Resting-State Functional Connectivity Differences Following Experimental Manipulation of the Orbitofrontal Cortex in Two Directions via Theta-Burst Stimulation.

Compulsive behaviors (CBs) have been linked to orbitofrontal cortex (OFC) function in animal and human studies. However, brain regions function not in isolation but as components of widely distributed brain networks-such as those indexed via resting-state functional connectivity (RSFC). Sixty-nine individuals with CB disorders were randomized to receive a single session of neuromodulation targeting the left OFC-intermittent theta-burst stimulation (iTBS) or continuous TBS (cTBS)-followed immediately by computer-based behavioral "habit override" training. OFC seeds were used to quantify RSFC following iTBS and following cTBS. Relative to cTBS, iTBS showed increased RSFC between right OFC (Brodmann's area 47) and other areas, including dorsomedial prefrontal cortex (dmPFC), occipital cortex, and a priori dorsal and ventral striatal regions. RSFC connectivity effects were correlated with OFC/frontopolar target engagement and with subjective difficulty during habit-override training. Findings help reveal neural network-level impacts of neuromodulation paired with a specific behavioral context, informing mechanistic intervention development.

A double-blind study assessing the impact of orbitofrontal theta burst stimulation on goal-directed behavior.

Patients with disorders of compulsivity show impairments in goal-directed behavior, which have been linked to orbitofrontal cortex (OFC) dysfunction. We recently showed that continuous theta burst stimulation (cTBS), which reduces OFC activity, had a beneficial effect on compulsive behaviors both immediately and at 1 week follow-up compared with inhibitory TBS (iTBS). In this same sample, we investigated whether two behavioral measures of goal-directed control (devaluation success on a habit override task; model-based planning on the two-step task) were also affected by acute modulation of OFC activity. Overall, model-based planning and devaluation success were significantly related to each other and (for devaluation success) to symptoms in our transdiagnostic clinical sample. These measures were moderately to highly stable across time. In individuals with low levels of model-based planning, active cTBS improved devaluation success. Analogous to previously reported clinical effects, this effect was specific to cTBS and not iTBS. Overall, results suggested that measures of goal directed behavior are reliable but less affected by cTBS than clinical self-report. Future research should continue to examine longitudinal changes in behavioral measures to determine their temporal relationship with symptom improvement after treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Reduced TMS-evoked fast oscillations in the motor cortex predict the severity of positive symptoms in first-episode psychosis.

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.

Effect of Experimental Manipulation of the Orbitofrontal Cortex on Short-Term Markers of Compulsive Behavior: A Theta Burst Stimulation Study.

OBJECTIVE: Compulsive behaviors are a core feature of obsessive-compulsive spectrum disorders but appear across a broad spectrum of psychological conditions. It is thought that compulsions reflect a failure to override habitual behaviors "stamped in" through repeated practice and short-term distress reduction. Animal models suggest a possible causal role of the orbitofrontal cortex (OFC) in compulsive behaviors, but human studies have largely been limited by correlational designs. The goal of this study was to establish the first experimental evidence in humans for a mechanistic model in order to inform further experimental work and the eventual development of novel mechanistic treatments involving synergistic biological-behavioral pairings. METHODS: After a baseline assessment, 69 individuals with compulsive behavior disorders were randomly assigned, in a double-blind, between-subjects design, to receive a single session of one of two active stimulation conditions targeting the left OFC: intermittent theta burst stimulation (iTBS), expected to increase OFC activity, or continuous TBS (cTBS), expected to decrease activity (both conditions, 600 pulses at 110% of target resting motor threshold). In both conditions, brain modulation was paired with a subsequent computer task providing practice in overriding a clinically relevant habit (an overlearned shock avoidance behavior), delivered during the expected window of OFC increase or decrease. Pre- and post-TBS functional MRI assessments were conducted of target engagement and compulsive behaviors performed in response to an idiographically designed stressful laboratory probe. RESULTS: cTBS and iTBS modulated OFC activation in the expected directions. cTBS, relative to iTBS, exhibited a beneficial impact on acute laboratory assessments of compulsive behaviors 90 minutes after TBS. These acute behavioral effects persisted 1 week after cTBS. CONCLUSIONS: Experimental modulation of the OFC, within the behavioral context of habit override training, affected short-term markers of compulsive behavior vulnerability. The findings help delineate a causal translational model, serving as an initial precursor to mechanistic intervention development.

Overnight Sleep Parameter Increases in Frontoparietal Areas Predict Working Memory Improvements in Healthy Participants But Not in Individuals With Posttraumatic Stress Disorder.

BACKGROUND: Preliminary evidence indicates that non-rapid eye movement (NREM) sleep is implicated in enhancing working memory (WM) performance across days in healthy individuals. While REM sleep has been implicated in other forms of memory, its role in WM remains unclear. Further, the relationship between sleep changes and WM improvement is largely unknown in posttraumatic stress disorder (PTSD). Examining the relationship between changes in sleep and WM improvement in healthy participants and participants with PTSD may inform cognitive enhancement strategies and intervention targets. METHODS: Repeated assessments of WM and overnight measurement of NREM and REM sleep parameters were performed in 79 participants (participants with PTSD: n = 33) during a 48-hour laboratory stay. Relationships between sleep parameter changes, WM performance changes, and clinical characteristics were analyzed in PTSD and healthy groups. RESULTS: A between-night enhancement in both NREM and REM sleep parameters in frontoparietal areas predicted across-day better WM performance in healthy participants, particularly in those with improved performance. In contrast, in participants with PTSD, an enhancement of these sleep parameters predicted a worse WM performance and was also associated with more PTSD-related sleep disturbances. CONCLUSIONS: This study shows that higher sleep activity in frontoparietal areas leads to enhanced WM performance in healthy individuals, whereas in individuals with PTSD, it likely reflects the presence of sleep disturbances that interfere with WM improvement. Interventions focused on addressing sleep disturbances could therefore ameliorate cognitive impairments in individuals with PTSD.

Sleep abnormalities in individuals at clinical high risk for psychosis.

Youth at clinical high risk (CHR) represent a unique population enriched for precursors of major psychiatric disorders. Sleep disturbances are consistently reported in CHR individuals. However, there is a dearth of studies investigating quantifiable objective measures of sleep dysfunction in CHR youth. In this study, sleep high density (hd)-EEG recordings were collected in twenty-two CHR and twenty healthy control (HC) subjects. Sleep architecture parameters, as well as sleep EEG power spectra in five frequency bands, were computed and compared between CHR and HC groups during non-rapid eye movement (NREM) sleep. Furthermore, correlation analyses between sleep EEG power spectra, sleep architecture parameters, and clinical symptoms, assessed with the scale of prodromal symptoms (SOPS), were conducted in CHR participants. Our results show that CHR individuals had more wakefulness after sleep onset (WASO) compared to HC participants. CHR also showed a higher NREM sleep gamma EEG power, which was observed in a large fronto-parieto-occipital area, relative to HC. Additionally, higher NREM gamma activity in lateral fronto-occipital regions was associated with more WASO, and increased NREM gamma power in medial fronto/parietal areas correlated with worse SOPS negative symptoms. Altogether, these findings suggest that topographically specific increases in EEG gamma activity during NREM sleep represent neurophysiological signatures underlying some of the objectively assessed sleep disturbances and clinical symptoms of CHR individuals.

Sleep disturbances in schizophrenia: what we know, what still needs to be done.

Sleep disturbances are commonly observed in schizophrenia (SCZ) and are associated with worse psychotic symptoms and poorer clinical outcomes. Early polysomnography studies have focused on characterizing differences in sleep architecture between patients with SCZ and healthy controls. More recently, research has focused on sleep-specific EEG oscillations, such as sleep spindles and slow waves, which reflect the integrity of underlying thalamo-cortical networks. Furthermore, high-density (hd)-EEG (≥64 channels), which affords enhanced spatial resolution, has been employed to better localize abnormalities in sleep characteristics and related thalamo-cortical circuits in patients with SCZ and related disorders. In this article, we will review the most relevant sleep abnormalities reported in SCZ, with an emphasis on recent findings, and propose directions for future research.

Topographic deficits in sleep spindle density and duration point to frontal thalamo-cortical dysfunctions in first-episode psychosis.

Sleep spindles are NREM sleep EEG oscillations, which are initiated within the thalamus and are regulated by thalamo-cortical circuits. Previous work from our and other research groups has shown marked spindle deficits in patients with schizophrenia (SCZ). However, the presence of spindle impairments at illness onset, including which parameters are most affected, their topographic characteristics, and their relationships with clinical symptoms have yet to be characterized. In this study we performed sleep high density (hd)-EEG recordings in twenty-seven first-episode psychosis (FEP) patients and twenty-three healthy controls (HC). Several spindle parameters-amplitude, duration, and density-were calculated and compared across groups. FEP patients showed reduced spindle duration and density, but not in spindle amplitude relative to HC. These spindles reductions were localized in a frontal area and predicted the severity of FEP patients' negative symptoms. Altogether, these findings indicate that spindle deficits are present at the beginning of psychosis, contribute to clinical symptomatology, and point to frontal thalamo-cortical dysfunctions, thus providing a potential treatment target for early interventions in SCZ and related psychotic disorders.

An increase in sleep slow waves predicts better working memory performance in healthy individuals.

Sleep is imperative for brain health and well-being, and restorative sleep is associated with better cognitive functioning. Increasing evidence indicates that electrophysiological measures of sleep, especially slow wave activity (SWA), regulate the consolidation of motor and perceptual procedural memory. In contrast, the role of sleep EEG and SWA in modulating executive functions, including working memory (WM), has been far less characterized. Here, we investigated across-night changes in sleep EEG that may ameliorate WM performance. Participants (N = 25, M = 100%) underwent two consecutive nights with high-density EEG, along with N-back tasks, which were administered at three time points the day before and after the second night of sleep. Non-rapid eye movement sleep EEG power spectra, power topography, as well as several slow-wave parameters were computed and compared across nights. Improvers on the 1-back, but not non-improvers, showed a significant increase in SWA as well as in down slope and negative peak amplitude, in a fronto-parietal region, and these parameters increases predicted better WM performance. Overall, these findings show that slow-wave sleep has a beneficial effect on WM and that it can occur in the adult brain even after minimal training. This is especially relevant, when considering that WM and other executive function cognitive deficits are present in several neuropsychiatric disorders, and that slow-wave enhancing interventions can improve cognition, thus providing novel insights and treatment strategies for these patients.

Abnormalities in the evoked frontal oscillatory activity of first-episode psychosis: A TMS/EEG study.

TMS with simultaneous EEG allows assessing the intrinsic oscillatory activity of cortical neurons. We recently showed reduced frontal cortical oscillations in chronic schizophrenia (SCZ). Here we investigated the oscillatory activity of first-episode psychosis (FEP) patients after TMS of a frontal area, the motor cortex. Compared to healthy controls, FEP patients had significantly reduced beta/low gamma oscillations, which were associated to worse clinical symptoms. Altogether, this study demonstrates that TMS/EEG recordings: 1) are feasible in acute, early-course psychotic patients; and 2) reveal intrinsic oscillatory deficits at illness onset, which may help design more effective, early interventions in SCZ.

Reduced frontal slow wave density during sleep in first-episode psychosis.

BACKGROUND: Sleep disturbances are commonly reported in psychotic patients and often contribute to the manifestation and severity of their symptoms. Slow waves characterize the deepest stage of NREM sleep, and their occurrence is critical for restorative sleep. Slow wave abnormalities have been reported in patient with schizophrenia, especially when experiencing an exacerbation of psychosis. However, their presence and delineation, with an emphasis on topography, in first-episode psychosis patients (FEP) have not yet been characterized. METHODS: We performed sleep high density (hd)-EEG recordings in twenty FEP patients and twenty healthy control subjects (HC). Slow wave activity (SWA) and several other slow wave parameters, e.g. density, amplitude, up- and down-slopes, were calculated at each electrode location and compared across groups. Additionally, the association between slow wave characteristics and clinical symptoms was assessed. RESULTS: FEP patients showed a reduction selectively in slow-wave density relative to HC, and this reduction was significant in a large frontal area, including channels overlying the prefrontal cortex. Furthermore, slow wave density was inversely correlated with the severity of FEP positive symptoms. CONCLUSIONS: Abnormalities in slow waves are present at the beginning of psychosis, occur in frontal-prefrontal regions that are highly dysfunctional in psychotic patients, and are associated with their positive symptom severity. Building on these findings, future work will help establish the direction of these associations (i.e., if clinical symptoms precede, coincide, or follow SW deficits), which will determine whether ameliorating slow wave sleep deficits is a viable treatment target in early psychosis.

Investigating the neurobiology of schizophrenia and other major psychiatric disorders with Transcranial Magnetic Stimulation.

Characterizing the neurobiology of schizophrenia and other major psychiatric disorders is one of the main challenges of the current research in psychiatry. The availability of Transcranial Magnetic Stimulation (TMS) allows to directly probe virtually any cortical areas, thus providing a unique way to assess the neurophysiological properties of cortical neurons. This article presents a review of studies employing TMS in combination with Motor Evoked Potentials (TMS/MEPs) and high density Electroencephalogram (TMS/hd-EEG) in schizophrenia and other major psychiatric disorders. Studies were identified by conducting a PubMed search using the following search item: "transcranial magnetic stimulation and (Schizophrenia or OCD or MDD or ADHD)". Studies that utilized TMS/MEP and/or TMS/hd-EEG measures to characterize cortical excitability, inhibition, oscillatory activity, and/or connectivity in psychiatric patients were selected. Across disorders, patients displayed a pattern of reduced cortical inhibition, and to a lesser extent increased excitability, in the motor cortex, which was most consistently established in Schizophrenia. Furthermore, psychiatric patients showed abnormalities in a number of TMS-evoked EEG oscillations, which was most prominent in the prefrontal cortex of Schizophrenia relative to healthy comparison subjects. Overall, results from this review point to significant impairments in cortical excitability, inhibition, and oscillatory activity, especially in frontal areas, in several major psychiatric disorders. Building on these findings, future studies employing TMS-based experimental paradigms may help elucidating the neurobiology of these psychiatric disorders, and may assess the contribution of TMS-related measures in monitoring and possibly maximizing the effectiveness of treatment interventions in psychiatric populations.

Schizophrenia and sleep disorders: links, risks, and management challenges.

Schizophrenia is a major psychiatric disorder that has a massive, long-lasting negative impact on the patients as well as society. While positive symptoms (i.e., delusions and hallucinations), negative symptoms (i.e., anhedonia, social withdrawal), and cognitive impairments are traditionally considered the most prominent features of this disorder, the role of sleep and sleep disturbances has gained increasing prominence in clinical practice. Indeed, the vast majority of patients with schizophrenia report sleep abnormalities, which tend to precede illness onset and can predict an acute exacerbation of psychotic symptoms. Furthermore, schizophrenia patients often have a comorbid sleep disorder, including insomnia, obstructive sleep apnea, restless leg syndrome, or periodic limb movement disorder. Despite accumulating data, the links between sleep disorders and schizophrenia have not been thoroughly examined, in part because they are difficult to disentangle, as numerous factors contribute to their comorbidity, including medication status. Additionally, sleep disorders are often not the primary focus of clinicians treating this population, despite studies suggesting that comorbid sleep disorders carry their own unique risks, including worsening of psychotic symptoms and poorer quality of life. There is also limited information about effective management strategies for schizophrenia patients affected by significant sleep disturbances and/or sleep disorders. To begin addressing these issues, the present review will systematically examine the literature on sleep disorders and schizophrenia, focusing on studies related to 1) links between distinct sleep disorders and schizophrenia; 2) risks unique to patients with a comorbid sleep disorder; and 3) and management challenges and strategies.