Fabio Ferrarelli | University of Pittsburgh (original) (raw)

Papers by Fabio Ferrarelli

International Journal of Molecular Sciences

Converging lines of evidence suggest that an imbalance between excitation and inhibition is prese... more Converging lines of evidence suggest that an imbalance between excitation and inhibition is present in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia (SCZ). Gamma-aminobutyric-acid (GABA) and, to a lesser extent, glutamate (Glu) abnormalities were reported in the DLPFC of SCZ patients, especially on the right hemisphere, by post-mortem studies. However, in vivo evidence of GABA, Glu, and Glu/GABA DLPFC abnormalities, particularly on the right side and the early stages of illness, is limited. In this preliminary study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to investigate bilateral Glu/Creatine (Cre), GABA/Cre, and Glu/GABA in the DLPFC of sixteen first episode schizophrenia (FES), seventeen clinical high risk (CHR), and twenty-six healthy comparison (HC) subjects. FES and CHR had abnormal GABA/Cre and Glu/GABA in the right DLPFC (rDLPFC) compared with HC participants, while no differences were observed in the left DLPFC (lDLPFC) among the th...

Brain Sciences

Despite the heavy burden of schizophrenia, research on biomarkers associated with its early cours... more Despite the heavy burden of schizophrenia, research on biomarkers associated with its early course is still ongoing. Single-pulse Transcranial Magnetic Stimulation coupled with electroencephalography (TMS-EEG) has revealed that the main oscillatory frequency (or “natural frequency”) is reduced in several frontal brain areas, including the premotor cortex, of chronic patients with schizophrenia. However, no study has explored the natural frequency at the beginning of illness. Here, we used TMS-EEG to probe the intrinsic oscillatory properties of the left premotor cortex in early-course schizophrenia patients (<2 years from onset) and age/gender-matched healthy comparison subjects (HCs). State-of-the-art real-time monitoring of EEG responses to TMS and noise-masking procedures were employed to ensure data quality. We found that the natural frequency of the premotor cortex was significantly reduced in early-course schizophrenia compared to HCs. No correlation was found between the n...

Brain Sciences

Resting-state electroencephalography (EEG) microstates reflect sub-second, quasi-stable states of... more Resting-state electroencephalography (EEG) microstates reflect sub-second, quasi-stable states of brain activity. Several studies have reported alterations of microstate features in patients with schizophrenia (SZ). Based on these findings, it has been suggested that microstates may represent neurophysiological biomarkers for the classification of SZ. To explore this possibility, machine learning approaches can be employed. Bayesian optimization is a machine learning approach that selects the best-fitted machine learning model with tuned hyperparameters from existing models to improve the classification. In this proof-of-concept preliminary study based on secondary analysis, 20 microstate features were extracted from 14 SZ patients and 14 healthy controls’ EEG signals. These parameters were then ranked as predictors based on their importance, and an optimized machine learning approach was applied to evaluate the performance of the classification. SZ patients had altered microstate f...

Sleep, 2021

Alertness, essential for optimal performance, may be modulated by acute stressors including: slee... more Alertness, essential for optimal performance, may be modulated by acute stressors including: sleep loss, caloric restriction, cognitive load, and physical exertion. Prior sleep may attenuate sleep loss-related alertness decrements, thereby influencing performance and safety. We examined the effects of prior sleep and changes in alertness throughout the day and across days during a simulated military operational stress (SMOS) protocol. As part of a 5-day SMOS protocol, fifty-eight active-duty or recently-separated military personnel (45 men; 26±6 years) completed subjective (Profile of Mood States, Vigor subscale) and objective (3-minute Psychomotor Vigilance Task; PVT) alertness assessments each morning (~0900) and evening (~2200). PVT outcomes included median reaction time (RT) and lapses. Day 2 (D2) reflected baseline testing, in which participants received an 8-hour sleep opportunity (2300-0700) and 100% of their estimated caloric need. Day 4 (D4) reflected peak stress, after two...

Schizophrenia Research, 2019

Sleep Medicine, 2015

In a sense, psychosis, loosely defined as “loss of contact with reality,” is a state of being tha... more In a sense, psychosis, loosely defined as “loss of contact with reality,” is a state of being that happens to all of us each night when we fall asleep. The association between psychosis and sleep is even further strengthened when one considers that psychosis implies not simply a lack of connection with external reality, but a bizarre transformation of consciousness where the mind sees what is not there, emotional content is intensified, the flow of information or time is disjointed, and the sense of one’s self is confused. This is what usually happens when we dream.

American Journal of Psychiatry, 2021

Sleep

Study Objectives Sleep spindles are waxing and waning EEG waves exemplifying the main fast oscill... more Study Objectives Sleep spindles are waxing and waning EEG waves exemplifying the main fast oscillatory activity occurring during NREM sleep. Several recent studies have established that sleep spindle abnormalities are present in schizophrenia spectrum disorders, including in early-course and first-episode patients, and those spindle deficits are associated with some of the cognitive impairments commonly observed in these patients. Cognitive deficits are often observed before the onset of psychosis and seem to predict poor functional outcomes in individuals at clinical high-risk for psychosis (CHR). Yet, the presence of spindle abnormalities and their relationship with cognitive dysfunction has not been investigated in CHR. Methods In this study, overnight high-density (hd)-EEG recordings were collected in 24 CHR and 24 healthy control (HC) subjects. Spindle density, duration, amplitude, and frequency were computed and compared between CHR and HC. Furthermore, WM was assessed for bot...

Schizophrenia Research, 2021

Brain Research, 2021

Transcranial magnetic stimulation (TMS) is increasingly used to examine lower extremity corticosp... more Transcranial magnetic stimulation (TMS) is increasingly used to examine lower extremity corticospinal excitability (CSE) in clinical and sports research. Because CSE is task-specific, there is growing emphasis on the use of ecological tasks. Nevertheless, the comparative test-retest reliability of CSE measurements during established (e.g. knee extensions; KE) and more recent ecological (e.g. squats; SQT) lower extremity tasks has received less attention. The aim of this study was to compare the test-retest reliability of CSE, force, and muscle activity (EMG) during isometric SQT and KE. 19 right-footed men (age: 25±5yrs) with similar fitness and body composition performed SQT (N=7) or KE (N=12) on two consecutive days. Force and EMG were recorded during maximum voluntary isometric contractions (MVC). Corticospinal excitability was determined in the dominant leg during light (15%MVC) contractions based on motor evoked potential (MEP) stimulus-response-curves (SRC). Test-retest reliability, absolute agreement, and consistency were determined for force, EMG, and SRC MEP maximum (MEPMAX) and rising phase midpoint (V50). As a secondary analysis, all outcomes were compared between groups with mixed-methods ANCOVAs (Task × Time, covariate: body-fat-percentage). Compared with SQT, KE displayed better test-retest reliability and agreement for MEPMAX whereas V50, force, and EMG were similarly reliable. Force (p<0.01) and MEPMAX (p=0.02) were also greater during KE despite a similar V50 (p=0.11). Differences in test-retest reliability, absolute agreement, and between-group comparisons highlight the need to carefully select lower limb TMS assessment tasks and encourage future efforts to balance ecological validity with statistical sensitivity.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2021

Accumulating evidence points to neurophysiological abnormalities of the motor cortex in Schizophr... more Accumulating evidence points to neurophysiological abnormalities of the motor cortex in Schizophrenia (SCZ). However, whether these abnormalities represent a core biological feature of psychosis rather than a superimposed neurodegenerative process is yet to be defined, as it is their putative relationship with clinical symptoms. in this study, we used Transcranial Magnetic Stimulation coupled with electroencephalography (TMS-EEG) to probe the intrinsic oscillatory properties of motor (Brodmann Area 4, BA4) and non-motor (posterior parietal, BA7) cortical areas in twenty-three first-episode psychosis (FEP) patients and thirteen age and gender-matched healthy comparison (HC) subjects. Patients underwent clinical evaluation at baseline and six-months after the TMS-EEG session. We found that FEP patients had reduced EEG activity evoked by TMS of the motor cortex in the beta-2 (25-34 Hz) frequency band in a cluster of electrodes overlying BA4, relative to HC participants. Beta-2 deficits in the TMS-evoked EEG response correlated with worse positive psychotic symptoms at baseline and also predicted positive symptoms severity at six-month follow-up assessments. Altogether, these findings indicate that reduced TMS-evoked fast oscillatory activity in the motor cortex is an early neural abnormality that: 1) is present at illness onset; 2) may represent a state marker of psychosis; and 3) could play a role in the development of new tools of outcome prediction in psychotic patients.

Neuropsychopharmacology, 2021

Theta Burst Stimulation (TBS) is a repetitive Transcranial Magnetic Stimulation (rTMS) neuromodul... more Theta Burst Stimulation (TBS) is a repetitive Transcranial Magnetic Stimulation (rTMS) neuromodulation protocol that employs short bursts (three, 50 Hz pulses) delivered at 5 Hz. Intermittent TBS (iTBS) increases, and continuous TBS (cTBS) decreases, cortical neuron excitability [1]. iTBS usually comprise 20, 2-s trains interleaved with 8 s of silence for 190 s, while cTBS blocks typically last 40 s. Both iTBS and cTBS are significantly shorter than rTMS paradigms, thereby allowing TBS to induce more rapid effects on neural activity and related clinical measures [2]. While TBS has been traditionally applied to the motor cortex, more recently both iTBS and cTBS paradigms have been employed over the prefrontal cortex (PFC) in healthy and psychiatric populations, including patients with Schizophrenia (SCZ) and Bipolar Disorder (BD). Specifically, in individuals with SCZ, TBS over PFC has been recently used to target negative symptoms (anhedonia, avolition), and cognitive deficits (attention, working memory) [3]. Regarding mood disorders, TBS of PFC has been primarily employed in Major Depressive Disorder individuals [4], and the safety and efficacy of iTBS was lately established in individuals with BD depression [5]. Yet, despite some promising initial results, there is a need to replicate these findings in larger groups of patients, ideally with the following methodological enhancements to establish treatment effectiveness in SCZ and BD. First, symptom improvement is presently the goal/main outcome measure of double-blind, randomized clinical trials in psychiatric populations. However, identifying and modulating the neural circuits and mechanisms underlying these symptoms is critical to developing more targeted, effective interventions. Thus, some biological measures (e.g., resting-state fMRI connectivity), are and should be increasingly used both to guide treatment (i.e., target engagement trials) and assess treatment response. Future studies should also employ resting state and task-based fMRI, to locate neural regions to be targeted at the individual level, as well as to identify new regions for targeting based on understanding of underlying neural circuitry abnormalities associated with SCZ and BD. Second, EEG measures offer non-invasive, direct assessments of cortical regions, including PFC, that are critically altered in both SCZ and BD. Thus, EEG could be utilized to provide more precise PFC and other cortical region targets for TBS-based interventions. Third, TBS paradigms can acutely modulate neural circuitries and behavioral (e.g., task performance) outcomes in healthy individuals [6]. However, far less is known about the acute effects of TBS of PFC in psychiatric populations. Using TBS to acutely modulate PFC, which is implicated in several domains of treatment (e.g., cognition, psychosis, impulsivity), and examining the impact of such interventions on neural, clinical, and behavioral biomarkers, will clarify TBS effects on these domains, thus better informing subsequent neuromodulation-based chronic treatments in SCZ and BD patients. Finally, optimizing TBS parameters, including coil placement, intensity of stimulation, frequency/total number of sessions, and employing a set of universally accepted standards in treatment to enhance reliability and precision holds promise to improve the effectiveness of PFC neuromodulation with TBS paradigms in these patients.