanghellini et al.,
2017). While their outer time speed perception is too fast as they per-
ceive events and objects in the outer world as too fast and changing
rapidly (even if they are objectively slow) – patients feel easily stressed
as soon as they are confronted with external demands. The opposite
pattern is observed in mania (Fuchs, 2013; Northoff et al., 2018). Manic
patients perceive their inner time and their self as extremely fast while
the events and objects in the outer world are perceived as too slow. As
in depression, there is an imbalance between inner and outer time
perception.
2.4.2. Neural data
During tasks of inner time speed perception, healthy subjects show
the involvement of regions in the somatomotor network (SMN) in-
cluding the supplementary motor area (SMA), premotor cortex, medial
and superior frontal gyrus, inferior parietal cortex, posterior insula, and
subcortical regions like thalamus, pallidum and putamen (Ortuño et al.,
2011; Wiener et al., 2010; Wittmann, 2013). Since these regions are
apparently involved in the perception of inner time speed, they have
been described as a “neural timing circuit” (Stevens et al., 2007; Tipples
et al., 2013). In contrast, primary sensory cortices like the visual cortex
or visual network (VN) may mediate outer time speed perception as
they are the first cortical encounter of external stimuli with the brain
(Northoff et al., 2018).
Time speed perception on the perceptual level is about change in
events. On the neural level, variability of ongoing activity can be con-
sidered to be an index of the degree of change. Different methods have
G. Northoff and S. Tumati
been used for this purpose including variance of the signal, mean sum of
squared deviations, and root mean square of the difference in signal
amplitude from time point to time point (standard deviation - SD)
(Garrett et al., 2013).
This facilitates a specific neuro-mental hypotheses. High SD in the
SMN, indicating large changes in the amplitude of spontaneous activity,
can be expected to be associated with fast perception of inner time
speed, and low SD in the SMN can be expected to be related to slow
perception of inner time speed. Analogously, SD in the VN can be ex-
pected to mediate outer time speed perception.
Results in depression and mania confirm this hypothesis (Northoff
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Fig. 5. A: Relationship between medial prefrontal cortical
(MPFC) resting state/task-evoked activity and self-focus.
Activity in the MPFC is linked to self-focus, which indicates
the degree to which thoughts related to oneself are pro-
cessed and perceived. For example, depression is associated
with increased self-focus (rumination and excessive self-re-
lated thoughts), accompanied with reduced focus on non-
self related or external thoughts. In these patients, MPFC
activity is found to be increased. In mania, the opposite case
occurs with reduced self-focus and increased focus on the
external environment. In these patients, MPFC activity is
reduced. These neural changes are present during task-
evoked states as well as in the resting state.
B: Inverted U-shaped relationship between MPFC activity
and self-focus. Viewing the degree of self-focus with respect
to functionality, both increased and decreased self-focus are
associated with increasingly pathological states. Both in-
creased and decreased self-focus are related to abnormal
activity in the MPFC - either too high (increased self-focus)
or too low (decreased self-focus). In contrast, the ‘normal’
state with optimal functioning shows intermediate activity
levels in the MPFC. This is related to an intermediate degree
of the internal self-focus and is presumably in balance with
external environment-focus. Accordingly, both high and low
extremes in MPFC activity lead to poor functionality.
et al., 2018). As expected, depressed bipolar patients showed decreased
SD in the SMN accompanied by abnormally high SD in the VN, which
accounts for their perception of abnormally slow inner time speed and
abnormally fast outer time speed. The perceptual imbalance between
inner and outer time speed in depressed subjects may thus be related to
imbalance in neural variability in SMN and in VN (Fig. 6A).
In manic bipolar patients, the opposite pattern was observed. SD
was increased in the SMN and reduced in the VN, which is consistent
with the subjective perception of abnormally fast inner time speed and
abnormally slow outer time speed (Northoff et al., 2018). The psy-
chopathological symptoms were also correlated with SD in SMN and
G. Northoff and S. Tumati
VN, and the ratio of SD in SMN and VN. These symptoms were corre-
lated with SMN-VN SD ratio but not with the SD in the single networks
themselves. This result suggests that the balance between the SD of the
two networks rather than the SD of each network is central to time
speed perception. The de-synchronization between inner and outer time
speed perception can thus be traced to a corresponding imbalance in SD
between SMN and VN (Fig. 6B).
2.4.3. Neuro-mental relationship
Both extremely low and high degrees of neural variability in SMN
and VN lead to suboptimal inner and outer time speed perception on the
mental level in depression and mania states of bipolar disorder. In
contrast, average values of SD in SMN and VN, as observed in healthy
subjects, allow for temporal synchronization in the perception of inner
and outer time speed, and thus for mental order. Together, this follows
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Fig. 6. A: Relationship between neural variability (SD) in
sensorimotor and visual networks and inner and outer time
speed perception in depression and mania.
Neural variability in the visual and sensorimotor network
together is associated with inner and outer time speed
perception. In other words, the relative balance of SD in the
two networks may determine the perception of time speed.
An increase in SD in the visual network along with a de-
creased SD in the sensorimotor network is associated with
the perception of fast outer time and slow inner time, which
occurs in depression. In contrast, decrease in SD in the vi-
sual network and increased SD in the sensorimotor network
is associated with the perception of fast inner time and slow
outer time, which occurs in mania. Note, the change in SD
in either of the two networks alone does not correlate with
the perception of time speed.
B: Inverted U-shaped relationship between neural varia-
bility and time speed perception. The data from Fig. 6A
show that a shift in the balance of SD in the visual and
sensorimotor network (VN and SMN) is associated with a
change in the balance between inner and outer time speed
perception. A shift in either direction is associated with a
decline in the functionality of time speed perception. When
the balance of SD shifts towards the VN (decreased SD in
SMN and increased SD in VN), inner time speed is perceived
as slow and outer time speed is perceived as fast. This state
is observed in anxiety and depression. A shift in the SD
balance towards the SMN (SD increased in SMN and re-
duced in VN) is associated with inner time speed being
perceived as too fast and outer time speed as too slow. This
state is manifested in mania. Accordingly, in both extremes
of SD balance, the individual’s balance between inner and
outer time speed perception becomes dysfunctional and
negatively affects behavior.
the inverted U-shaped relationship between the degree of the neural
mechanism (SD SMN-VN balance) and the balance between inner and
outer time speed perception across the normal and pathological spec-
trum. Thinking about potential diagnostic markers, these and other
(Martino et al., 2016a) findings suggest that we may want to focus more
on balances or ratios between neuronal networks rather than on single
neuronal measures (like the neuronal networks themselves). Hence,
what seems to be important for functionality is the balance between
different neuronal networks which may then also operate as a potential
diagnostic marker.
3. Discussion
We presented four examples from recent neuroimaging research
about the relationship between neural mechanisms and mental features
G. Northoff and S. Tumati
across the divide of normal and pathological states. Despite their dif-
ferences, all examples show that intermediate or average degrees in the
expression of a neural mechanism lead to optimal manifestation of the
respective mental feature. Extreme degrees of the same neural me-
chanism induce suboptimal expression of the same mental function.
Thus, we propose that the neuro-mental relationship is non-linear and
forms an inverted U-shaped model. Below, we discuss the implications
of the inverted U-shaped model for our understanding of the neuro-
mental relationship in healthy and pathological states.
3.1. “Neuro-mental spectrum” and non-linear relationship
In addition to demonstrating that extreme neural values are sub-
optimal for functioning, the above examples show that the range of
possible values of a neural mechanism corresponds to a range of ex-
pression of mental features. We describe this as a “neuro-mental spec-
trum”. Importantly, this neuro-mental spectrum, captured by an in-
verted-U shaped model provides a bridge between the normal and
pathological states. In a linear model, low and high degrees of expres-
sion of a neural mechanism are expected to lead to opposite degrees of
functioning of the respective mental feature. Thus, a sharp boundary
between “normal” and “pathological” states, as expected in a linear
model of neuro-mental relationship may not be precise. The inverted U-
shaped model suggests that a continuous transition exists between the
“normal” and the “pathological” states where an optimum range of
neural expression defines the optimal mental state. This view aligns
clinical neuroscience with that of medicine and biology (Canguilhem,
1991; Jonas and Jonas, 2001; Schiff and Fins, 2016).
The assumption of an inverted U-shaped relationship between
neural mechanisms and mental features carries major methodological
implications for investigations of the relationship between neural and
mental features in normal and pathological states.
Linear statistical models will fail to capture the inverted-U shaped
relation, and as suggested by the first example, this may also be true for
healthy subjects. At best, linear models can be expected to capture ei-
ther the ascending or descending part of the inverted-U relationship. As
a result, only one half of the “normal” neuro-mental relationship is
quantified. At worst, no significant relation will be found in such
models and inferred as the neuro-mental relationship being absent.
Thus, it may be necessary to also estimate a multivariate fit in such
studies, especially in large samples where a wider neuro-mental spec-
trum can be expected (Johnson and Wichern, 2006; Tabachnick and
Fidell, 2007).
Recently, limitations of conventional statistics are being pointed
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Fig. 7. Neuro-mental transformation:
“common currency” for neural and mental
features.
The thematic figure desccribes a putative
model for the transformation of neural activity
into mental features and its relation to mental
disorders. For example, the frequencies of
neural activity may be related to psychomotor
speed. In healthy subjects (b), a ‘normal’ fre-
quency range is likely to be associated with
optimal psychomotor function. A slowing in
neural frequencies would be associated with
psychomotor retardation as seen in major de-
pressive disorder, whereas faster neural fre-
quencies would be associated with psycho-
motor excitation as seen in the manic phase of
bipolar disorder. In this schema, temporo-spa-
tial dynamics form the common currency be-
tween neural and mental features.
Accordingly, a shift in neural dynamics will
lead to a corresponding shift in mental features
and thus to symptoms of various disorders.
out. Emphasis is being laid upon moving away from determining sig-
nificant group differences and towards reporting effect sizes, confidence
intervals, and using adequate sample sizes (Amrhein et al., 2019;
Button et al., 2013). As noted, investigating group differences leads to
the study subjects being conceptualized as categorically different, thus
creating a false dichotomy (Amrhein et al., 2019). In addition to these
widely known statistical issues, our proposal also implicates symptom
variability within samples in psychiatric studies as a contributing
factor. As a continuous neuro-mental relationship is suggested, in-
vestigating the statistical spread of the neural as well as mental measure
of interest maybe important.
3.2. Neuro-mental transformation and internal-external content balance
Here, we used examples of abnormal states to demonstrate a link
between neural measures and mental functions, implying an underlying
neuro-mental transformation. Although, the mechanisms of this trans-
formation are not clear, evidence indicates that temporo-spatial dy-
namics of neural activity modulate the expression of mental features.
For example, mental features such as perception and attention are
shown to be oscillatory in nature in the order of milliseconds (Busch
et al., 2009; Helfrich et al., 2018). That is, perceptive and attentional
capacity goes through peaks and troughs. Remarkably, the capacity of
these mental features are coupled to the phases of neural oscillations.
For example, external visual stimuli are best perceived at the troughs of
alpha oscillations (8–12 Hz) (Busch et al., 2009). It has been suggested
that such neural dynamics facilitate switching between internal and
external modes of processing, which allow for building and updating
models of the world (Honey et al., 2018). Thus, the temporo-spatial
dynamics of neural activity may provide a ‘common currency’ of neuro-
mental transformation (Northoff et al., 2019).
Mental features can be represented under an overarching scheme of
internal and external contents. The relation between the internal and
external mental contents can be considered to be balanced and the
corresponding neural dynamics to be optimal in healthy individuals. A
shift in neural activity would then lead to a corresponding shift in the
balance between internal and external contents, which would be asso-
ciated with sub-optimal mental functioning. We elucidate this principle
of neuro-mental transformation in Fig. 7. The temporal dynamics of
neural activity represented by its frequency are posited to be directly
linked to a psychomotor speed. In healthy individuals, this activity
results in optimum psychomotor function. A slower or faster frequency
of neural activity is associated with a slower or faster psychomotor
speed, which are symptoms of depression and mania, respectively.
G. Northoff and S. Tumati
Accordingly, understanding the full range of the relationship be-
tween internal-external content balance and mental feature expression
will allow for determining where an individual lies on this continuous
spectrum. That, in turn, will foster the development of diagnostic and
therapeutic markers such as the precise neural parameters to be mod-
ified. Below, we consider the implications of such a proposal for clas-
sifying mental disorders.
3.3. Non-linear inverted U-shape and the dimensional classification of
mental disorders
Traditional systems like the Diagnostic and Statistical Manual of
Mental Disorders (DSM 5) (American Psychiatric Association, 2013)
and the International Classification of Diseases (ICD 10) by the World
Health Organisation (World Health Organization, 1993) presuppose a
categorical (present or absent) view of mental disorders. In a nutshell,
such a categorical approach assumes the presence of a neural me-
chanism with “normal” mental function while its absence leads to
“pathological” manifestation as in a mental disorder.
This approach has been challenged by the recent proposal termed
Research Domain Criteria (RDoC), which assumes mental disorders to
be dimensional rather than categorical and to be based on alterations in
neural circuits (Cuthbert and Insel, 2013; Insel et al., 2010; Insel, 2014).
Another cognitive-based classification is ‘Cognitive ontology’ (CO) that
aims to provide a cognitive atlas with standardized description of
cognitive processes and mental concepts which can be applied to
mental disorders (Bilder et al., 2013, 2009; Hastings et al., 2014;
Poldrack et al., 2011). The Hierarchical Taxonomy of Psychopathology
(HiTOP) aims to advance the assessment of psychopathology and per-
sonality (accounting for both, transient and stable maladaptive traits).
Individual’s signs and symptoms are combined and grouped into a di-
mensional continuum in the personality between internalizing and ex-
ternalizing symptoms (Kotov et al., 2018, 2017).
Despite their different foci - neural circuits, cognitive processes, and
personality features, these novel classification systems presume a con-
tinuum between “normal” and “pathological” manifestations of mental
features. Hence, they are called dimensional classifications and termed
as ‘dimensional psychiatry’ (Hägele et al., 2015; Heinz et al., 2016).
However, they do not describe a neuro-mental relationship that can
account for such a dimensional view with smooth transitions between
the “normal” and the “pathological” states.
Our proposal of an inverted U-shaped relationship between neural
mechanisms and mental features provides an operational model for
these dimensional classification systems in psychiatry. This model al-
lows for a range in the expression of a neural mechanism which can
bridge the artificial boundary between “normal” and the “patholo-
gical”. Therefore, it fills an important gap in the proposed dimensional
classification systems of psychiatric disorders (Fig. 2B).
The dimensional nature of inverted U-shape relationship requires
novel methodological approaches in psychiatry. A concrete example
can be seen in an early investigation on catatonia, a psychomotor
syndrome that can occur in various disorders including schizophrenia
and depression (Northoff, 2002). Emotional stimulation was in-
vestigated in subjects with catatonic and non-catatonic schizophrenia
and depression (major depressive disorder/MDD) (Northoff et al.,
2004). Compared to healthy subjects, changes in the lateral prefrontal
cortical in schizophrenia and depression were found. However, this
result does not reveal the neural correlate of catatonia. When catatonic
subjects (with schizophrenia and MDD) were compared with non-
catatonic patients and healthy subjects, changes in orbitofrontal cortex
and orbitofrontal-premotor cortex were found. These changes were
assumed to be related to catatonia rather than its parent disorder (MDD
and schizophrenia) (see also (Martino et al., 2016a,b) for comparison of
psychomotor inhibition and excitation across bipolar depression, MDD
depression, and schizophrenia). Extending the above example to psy-
chiatric disorders in general, it can be expected that a specific degree of
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neural expression is linked to a specific degree of expression of a mental
feature, and is not specific to a diagnostic category.
4. Conclusion
The relationship between neural and mental features is subject to
intense debate. Traditional models assume linear relationship entailing
that higher degrees in the expression of a neural mechanism lead to
better and more optimal manifestation of the respective mental feature.
We here demonstrate that such linear model of neuro-mental relation-
ship does not conform to the data when conceiving results from across
the divide of normal vs pathological states. Presenting various examples
from recent research on neuroimaging, we show that only intermediate
or average degrees in the expression of a neural mechanism lead to
optimal, e.g., “normal” manifestation of the respective mental feature –
“average is good”. In contrast, the data show that extremes at both
ends, i.e., “too low” and “too high” degrees of the same neural me-
chanism lead to suboptimal, e.g., “pathological” manifestation of the
same mental feature. Together this corresponds to a non-linear model
with an inverted U-shape relationship between neural mechanism and
mental feature.
Put in a nutshell, the inverted U-shape model entails that, con-
cerning the degree of expression of the neural mechanism, “average is
good, extremes are bad”. This provides a novel view of neuro-mental
relationship which carries major implications for both neuroscience and
neurology/psychiatry. The non-linear inverted U-shape model allows
connecting neural and mental features in a novel way, i.e., in terms of
neuro-mental transformation, in the neuroscience of the healthy brain.
At the same time, the inverted U-shape model enables us to understand
both inter-individual variability and the normal-pathological con-
tinuum in psychiatry as an intrinsic (rather than extrinsic) feature of the
brain’s way of processing neuro-mental relationships.
Acknowledgments
This work was supported by the European Union’s Horizon 2020
Framework Programme for Research and Innovation under the Specific
Grant Agreement No. 785907 (Human Brain Project SGA2), the
Ministry of Science and Technology of China, National Key R&D
Program of China (2016YFC1306700), Canadian Institute of Health
Research (CIHR), Physicians’ Services Incorporated Foundation (PSI),
and Michael Smith Foundation—Canada Institute of Health Research
(EJLB-CIHR), and by the National Natural Science Foundation of China
(No. 31271195) to G.N.
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