ADHD syndrome and tic disorders: two sides of the same coin

Paolo Mariotti PhD1, Simona Lucibello MD1, Valentina De Clemente PhD1, Stefania Veltri PhD1, Delfina Janiri
PhD3 ,Paolo Calabresi PhD2, Anna Rita Bentivoglio PhD2

1 Unit of Child Neuropsychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS,

2 Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli
IRCCS, Institute of Neurology

3 Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli
IRCCS, Institute of Psychiatry

Corresponding Author:

Paolo Mariotti, MD,

Unit of Child Neuropsychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Largo Agostino Gemelli, 8 – 00168 Rome, Italy

paolo.mariotti@policlinicogemelli.it

Tel. 00390630155340
Abstract

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioural condition in children and it is
highly comorbid with Tourette Syndrome.

Aim of this study was to investigate the distribution patterns of tics and stereotypies in a large sample of
individuals with the Inattentive (ADHD-I) and Combined type (ADHD-C). In this perspective, we also
investigated severity of Tourette symptoms in the two groups.

We assess the occurrence of tic and stereotypies in 644 ADHD patients, aged 6-17, compared with 88 age-
matched individuals with Tourette Syndrome. All patients were assessed through the Stereotypy Severity Scale,
the Yale Global Tic Severity Scale.

Among the 576 children with ADHD-C, 571 had abnormal involuntary movements: 230 presented with tics,
162 only stereotypies and 179 either tics or stereotypies. Only 5 patients didn’t report tics nor stereotypies. The
severity of tics and stereotypies in the ADHD group was lower than in the TS group. Among the 68 children in
the ADHD-I subgroup, 5 presented with stereotypies, no one presented with tics.

Our results support the hypothesis that the ADHD-C type includes abnormal involuntary movements in its
phenomenology, thus indicating a broad spectrum of fronto-striatal dysfunction, of which Tourette plus possibly
is the complete expression. The detection of tics and stereotypies could be a useful support to the diagnosis of
ADHD. Moreover, the absence of tics in the Inattentive subgroup is an additional element in favour of
considering the Inattentive subgroup as a separate disorder instead of a subtype of ADHD.
Introduction

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioural condition and the second
most common chronic illness in children. Recent national survey data indicated that 9·4% of US children
received an ADHD diagnosis at some point and that 8.4% currently had ADHD (1). ADHD is now recognized
as a lifelong disorder and it presented with a high comorbidity rate. Of particular importance is its association
with Tourette Syndrome (TS), which is considered the most severe chronic Tic Disorder. According to this
clinical overlap, ADHD and TS are included in the same diagnostic group in the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM -V) (2). Previous epidemiological studies in the general
population found that the co-occurrence of these two disorders is markedly higher than expected by chance
association: about 50% of the cases with TS meet the criteria for ADHD and Tic Disorders are reported to occur
in around 20% of children with ADHD (3The speculation on the relation between ADHD and TS is indeed
intriguing, and the first paper dealing with this matter, by Robertson and Eapen, is dated 1992 (4).Subsequently,
Palumbo and colleagues (5) suggested that the comorbidity of tics and ADHD, as well as Obsessive Compulsive
Disorders (OCD) and Autism, might be the result of shared underlying genetic factors converging at the level of
cortico-striatal-thalamocortical circuitry. Nowadays we see an increasing acceptance of this idea, suggesting that
the comorbidity between ADHD and TS is based on a general genetic susceptibility for neurodevelopmental
disorders, rather than on mutations to specific genes causing a specific disorder (6). Therefore, instead of
viewing TS, OCD, ADHD, and autism as separate and co-morbid conditions, these disorders should be
considered as part of a spectrum with overlapping aetiologies, which converge on an underlying dysfunctional
cortico-striatal circuitry (7). ADHD and TS, in fact, share a common connectivity deficit (8), characterized by
underlying neural long-range underconnectivity and short-range overconnectivity (9).

From a clinical perspective, a medical literature review focused on the co-occurrence of ADHD and TS
highlighted that data on this topic did not come from direct observations by expert neurologists and were either
based on small sample size or on pre-selected subjects followed for a short period of time (10-15). However, in
Schneider’s study (16) a 15-minutes videotape revealed tics in 41% of ADHD children, a figure about twice that
generally reported in the literature Therefore, a presumably substantial number of individuals with tic disorders,
in particular when tics are mild, remain undiagnosed, while ADHD impacts on several aspects of daily life and
is mostly diagnosed (17).

We would like to stress that ADHD is accepted as encompassing several subtypes, characterised according to
clinical peculiar and predominant features. Some authors categorise patients from their study sample based on
their ADHD, i.e. inattentive, hyperactive/impulsive or combined phenotype (10-15), but the occurrence of tics in
these subtypes is not taken into account.

Considering the above-mentioned evidence and everyday clinical observations, we hypothesize that tics are
underestimated in most ADHD subjects, as it has been noted in TS, often undiagnosed, since symptoms are
attributed to habits or other conditions. (18)
The aim of this study is to assess the occurrence of tic disorder in an ADHD clinical sample referred to a tertiary
university-affiliated Child Neuropsychiatric Clinic, regional referral centre for ADHD. We also evaluated the
occurrence of primary stereotypies, as in our observation - consistently with literature data - they are commonly
observed in ADHD subjects (19).

Patients and Methods

Young patients, children and adolescents (aged 6-17), referred to our regional referral centre for ADHD of the
Child Neuropsychiatry Unit of the Fondazione Policlinico Universitario A. Gemelli IRCSS, were consecutively
enrolled in the study in the period January 2013- December 2018. Diagnosis of ADHD was independently
confirmed by two expert paediatric neurologists, a senior (PM) physician and one of the other authors of this
article (VDC, SL, SV), and it was based upon medical interview with both patient’s parents and on a clinical
observation of the patient lasting about 45 minutes. The Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV-TR) ADHD Criteria Rating Scale was administered to parents, and subsequently to
teachers, for diagnosis confirmation (2). Children who did not have the same profile according to parents and
teachers assessment were not included in the study.

Exclusion criteria were (i) no additional diagnoses according to DSM-IV-TR Criteria, including, Autistic
Spectrum Disorder (ASD); (ii) lifetime history of major neurological disorders, such as epilepsy and stroke; (iv)
intellectual disability (intelligence quotient < 70); (v) major medical illness.

In order to compare the burden of tics in the daily activity of ADHD patients, ADHD probands were compared
with age-matched patients with Tourette Syndrome followed at our Paediatric Neuropsychiatry Unit. Each
diagnosis of TS was based upon a medical interview with both patient's parents and on a clinical observation
lasting about 45 minutes performed by two expert paediatric neurologists, according to DSM-IV-TR Criteria.
Exclusion criteria were the same for the ADHD group.

All patients were assessed through a dedicated anamnessis and clinical observation. If present stereotypies and
tics were further investigated through the Stereotypy Severity Scale (20) and the Yale Global Tic Severity Scale
(21).

Statistical analyses

Continous variables were be presented as mean and standard deviation, categorical variables as absolute or
relative frequency. T-test was performed to compare YGTSS index scores and SSS index scores between
ADHD and Tourette groups.

Role of the funding source

No funding was received for this study

Results

A total of 732 patients were enrolled in the study according to inclusion and exclusion criteria, 644 with ADHD
and 88 with TS (control group).

ADHD group

The ADHD sample included 549 males (85%) and 95 females (15%), aged 6-16, mean age of 11 (standard
deviation [SD] 3·3). All subjects (100%) met the DSM-IV-TR criteria for ADHD; 576 (89%) for ADHD
Combined subtype, and 68 (11%) for ADHD Inattentive subtype. In the combined subtype subgroup, the
average score for inattention symptoms, assessed according to DSM-IV-TR, was 8 (range 6-9), and for
hyperactivity-impulsivity symptoms was 7 (range 6-9). In the second (inattentive) subgroup the average score
for inattentive symptoms was 7 (range 6-9), while the score for hyperactivity was 2 (range 0-5).

According to the clinical questionnaire, among the 576 children with ADHD combined subtype, 571 presented
with abnormal involuntary movements (AIMs) (i.e., excessive blinking, tics, stereotypical hand movements),
while only 5 (<1%) never reported tics nor stereotypies. In 230 (40%) only tics were reported, in 162 (28%)
only stereotypies and in 179 (31%) either tics or stereotypies. Among 409 ADHD patients with tics (72%), 118
patients (28%) presented with only motor tics (eye blinking, shoulder shrugging, facial grimacing, neck
stretching, mouth movements); 291 (72%) had motor and vocal tics (throat clearing, grunting, coughing, and
sniffing).

The YGTS Score in the ADHD combined subgroup was administered to all ADHD patients presenting tics (404
individuals). Mean YGTSS Social Impairment was 1·31 (SD 5·43); mean Total Tic Severity Score was 14 (SD
8) and mean Total Yale Severity Score was 15·94 (SD 12·22).

Three hundred forty two (59%) patients with ADHD combined subtype exhibited common types of primary
motor stereotypies (e.g., nail biting, head banging, rocking, finger drumming, pencil tapping or hair twisting),
while primary complex motor stereotypies were only observed in 3·5% of patients (20 patients).

The SSS Score in the ADHD combined subgroup was administered to all ADHD patients presenting
stereotypies (342 individuals). Mean SSS Social Impairment was 1·24 (SD 3·72); mean Total Stereotypies
Severity Score was 5·2 (SD 7·1) and mean Maximum Total Score was 8·8 (SD 6·5)

Among 68 children from the Inattentive subgroup, five presented stereotypies.

TS group

The Tourette sample included 88 patients with a diagnosis of Tourette’s Disorder (according to the DSM-IV-TR
criteria), 72 males (82%) and 16 females (17%) with a mean age of 13 (standard deviation [SD] 3·6), 45% of
these patients meet also the criteria for ADHD.

All the 88 patients were reportedly suffering from tics and stereotypies, which were also observed during the
clinical evaluation in 100% of cases.

In the TS group, mean YGTSS Social Impairment was 13·90 (SD 10·78); mean Total Tic Severity Score was
24·13 (SD 10·02), and mean Total Yale Severity Score was 39·37 (SD 19·52).
These values were statistically higher than those found in the ADHD combined subtype group (p value<0·05)

In the TS group, mean SSS Social Impairment was 21·45 (SD 7·44); mean Total Stereotypies Severity Score
was 15·9 (SD 6·3) and mean Maximum Total Score was 33·4 (SD 10·4).These values were statistically higher
than those found in the ADHD combined subtype group (p value<0·05).

All results were resumed in Table 1.

Discussion

Among patients with ADHD combined subtype, 71% presented with tics, with (31%) or without (40%)
Stereotypies, and 29% presented only with stereotypies. all of them presented a movement disorder, in most
cases tics; however, YGTSS, Total tic severity Scale, Social impairment, Total Yale severity Scale indicated a
minimal-mild severity of tics with a consequent low or no impact on daily living. When considering the ADHD
inattentive subtype, we failed to observe tics and even stereotypies were only rarely reported (5/67). In neither
group, the presence of stereotypies was associated with low self-esteem, nor with impairment in family life,
school, or social acceptance, or interrupted flow of behaviour. All patients scored 0 in global impairment rating
and interference.

Mink proposed a model of inhibitory control dysfunction and subsequent aberrant activity of striatal neurons
involving several cortico-basal ganglia circuits to explain tic and behaviours in TS (23).

Recent studies strongly support this hypothesis as a loss of parvalbumin inhibitory interneurons in the anterior
striatum was demonstrated. The extent and preferential localization of the loss of these interneurons inside the
striatal territories, which can affect different cortico-basal ganglia (BG) circuits, explains the variability in
symptoms expression in TS (24). Moreover, the impairment of the striatum and its connections has been
hypothesized to explain hyperactivity/impulsivity in children with ADHD (25). The hypothesis of the
involvement of BG in ADHD is supported by experimental results on nonhuman primates. In these experiments,
local disinhibition within functional territories of BG permitted a precise mapping of their motor and nonmotor
functions; interestingly, although the neuronal networks underlying the behavioural effects elicited from
different parts of the anterior striatum were largely distinct, in some cases there was a partial overlap (26).

A latest study showed that tic expression and hyperactivity share similar local neuronal activity changes which
manifest as different neuronal and behavioral outcomes, confirming the striatal disinhibition as the common
mechanism underlying tics and hyperactivity (25)
On the basis of such experimental evidence, a hypothesis was proposed that striatal interneurons loss underlies
the variations in symptom expression, causing defective inhibitory mechanisms in selecting muscular groups,
resulting in involuntary movements (simple motor tics) and inappropriate actions (complex tics) or inappropriate
behaviours observed in TS. Specifically, motor disorders occur when defective inhibition is located in the
sensorimotor territories of BG, while behavioural disorders (AD/HD and OCDs) occur if the dysfunction is
inside the associative and limbic BG territories. Thus, the same dysfunction within a structure can impact
movement or behaviour, depending on the territory involved (23, 28).

In this regard, we would also like to stress that since cortical and basal ganglia interneurons originate from the
same structures during brain development (29), a reduced number of inhibitory interneurons may also be present
in the cortex, leading to both structural changes and functional abnormalities.

All this evidence also fits with the morphological and functional research on circuitry underlying tics and
hyperactivity, suggesting that these symptoms share a common neuro-anatomical basis consisting of a common
connectivity deficit and delay in cortical maturation (30, 31). This model might also be applicable to
neurodevelopmental disorders, apparently extremely heterogeneous, as their constituent symptom dimensions
may actually overlap (32). This model fits with the results of our research as it highlights that prolonged clinical
observation and accurate anamnestic investigation are able to identify the presence of tics in a high percentage
of children with ADHD Combined Type.

An interesting hypothesis that can supplement those mentioned above might involve aberrant cortical and
subcortical synaptic plasticity in different types of hyperactive disorders. As a matter of fact, experimental and
clinical and preclinical studies found that hyperkinetic disorders such as Huntington's disease, dystonia and l-
DOPA-induced dyskinesia in Parkinson's disease are all characterized by a loss of the ability to reverse synaptic
plasticity at the cortico-striatal level. This effect is coupled with an abnormal increase of excitatory neuronal
inputs to cortical and subcortical brain areas. Interestingly, these changes have been measured in subjects with
hyperkinetic disorders by direct recordings from implanted deep brain electrodes or using transcranial magnetic
stimulation. Thus, a hypothesis has been made that the loss of bidirectional plasticity (lack of depotentiation) of
cortico-striatal pathways represents a common mechanism for hyperkinetic movement disorders (33). In line
with this hypothesis, aberrant cortical associative plasticity has also been associated with severe adult Tourette
syndrome (34).

In conclusion, we propose that tic disorders are part of the phenotype of ADHD– Combined Type, and their
observation or anamnestic detection strongly supports the diagnosis. It could be argued - why were these
involuntary movements, apparently so common among ADHD patients, not considered? The answer may come
from patients and their relatives: when asked on this matter, most parents answered that they had not noticed
them, as these movements were considered part of a hyperkinetic behaviour, while phonic tics were attributed to
other causes (i.e. allergy or impolite habits). Moreover, during the observation of children, clinicians noticed
mild tics (mostly unrecognized) in several parents. Consistently, when comparing the burden of tics among our
patients to the TS group, the YGTSS showed significant differences, especially in the items of Social
Impairment (ADHD < 10 while patients with TS > 10), Total Severity Score (ADHD <15 while patients with
TS >15), and Interference (ADHD < 20 and TS > 20). This evidence and the subsequently lower impact on daily
life, according to Schandler (17), can explain the underestimation of the rate of tic disorders in ADHD in the
previous research works.

The model is also strengthened by the fact that the near totality of subjects without tics presented motor
stereotypies that, as accepted by most authors, frequently co-occur with other disorders affecting fronto-striatal
brain systems, including ADHD, obsessive–compulsive disorder, and tic disorders, which belong to the
neurodevelopmental movement disorders group (35).

The stereotypic movements observed in our study were mostly characterized by common stereotypies.
Movements in this category have been frequently labelled as habits. Numerous behaviours are included, such as
thumb sucking, nail biting/chewing, rocking, hair twirling, finger and foot tapping, and others (36).

Nail biting has been observed as the most common stereotypic behaviour in children with ADHD,74·6% (37);
consistently, it was the most frequent habit also in our sample, in several cases involving foot nails as well.

We would like also to highlight on another observation in our study: besides the presence of tics in ADHD-
combined subtype, we remark a total absence of tics in the predominantly Inattentive ADHD subtype, diagnosed
according to DSMIV-TR classification (2). As in previous papers focused on tics in ADHD the authors did not
distinguish among subtypes, the absence of tics in the Predominant Inattentive Subtype could partially explain
the underestimation of the rate of tic disorders in ADHD. The ADHD-inattentive phenotype presented
stereotypies with a rate similar to that of the general population and with lower intensity, frequency and number
- on the Stereotypy Severity Scale - compared to ADHD-combined subtype.

Despite the classical categorisation of ADHD in three subtypes: PI, CT, Predominantly Hyperactive/Impulsive
(HI), debate is growing whether PI is a separate disorder instead of a subtype of ADHD. Several authors
proposed that the differences between the CT subtype and the PI subtype are significant enough and that rather
than these being two different subtypes of the same disorder, the CT and PI subtypes should be considered as
two distinct disorders (38-41). The presence of tics in CT and their absence in PI strongly support Diamond’s
hypothesis, also in line with recent papers by other authors, according to which the primary neural circuit
affected in ADHD CT is a frontal–striatal loop, whereas the primary neural circuit affected in truly inattentive-
type ADHD (ADD) is in the cortex, a frontal–parietal loop (42,43). Moreover, to confirm this hypothesis,
growing evidence from neuroimaging studies highlighted neurobiological differences between ADHD clinical
subtypes, namely findings from fMRI and DTI imaging modalities consistently indicate disrupted connectivity
in regions and tracts involving frontal striatal thalamic in CT and frontoparietal neural networks in PI (44).

Finally, if we consider ADD a separate disorder from ADHD-CT, we can probably consider stereotypies, tic
disorder, Tourette spectrum and ADHD - belonging to neurodevelopmental disorders - as expression of the
fronto-striatal dysfunction spectrum disorder underpinned by multiple traits as well as biological liabilities.
According to the multi-strike model (45), different sites of the circuitry may be affected based on the different
time points in the development (intrauterine and postnatally) as well as on the extent of involvement of the
cortico–striatal-thalamo-cortical circuitry determining the final clinical expression, including severity and
comorbidities (46).

In conclusion, we suggest the ADHD combined type includes, in its phenotypic spectrum, motor and vocal tics
and stereotypies. ADHD-CT and TS are classified among the neurodevelopmental disorders underlying a
fronto-striatal dysfunction spectrum, of which Tourette plus could be considered the complete expression.
The ADHD diagnosis remains a largely clinical diagnosis, since the objective assessments currently available
are of limited use for clarifying the diagnosis; these include neuropsychological tests, which have a low strength
of evidence, as well as EEG and neuroimaging, for which the evidence remains insufficient (47-49). The
detection of tic and stereotypies could be useful to support the diagnosis.

Author’s contributions

Paolo Mariotti: conceptualization, investigation, methodology, writing

Simona Lucibello: investigation, data curation, formal analysis, writing

Valentina De Clemente: investigation

Stefania Veltri: investigation

Delfina Janiri: methodology

Paolo Calabresi: supervision

Anna Rita Bentivoglio: writing, supervision

Declaration of interests

No author has relationships/conditions/circumstances that present a potential conflict of interest

Acknowledgment

No acknowledgment

Patient and other consents

This is a retrospective study, performed using clinical data from standard care according to Good Clinical
Practice methods for the specific diseases considered in the study; according patients and their parents gave their
consent to use data from the medical records. The study was approved by the Ethics Committee of the
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore of Rome.
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Table 1 Tic and stereotypies details

Variables ADHD combined subtype Tourette Syndrome

Number 576 88

Number of patients with tic only 230 (40%) 0

Number of patients with stereotypies only 162 (28%) 0

Number of patient with both tics and stereotypies 179 (31%) 88 (100%)

YGTSS Social Impairment Score 1·31 + 5·43 13·9 + 10·78

(mean + SD)

YGTSS Total Tic Severity Score 14·0 + 8 24·13 + 10·02

(mean + SD)

YGTSS Total Yale Severity Score 15·94 + 12·22 39·37 + 19·52

(mean + SD)

SSS Score Impairment 1·24 + 3·72 21·45 + 7·44

(mean + SD)

SSS Total Stereotypies Severity Score 5·2 + 7·1 15·9 + 6·3

(mean + SD)

SSS Maximum Total Score 8·8 + 6·5 33·4 + 10·4

(mean + SD)