Neurophysiological Correlates of Positive and Negative Symptoms in Frontotemporal Dementia

Abstract

Background:

The neural correlates of behavioral symptoms in frontotemporal dementia (FTD) are still to be elucidated. Neurotransmitter abnormalities could be correlated to the pathophysiology of negative and positive symptoms in FTD.

Objective:

To evaluate if the imbalance between inhibitory and excitatory cortical circuits, evaluated with transcranial magnetic stimulation (TMS), correlate with the magnitude of negative and positive symptoms, as measured by Frontal Behavioral Inventory (FBI) scores, in patients with FTD.

Methods:

Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 186 FTD patients (130 bvFTD, 35 avPPA, 21 svPPA). We applied short interval intracortical inhibition (SICI – GABA_Aergic transmission), intracortical facilitation (ICF – glutamatergic transmission), long interval intracortical inhibition (LICI – GABA_Bergic transmission), and short latency afferent inhibition (SAI – cholinergic transmission). Linear and stepwise multiple regression analysis were used to determine the contribution of each neurophysiological measures to the total variance of FBI scores.

Results:

At the stepwise multivariate analysis, we observed a significant negative correlation between FBI-A scores (negative symptoms) and ICF (β = -0.57, p < 0.001, adjusted R² = 0.32). For FBI-B scores (positive symptoms), we observed a significant positive correlation for SICI (β = 0.84, p < 0.001, adjusted R² = 0.56). Significant correlations were observed for single items of the FBI-A score with ICF and FBI-B scores with SICI, with a medium-large size effect for several items.

Conclusions:

The present study shows that the imbalance between inhibitory and excitatory intracortical circuits, evaluated with TMS, correlated with the magnitude of negative and positive symptoms in FTD, respectively.

Keywords

Frontal Behavior Inventory frontotemporal dementia long interval intracortical inhibition short interval intracortical inhibition-intracortical facilitation transcranial magnetic stimulation

INTRODUCTION

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder, characterized by a broad series of symptoms, including personality and behavioral disturbances, language deficits, and impairment of executive functions [1]. Three phenotypic variants have been characterized based on the predominant clinical presentation, including the behavioral variant of FTD (bvFTD), the agrammatic variant of primary progressive aphasia (avPPA), and the semantic variant of PPA (svPPA) [2,3, 2,3]. Although clinical presentations may vary, these conditions frequently overlap during the course of the disease and behavioral disturbances are described variably in virtually all phenotypes [4,5, 4,5]. These symptoms may be classified, according to the Frontal Behavioral Inventory (FBI), which was specifically developed to highlight the behavioral disturbances in FTD, in negative or deficient behaviors, such as apathy, aspontaneity, and indifference, and positive or disinhibited behaviors, such as irritability, impulsivity, and aggressiveness [6]. Moreover, symptomatic therapies for the management of behavioral symptoms in FTD are largely inadequate and have limited evidence of efficacy [7].

Several structural and functional neuroimaging studies have tried to elucidate the neural correlates of behavioral symptoms in FTD, identifying increased atrophy or impairment in discrete brain regions or networks, which correlate with specific behavioral manifestations. This has greatly enhanced the comprehension of the neural basis of behavioral symptoms in FTD, also providing novel understandings regarding the specific neurotransmitter modifications occurring in these areas [8 –10]. It is now well established that FTD is characterized by a series of neurotransmitter changes, including GABAergic, glutamatergic, dopaminergic, and serotoninergic neurotransmission [11,12, 11,12]. Pathological studies in FTD patients have shown that glutamatergic pyramidal neurons are reduced in the thalamus, frontal and temporal cortex, while GABAergic neurons are reduced in upper neocortical layers of the frontal and temporal cortex [13]. The degeneration of dopaminergic tracts, especially the mesocortical pathway, have been postulated to contribute to behavioral symptoms of FTD, with the observation of reduced D2 dopamine receptors in the frontal lobes of patients with FTD [14]. Moreover, serotonin has been shown to exert a modulatory effect on both glutamatergic and GABAergic transmission [15].

It could be thus hypothesized that positive symptoms may arise as a result of deficient inhibitory circuits (GABA), while negative symptoms may occur following a loss of excitatory circuits (glutamate), parallelly as to what has been postulated for schizophrenia, in which the manifestation of positive and negative symptoms has been partially attributed to the imbalance between inhibitory and excitatory circuits, respectively [16 –18], exerting their control over dopamine functioning in mesolimbic pathways as the final common pathway where multiple neurotransmitters abnormalities converge.

To evaluate the dysfunction of specific neurotransmitters in vivo, transcranial magnetic stimulation (TMS) has provided a unique method to assess inhibitory and excitatory intracortical circuits, which largely depend on GABAergic and glutamatergic transmission [19].

In the present work, we aimed to assess the degree of positive and negative symptoms in a large cohort of FTD patients, and if these independently correlated with the impairment of inhibitory and excitatory intracortical circuits evaluated with TMS. If this hypothesis was confirmed, this might give new clues for symptomatic treatment interventions and therapeutic targets in FTD patients.

METHODS

Standard protocol approvals, registrations, and patient consents

Informed consent was acquired from all participants in accordance to the Declaration of Helsinki. The local ethics committee of the Brescia Hospital approved the study (05.19.2015, #NP1965).

Participants

In the present study, 190 patients fulfilling current clinical criteria for probable FTD, of whom 132 patients with bvFTD [3], 37 with avPPA, and 21 with svPPA [2] were consecutively recruited from the Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy.

Four patients out of 190 (n = 2 bvFTD, n = 2 avPPA) were excluded (2.1%), because carrying electronic implants (n = 1) or because motor cortex excitability was unreliable (n = 3).

The diagnostic assessment consisted in the comprehensive evaluation of the past medical history, a complete neurological and neuropsychological assessment, and an MRI brain scan in all patients.

Disease severity was measured using the Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating (FTLD-CDR) scale sum of boxes [20], while behavioral disturbances were rated employing the Italian version of the FBI, a 24-item scorable caregiver questionnaire, half of which assesses deficient or negative behaviors – part A (apathy, aspontaneity, indifference, inflexibility, concreteness, personal neglect, disorganization, inattention, loss of insight, logopenia, verbal apraxia, and perseveration) and the other disinhibited or positive behaviors – part B (irritability, excessive jocularity, poor judgement, inappropriateness, impulsivity, restlessness, aggression, hyperorality, hypersexuality, utilization behavior, incontinence, and alien hand) [6,21, 6,21]. Each item (12 negative and 12 positive) is scored based on the extent of the behavioral change, ranging from 0 = none; 1 = mild, occasional; 2 = moderate 3 = severe, most of the time.

Basic Activities of Daily Living (BADL) [22] and Instrumental Activities of Daily Living (IADL) [23] were also considered.

In the majority of patients (64.5%), cerebrospinal fluid (CSF) tau and Aβ₄₂ determinations (48.4%) or amyloid PET imaging (16.1%) were performed to exclude focal Alzheimer’s disease (AD) pathology before inclusion, as previously reported [24]. Briefly, a CSF AD-like profile was defined as tau≥400 ng/L and Aβ₄₂ ≤ 600 ng/L using an ELISA assay (INNOTEST, Innogenetics, Ghent, Belgium) [25], while PET amyloid imaging was acquired using 370 MBq (10 mCi) of [18F]-florbetapir and visual readings were performed by nuclear medicine physicians.

Genetic analysis identified 30 patients (16.1%) with pathogenic mutations (n = 21 Granulin mutations, n = 9 C9orf72 expansions).

None of the patients were treated with drugs that could have altered the cerebral cortex excitability in the previous three months.

Clinical and behavioral assessments were carried out concomitantly to TMS protocol (±1 week).

Transcranial magnetic stimulation variables and protocols

For the purpose of the present study, we considered short interval intracortical inhibition and intracortical facilitation (SICI-ICF), long interval intracortical inhibition (LICI), and short latency afferent inhibition (SAI). These measures partially and indirectly reflect the activity of several neurotransmitter circuits: SICI reflects GABA_A, ICF glutamate, LICI GABA_B, and SAI acetylcholine [19,26, 19,26].

A TMS figure-of-eight coil (each loop diameter 70 mm – D70² coil) connected to a monophasic Magstim Bistim² system (Magstim Company, Oxford, UK) was employed for all TMS paradigms, as previously reported [27].

Resting motor threshold (RMT) was determined on the left motor cortex as the minimum intensity of the stimulator required to elicit motor evoked potentials (MEPs) with a 50 μV amplitude in 50% of 10 consecutive trails, recorded form the right first dorsal interosseous muscle during full muscle relaxation.

SICI-ICF, LICI, and SAI were studied using a paired-pulse technique, employing a conditioning-test design. For all paradigms, the test stimulus (TS) was adjusted to evoke a MEP of approximately 1 mv amplitude in the right first dorsal interosseous muscle.

For SICI and ICF, the conditioning stimulus (CS) was adjusted at 70% of the RMT, employing multiple interstimulus intervals (ISIs), including 1, 2, 3 ms for SICI and 7, 10, 15 ms for ICF [28,29, 28,29]. LICI was investigated by implementing two supra-threshold stimuli, with the CS adjusted at 130% of the RMT, employing ISIs of 50, 100, and 150 ms [30]. SAI was evaluated employing a CS of single pulses (200 μs) of electrical stimulation delivered to right median nerve at the wrist, using a bipolar electrode with the cathode positioned proximally, at an intensity sufficient to evoke a visible twitch of the thenar muscles [31]. Different ISIs were implemented (-4, 0, +4, +8 ms), which were fixed relative to the N20 component latency of the somatosensory evoked potential of the median nerve.

For each ISI and for each protocol, ten different paired CS-TS stimuli and fourteen control TS stimuli were delivered in all participants in a pseudo randomized sequence, with an inter trial interval of 5 s (±10%).

The conditioned MEP amplitude, evoked after delivering a paired CS-TS stimulus, was expressed as percentage of the average control MEP amplitude. Stimulation protocols were conducted in a randomized order. Audio-visual feedback was provided to ensure muscle relaxation during the entire experiment and trials were rejected if electromyographic activity was greater than 100 μV in the 250 ms before TMS stimulus application. All of the participants were capable of following instructions and reaching complete muscle relaxation; if, however the data was corrupted by patient movement, the protocol was restarted and the initial recording was rejected.

For all analysis, average values were considered for SICI (ISI 1, 2, 3 ms), ICF (ISI 7, 10, 15 ms), LICI (ISI 50, 100, 150 ms), and SAI (ISI 0, ⁺4 ms).

Statistical analysis

Demographic, neuropsychological, and neurophysiological scores are reported as average ± standard deviation. Average neurophysiological measures were compared using one-way ANCOVAs, correcting for age, sex, and disease duration, applying post hoc Bonferroni corrections for multiple comparisons.

For the association analysis, FBI scores and FBI items were considered first. We then considered behavioral phenotypes, and symptoms were cluster into three groups as previously reported [32]. These behavioral clusters have been shown to be associated with selective hypoperfusion in specific brain regions, independently of the effect of other behaviors. We considered the “disinhibited phenotype” (lack of judgment, personal neglect, perseverations, hyperorality, utilization behaviors, hoarding, euphoria, and social inappropriateness), the “apathetic phenotype” (apathy and aspontaneity), and the “aggressive phenotype” (inflexibility, irritability, and aggressiveness) [32].

Linear regression and stepwise multiple regression analysis were used to identify the most fitting explanatory variable/s for negative and positive symptoms’ scores, including disease duration, considering its’ possible role on symptom onset and magnitude. There was linearity as assessed by partial regression plots and a plot of studentized residuals against the predicted values. There was independence of residuals, as assessed by a Durbin-Watson statistics. There was homoscedasticity, as assessed by visual inspection of a plot of studentized residuals versus unstandardized predicted values. There was no evidence of multicollinearity, as assessed by tolerance values greater than 0.1. There were no studentized deleted residuals greater than ±3 standard deviations, no leverage values greater than 0.2, and values for Cook’s distance above 1. The assumption of normality was met, as assessed by a Q-Q Plot.

Statistical significance was assumed at p < 0.05. Data analyses were carried out using SPSS 21.0 software.

Data availability

All study data, including study design, protocol, statistical analysis plan, and results are available from the corresponding author, B.B., upon reasonable request.

RESULTS

Participants

One hundred and eighty-six FTD patients (age 65.8±9.1) were included in the present study. Of these, 130 were classified as bvFTD, 35 as avPPA, and 21 as svPPA. Demographic and clinical characteristics are reported in Table 1. We did not observe significant differences in the severity of behavioral symptoms in the three different phenotypes: for FBI-A, F(1,185)=0.393, p = 0.531; for FBI-B, F(1,185)=0.173, p = 0.678; nor we observed a significant correlation between disease duration and the entity of negative (for bvFTD, r = 0.153, p = 0.083; for PPA r = 0.083, p = 0.542) and positive symptoms (for bvFTD, r =-0.023, p = 0.791; for PPA r = 0.093, p = 0.493).

Table 1

Demographic, clinical, and neurophysiological characteristics of included patients

	FTD	bvFTD	avPPA	svPPA
Patients (n)	186	130	35	21
Age (y)	65.8±9.1	65.4±9.2	68.6±9.0	63.4±7.5
Gender (% female)	44.6%	39.2%	62.9%	47.6%
Disease duration (y)	3.1±2.4	3.3±2.5	2.6±1.9	3.2±2.5
Education (y)	10.1±4.4	9.8±4.4	10.8±4.0	11.6±5.0
FTLD-CDR	6.6±4.7	6.9±4.6	6.2±5.0	5.4±5.2
MMSE	21.0±8.3	21.0±8.1	19.7±9.2	22.6±8.2
BADL	0.8±1.5	0.9±1.5	0.8±1.7	0.3±1.0
IADL	1.8±2.4	2.0±2.4	1.6±2.6	0.9±2.0
FBI-A (negative)	14.0±7.7	13.8±7.8	15.6±7.1	12.8±7.7
FBI-B (positive)	9.9±6.4	10.0±6.2	11.8±6.9	6.0±4.9
TMS measures
RMT (% MSO)	0.45±0.09	0.45±0.09	0.45±0.09	0.46±0.09
SICI	0.85±0.43	0.86±0.42	0.95±0.41	0.60±0.40
ICF	0.81±0.20	0.82±0.18	0.77±0.22	0.86±0.25
LICI	0.84±0.53	0.84±0.52	0.83±0.56	0.81±0.56
SAI	0.56±0.15	0.57±0.14	0.55±0.17	0.54±0.12

Demographic and clinical characteristics, and neurophysiological parameters are expressed as mean±SD; resting motor threshold is expressed as ratio of the MSO; SICI, ICF, LICI, and SAI are represented as ratio of mean motor evoked potential (MEP) amplitude related to the control MEP. bvFTD, behavioral variant frontotemporal dementia; avPPA, agrammatic variant primary progressive aphasia; svPPA, semantic variant primary progressive aphasia; FTLD-CDR, frontotemporal lobar degeneration-modified clinical rating scale sum of boxes; MMSE, Mini Mental State Examination; BADL, basic activities of daily living; IADL, instrumental activities of daily living; TMS, transcranial magnetic stimulation; RMT, resting motor threshold; MSO, percentage of maximal stimulator output; SICI, mean short interval intracortical inhibition (1, 2, 3 ms); ICF, mean intracortical facilitation (7, 10, 15 ms); LICI, mean long interval intracortical inhibition (50, 100, 150 ms); SAI, mean short latency afferent inhibition (0, ⁺4 ms); MEP, motor evoked potential; n.s., not significant. ^*p-values for one-way ANOVA (post hoc tests with Bonferroni correction for multiple comparisons) or Chi-Square’s test, as appropriate.

At the one-way ANCOVA we observed a significant interaction between genetics and both SICI, F(2,186)=5.78, p = 0.004, η² = 0.06, and LICI, F(2,186) = 4.37, p = 0.014, η² = 0.05, with a greater impairment in GRN carriers compared to non-carriers (p = 0.003 for SICI, p = 0.011 for LICI). No significant interactions were observed for ICF or SAI.

We did not observe a significant association with brain asymmetry (left versus right predominant), for SICI (β = 0.01, p = 0.909, adjusted R² = -0.01), ICF (β = 0.03, p = 0.710, adjusted R² = -0.01), LICI (β = -0.08, p = 0.294, adjusted R² < 0.01), or SAI (β = 0.03, p = 0.729, adjusted R² = -0.01).

Neurophysiological measures as predictors of FBI scores

A linear regression analysis was run to understand the effect of neurophysiological measures on FBI scores. We observed a significant association for average SICI (β = 5.86, p < 0.001, adjusted R² = 0.10), ICF (β = -23.09, p < 0.001, adjusted R² = 0.36), and LICI (β = 4.05, p < 0.001, adjusted R² = 0.07) with negative symptoms (FBI-A scores) but not for SAI (see Table 2).

Table 2

Univariate linear regression and stepwise multivariate regression models for predictors of FBI-A and FBI-B

	Univariate				Stepwise multivariate
	B	SE_B	β	p	B	SE_B	β	p
FBI-A (negative symptoms)
Disease duration	0.42	0.23	0.13	0.076	–	–	–	–
SICI	5.86	1.25	0.32	<0.001	–	–	–	–
ICF	–23.59	2.27	–0.60	<0.001	–21.39	2.48	-0.57	<0.001
LICI	4.05	1.08	0.28	<0.001	–	–	–	–
SAI	–1.37	4.00	–0.03	0.732	–	–	–	–
FBI-B (positive symptoms)
Disease duration	0.03	0.20	0.01	0.872	–	–	–	–
SICI	11.06	0.74	0.74	<0.001	11.10	0.79	0.74	<0.001
ICF	–8.16	2.29	–0.26	<0.001	–	–	–	–
LICI	4.90	0.88	0.40	<0.001	–	–	–	–
SAI	2.61	3.43	0.06	0.448	–	–	–	–

FBI, frontal behavioral inventory; SICI, mean short interval intracortical inhibition (1, 2, 3 ms); ICF, mean intracortical facilitation (7, 10, 15 ms); LICI, mean long interval intracortical inhibition (50, 100, 150 ms); SAI, mean short latency afferent inhibition (0, ⁺4 ms). B, unstandardized regression coefficient; SE_B, standard error of the coefficient; β, standardized coefficient. Significant values are reported in bold-face.

Regarding positive symptoms (FBI-B scores), we also observed a significant association for SICI (β = 11.06, p < 0.001, adjusted R² = 0.54), ICF (β = -8.16, p < 0.001, adjusted R² = 0.06), and LICI (β = 4.90, p < 0.001, adjusted R² = 0.15) but not for SAI (see Table 2).

We then applied a stepwise multiple regression analysis including all variables with a p < 0.100 at univariate analysis to determine the overall fit of the model and the relative contribution of each of the predictors to the total variance explained.

For FBI-A scores, only ICF (β = -0.57, p < 0.001, adjusted R² = 0.32) resulted significant in the multiple regression analysis model, while SICI and LICI did not. For FBI-B scores, only SICI (β = 0.84, p < 0.001, adjusted R² = 0.56) resulted significant in the multiple regression analysis model, while ICF and LICI did not (see Fig. 1 and Table 2).

Fig.1

Scatter plots of significant associations between neurophysiological measures and FBI scores. A) Average ICF at ISI 7, 10, 15 ms and FBI-A scores; (B) average SICI at ISI 1, 2, 3 ms and FBI-B scores; FBI, frontal behavioral inventory; ISI, inter stimulus interval.

These findings were confirmed also considering bvFTD and PPA patients separately. In bvFTD, for FBI-A scores, only ICF (β = -0.58, p < 0.001, adjusted R² = 0.33), while for FBI-B scores, only SICI (β = 0.73, p < 0.001, adjusted R² = 0.53) resulted significant; in PPA patients, for FBI-A scores, only ICF (β = -0.56, p < 0.001, adjusted R² = 0.29), while for FBI-B scores, only SICI (β = 0.78, p < 0.001, adjusted R² = 0.60) resulted significant.

Results were also confirmed with an even stronger correlation in patients with a GRN mutation; for FBI-A scores, only ICF (β = -0.80, p < 0.001, adjusted R² = 0.63), while for FBI-B scores, only SICI (β = 0.77, p < 0.001, adjusted R² = 0.58) resulted significant in the multiple regression analysis model.

Association of neurophysiological measures and single FBI items

Regarding single items of the FBI score, at the stepwise multiple regression analysis we observed significant associations with a medium-high effect size (adjusted R²≥0.15 according to Cohen [33]), with ICF and several negative symptoms (FBI-A), including apathy (β = -0.37, p < 0.001, adjusted R² = 0.15), aspontaneity (β = -0.39, p < 0.001, adjusted R² = 0.15), indifference (β = -0.43, p < 0.001, adjusted R² = 0.18), and logopenia (β = 0.42, p < 0.001, adjusted R² = 0.15) (see Supplementary Table 1).

For positive symptoms (FBI-B), we observed significant associations with a medium-high effect size (adjusted R²≥0.15) with SICI and perseverations/obsessions (β = 0.44, p < 0.001, adjusted R² = 0.19), hoarding (β = 0.49, p < 0.001, adjusted R² = 0.23), excessive jocularity (β = 0.53, p < 0.001, adjusted R² = 0.27), poor judgement and impulsivity (β = 0.49, p < 0.001, adjusted R² = 0.24), restlessness/roaming (β = 0.49, p < 0.001, adjusted R² = 0.24), irritability (β = 0.41, p < 0.001, adjusted R² = 0.16), aggression (β = 0.45, p < 0.001, adjusted R² = 0.20), hyperorality (β = 0.48, p < 0.001, adjusted R² = 0.22), hypersexuality (β = 0.52, p < 0.001, adjusted R² = 0.26) and incontinence (β = 0.41, p < 0.001, adjusted R² = 0.16) (see Supplementary Table 1).

Association of neurophysiological measures and behavioral phenotypes

We observed significant associations with at the stepwise multiple regression analysis for the “disinhibited phenotype” and SICI (β = 0.70, p < 0.001, adjusted R² = 0.49), for the “apathetic phenotype” and ICF (β = -0.41, p < 0.001, adjusted R² = 0.16) and for the “aggressive phenotype” and SICI (β = 0.55, p < 0.001, adjusted R² = 0.30) (see Fig. 2).

Fig.2

Scatter plots of significant associations for single “behavioral phenotypes”. A) Average SICI at ISI 1, 2, 3 ms and FBI subscores in the “disinhibited phenotype”. B) Average ICF at ISI 7, 10, 15 ms and FBI subscores in the “apathetic phenotype”. C) Average SICI and FBI subscores in the “aggressive phenotype”. FBI, frontal behavioral inventory; ISI, inter stimulus interval.

DISCUSSION

Currently there are no FDA approved therapies for behavioral disturbances in FTD and clinicians are faced to use symptomatic therapies based on the rationale and efficacy in treating other neurodegenerative disorders or psychiatric conditions with similar behavioral complaints.

This has been the result of only few well-designed clinical trials [7] and the current lack of knowledge regarding the pathophysiology of these symptoms, and if they are associated with specific neurotransmitter deficiencies or imbalances.

In the present study, we observed a significant association between neurophysiological markers of intracortical inhibition and facilitation and behavioral symptoms in FTD patients. In particular we observed that a reduction of intracortical inhibition, assessed with SICI and LICI, which predominantly depend on GABA_A and GABA_B circuits, respectively, correlated with an increase in positive symptoms of the FBI score, as restlessness, irritability, and aggression. On the other hand, negative symptoms as apathy, aspontaneity, and indifference were associated with reduced intracortical facilitation, assessed by ICF, which partially reflects a facilitation likely mediated by glutamatergic NMDA receptors. These results were also confirmed clustering patients in behavioral phenotypes, which have been shown to be associated with cerebral hypoperfusion in specific brain regions involving distinct cerebral networks [32].

We did not observe any associations between behavioral symptoms and SAI, a marker of cholinergic transmission, further underlying how cholinergic dysfunction is not predominant in FTLD pathology and does not influence behavioral disturbances in FTD.

These changes seem to reflect the neurotransmitter abnormalities which are now clearly associated with FTLD, particularly in serotonin, dopamine, GABA, and glutamate [11], possibly reflecting the underlying pathological process and the imbalance in intracortical inhibitory and excitatory circuits in patients with FTD [34 –41].

In schizophrenia, positive and negative symptoms have been historically attributed to the “dopamine hypothesis”, where it is postulated that overactive mesolimbic dopamine neurons cause the positive symptoms of psychosis while the underactive mesocortical dopamine neurons, cause the negative, cognitive, and affective symptoms [42]. This theory is also supported by pharmacological observations that drugs that increase dopamine can augment psychotic symptoms, whereas antipsychotic drugs that decrease dopamine by antagonizing dopamine D2 receptors actually diminish psychotic symptom [43]. However, the oversimplification dictated by the “dopamine hypothesis” also suggests that dopamine hyperactivity could be the final common pathway where multiple other neurotransmitters, receptors, and neuronal pathways converge on the mesolimbic system allowing dopamine hyperactivity to finally ensue under the influence of non-dopamine neurotransmitters [43]. Indeed, it is now well known that glutamatergic and GABAergic interneurons in the frontal cortex descend into the mesolimbic structures to exert their control over dopamine functioning [16]; regions that are disrupted also in FTD patients and correlate with the magnitude of behavioral disturbances [14,32,44–46 , 14,32,44–46]. This imbalance between inhibitory and excitatory circuits could thus give rise to positive and negative symptoms, respectively, also in patients with FTD [47,48, 47,48].

An interesting parallelism has also been observed in neural oscillations in FTD and schizophrenia, in which significant abnormalities of synchronization of the beta-band activity have emerged, which may arise owing to anomalies in the brain’s rhythm-generating networks of GABA interneurons [49,50, 49,50]. However, this theory is merely speculative and has to be corroborated by further studies.

Parallelly to FTD, studies with TMS in schizophrenia have consistently shown a decrease in SICI in virtually all patients, with several studies reporting correlations between positive symptoms and SICI impairment [51 –53]. However, no significant differences have been observed in ICF [54] and, only partially, in LICI [55,56, 55,56].

Overall, these results could raise crucial implications for pharmacologic therapies, justifying the use of specific pharmacological categories to treat different behavioral symptoms, depending on whether positive or negative symptoms predominate. Indeed, the current lack of knowledge regarding the pathophysiology of behavioral symptoms in FTD has precluded the design of evidence-based pharmacological clinical trials and a rational approach in treating these symptoms.

Currently we lack effective therapies for seriously disabling symptoms in FTD, not only in the positive domain, as aggression, irritability and restlessness, but also for negative symptoms as apathy and indifference. These findings provide novel evidence regarding the basis of these symptoms, adding up to the current knowledge in FTD. Moreover, the correlation between intracortical connectivity measures and core symptoms in FTD might suggest the use of TMS as an outcome marker to monitor the efficacy of pharmacological and non-pharmacological interventions, as suggested by previous studies [57 –59].

We did not observe a significant linear association between disease duration and the entity of positive or negative symptoms in both bvFTD and PPA patients. This has been assessed in a recent study in which behavioral symptoms in FTD phenotypes have a non-linear progression, with the entity of several symptoms increasing and then declining over time [60].

We acknowledge that this study entails some limitations. First, we did not have pathological confirmation for each diagnosis, with the exception of monogenic FTD, even though in a number of cases we performed CSF analysis to rule out focal variants of AD. Moreover, this a single center study, and results should be confirmed in larger multicenter studies.

Our findings suggest that the imbalance between GABA and glutamatergic transmission, evaluated indirectly with TMS, may have a direct effect on the magnitude of positive and negative symptoms in FTD, hypothetically mediated by a diverse modulation of dopaminergic mesolimbic pathways. The non-invasive in vivo monitoring of intracortical connectivity using TMS may provide novel insights into the pathophysiology of behavioral disturbances in FTD, providing a robust biomarker for an evidence-based approach to the treatment of these disabling symptoms for which we currently lack an effective therapy.

Footnotes

ACKNOWLEDGMENTS

This study was partially supported by grants from “AIRAlzh Onlus” and “ANCC-COOP” issued to VC, and partially supported by a grant from the Italian Ministry of Health (GR-2013-02357415) issued to MC.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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