Subthalamic stimulation modulates motor network in Parkinson's disease: recover, relieve and remodel.

Aberrant dynamic switches between internal brain states are believed to underlie motor dysfunction in Parkinson's disease. Deep brain stimulation of the subthalamic nucleus is a well-established treatment for the motor symptoms of Parkinson's disease, yet it remains poorly understood how subthalamic stimulation modulates the whole-brain intrinsic motor network state dynamics. To investigate this, we acquired resting-state functional magnetic resonance imaging time-series data from 27 medication-free patients with Parkinson's disease (mean age: 64.8 years, standard deviation: 7.6) who had deep brain stimulation electrodes implanted in the subthalamic nucleus, in both on and off stimulation states. Sixteen matched healthy individuals were included as a control group. We adopted a powerful data-driven modelling approach, known as a hidden Markov model, to disclose the emergence of recurring activation patterns of interacting motor regions (whole-brain intrinsic motor network states) via the blood oxygen level-dependent signal detected in the resting-state functional magnetic resonance imaging time-series data from all participants. The estimated hidden Markov model disclosed the dynamics of distinct whole-brain motor network states, including frequency of occurrence, state duration, fractional coverage and their transition probabilities. Notably, the data-driven decoding of whole-brain intrinsic motor network states revealed that subthalamic stimulation reshaped functional network expression and stabilized state transitions. Moreover, subthalamic stimulation improved motor symptoms by modulating key trajectories of state transition within whole-brain intrinsic motor network states. This modulation mechanism of subthalamic stimulation was manifested in three significant effects: recovery, relieving and remodelling effects. Significantly, recovery effects correlated with improvements in tremor and posture symptoms induced by subthalamic stimulation (P < 0.05). Furthermore, subthalamic stimulation was found to restore a relatively low level of fluctuation of functional connectivity in all motor regions to a level closer to that of healthy participants. Also, changes in the fluctuation of functional connectivity between motor regions were associated with improvements in tremor and gait symptoms (P < 0.05). These findings fill a gap in our knowledge of the role of subthalamic stimulation at the level of neural activity, revealing the regulatory effects of subthalamic stimulation on whole-brain inherent motor network states in Parkinson's disease. Our results provide mechanistic insight and explanation for how subthalamic stimulation modulates motor symptoms in Parkinson's disease.

Acute Effects of Subthalamic Deep Brain Stimulation on Motor Outcomes in Parkinson's Disease; 13 Year Follow Up.

Objective: Deep brain stimulation of the Subthalamic nucleus (STN-DBS) is a safe and well-established therapy for the management of refractory motor symptoms in Parkinson's disease (PD). Marked improvement in axial symptoms has been reported in the short term with STN-DBS but questions remain regarding the long-term efficacy of this intervention. We assessed the acute ON and OFF effects of STN-DBS in PD patients who have been treated with STN-DBS for over a decade. Methods: We assessed 11 patients with early-onset PD (9 men, 2 women; mean age, 57.1 ± 7.2 y; mean age at illness onset, 38.9 ± 7.5 y) managed with long-term bilateral STN-DBS (mean treatment duration, 13.4 ± 1.3 y). Motor symptoms were assessed by means of the Unified Parkinson's Disease Rating Scale (UPDRS)-III, Timed Up and Go test (TUG), and Hoehn-Yahr scale. Motor assessments in the medication ON and OFF states with stimulation ON and OFF conditions were documented and video recorded. Results: Patients showed a significant improvement in motor symptoms both in the off-medication and on-medication state by a 54% reduction (off-medication/on-stimulation vs. off-medication/off-stimulation) and a 48% reduction (on-medication/on-stimulation vs. on-medication/off-stimulation) in the total UPDRS-III score. Specifically, improvement in axial symptoms (off-medication: 51% reduction; on-medication: 44% reduction), including gait but not posture. Similarly, STN-DBS reduced TUG scores (off-medication: 70% reduction; on-medication: 47% reduction). Conclusions: On stimulation long-term, bilateral STN-DBS can improve appendicular and axial symptoms of patients with early-onset PD in the acute setting.

Pallidal deep brain stimulation combined with capsulotomy for Tourette's syndrome with psychiatric comorbidity.

OBJECTIVE: A current challenge is finding an effective and safe treatment for severely disabled patients with Tourette's syndrome (TS) and comorbid psychiatric disorders, in whom conventional treatments have failed. The authors aimed to evaluate the utility of globus pallidus internus deep brain stimulation (GPi-DBS) combined with bilateral anterior capsulotomy in treating these clinically challenging patients. METHODS: The authors conducted a retrospective review of the clinical history and outcomes of 10 severely disabled patients with treatment-refractory TS and a psychiatric comorbidity, who had undergone GPi-DBS combined with bilateral anterior capsulotomy in their hospital. At the time of surgery, patients presented mainly with obsessive-compulsive disorder and affective disorders. Clinical outcome assessments of tic and psychiatric symptoms, as well as of general adaptive functioning and quality of life, were performed at the time of surgery and at 6, 12, and between 24 and 96 months postsurgery. RESULTS: After surgery, all patients showed significant progressive improvements in tic and psychiatric symptoms, along with improvements in general adaptive functioning and quality of life. Tic alleviation reached 64% at 12 months and 77% at the last follow-up on the Yale Global Tic Severity Scale. At the final follow-up, patients had functionally recovered and displayed no or only mild tic and psychiatric symptoms. All patients tolerated treatment reasonably well, with no serious side effects. CONCLUSIONS: GPi-DBS combined with bilateral anterior capsulotomy seems to offer major clinical benefits to severely disabled patients with otherwise treatment-refractory TS and psychiatric comorbidities.

Application of electroencephalography to the study of cognitive and brain functions in schizophrenia.

The electroencephalogram (EEG) recorded from the human scalp is widely used to study cognitive and brain functions in schizophrenia. Current research efforts are primarily devoted to the assessment of event-related potentials (ERPs) and event-related oscillations (EROs), extracted from the ongoing EEG, in patients with schizophrenia and in clinically unaffected individuals who, due to their family history and current mental status, are at high risk for developing schizophrenia. In this article, we discuss the potential usefulness of ERPs and EROs as genetic vulnerability markers, as pathophysiological markers, and as markers of possible ongoing progressive cognitive and cortical deterioration in schizophrenia. Our main purpose is to illustrate that these neurophysiological measures can offer valuable quantitative biological markers of basic pathophysiological mechanisms and cognitive dysfunctions in schizophrenia, yet they may not be specific to current psychiatry's diagnosis and classification. These biological markers can provide unique information on the nature and extent of cognitive and brain dysfunction in schizophrenia. Moreover, they can be utilized to gain deeper theoretical insights into illness etiology and pathophysiology and may lead to improvements in early detection and more effective and targeted treatment of schizophrenia. We conclude by addressing several key methodological, conceptual, and interpretative issues involved in this research field and by suggesting future research directions.

Attentional modulation of early-stage visual processing in schizophrenia.

This study shows that paying attention to the color of a visual stimulus is manifested by an early endogenous scalp-positive event-related brain potential (ERP) component, referred to as "selection positivity", that emerges within the first 100 ms after stimulus onset in healthy observers. In contrast, recently ill and chronically ill schizophrenia patients as well as patients at high risk for schizophrenia all failed to show this early ERP component while attending to color. These results suggest that a relatively early stage of visual-selective processing in posterior extrastriate cortex is disrupted in schizophrenia.

Auditory P300 in high-risk, recent-onset and chronic schizophrenia.

BACKGROUND: The present study examined the integrity of the P300 component of the event-related potential (ERP) in patients at high imminent risk for schizophrenia in relation to healthy comparison subjects and patients in the recent-onset and chronic stages of schizophrenia. METHODS: The P300 was recorded by using an auditory oddball task in 10 patients clinically considered at risk of being prodromally symptomatic for schizophrenia, 10 patients with recent-onset schizophrenia, 14 patients with chronic schizophrenia, 14 young healthy comparison subjects, who were age-matched to the high-risk and recent-onset schizophrenia groups, and 14 older healthy comparison subjects, who were age-matched to the chronic schizophrenia group. RESULTS: High-risk subjects displayed smaller than normal P300 amplitudes at the parietal, centroparietal and central scalp locations. The observed P300 amplitude abnormalities in high-risk subjects were severe, being comparable in magnitude to the abnormalities seen in recent-onset and chronic schizophrenia subjects. However, whereas high-risk subjects showed P300 amplitude abnormalities that were bilaterally symmetrical, subjects with recent-onset schizophrenia and, particularly, subjects with chronic schizophrenia exhibited abnormalities that were markedly larger over the left temporal scalp sites. CONCLUSIONS: Patients at high imminent risk for developing a first florid psychotic episode seem to manifest auditory P300 amplitude abnormalities that are similar, but not identical, to those observed in patients in the recent-onset and chronic stages of schizophrenia. These results support the idea that auditory P300 abnormalities in schizophrenia reflect a primary cognitive and pathophysiological feature of the illness.

Impaired P3 generation reflects high-level and progressive neurocognitive dysfunction in schizophrenia.

BACKGROUND: In this study, we assessed the integrity of several components of the event-related potential (ERP) associated with different levels of visual and auditory processing in patients with schizophrenia. The objective was to clarify whether high-level attention-dependent cognitive deficits, as indexed by the P3 component, in patients with schizophrenia are related to or originate from potential preceding deficits at lower levels of information processing, as indexed by earlier-occurring ERP components. Also, given that the auditory P3 amplitude has recently been observed to be inversely correlated with illness duration and, hence, may potentially track the operation of a putative neurodegenerative process across the illness course, we recruited patients with schizophrenia varying greatly in illness duration to attempt to replicate this observation. METHODS: Multichannel ERPs were recorded in 22 patients with schizophrenia at different stages of illness and 22 age-matched healthy control subjects while they performed a visual and auditory oddball task. RESULTS: Patients displayed smaller P3 amplitudes to visual novel and auditory target stimuli than did control subjects, whereas small or no significant between-group differences were observed in sensory-evoked and cognitive-related ERP components preceding P3. Additionally, patients showed a distinct left-smaller-than-right auditory P3 temporal scalp voltage asymmetry. Furthermore, we replicated previous study results of an inverse correlation between the auditory P3 amplitude and illness duration. CONCLUSIONS: These results indicate that high-level attention-dependent cognitive deficits central to schizophrenia do not originate from potential preceding impairments at lower levels of sensory, perceptual, or cognitive processing. The data support the view that schizophrenia is characterized by fundamental deficits in integrative cortical functions that specifically impair the ability to analyze and represent stimulus context to guide behavior. Moreover, abnormalities of the auditory P3 amplitude in schizophrenia seem to reflect a basic underlying pathophysiological process that is present at illness onset and progresses across the illness course.

Caffeine intake during pregnancy and risk of problem behavior in 5- to 6-year-old children.

BACKGROUND AND OBJECTIVE: Human studies that have investigated the association between caffeine intake during pregnancy and offspring's behavioral outcomes are scant and inconclusive. We prospectively investigated the association between maternal caffeine intake during pregnancy and children's problem behavior at age 5 to 6 years. Mediation by fetal growth restriction and gestational age as well as effect modification by the child's gender and maternal smoking was tested. METHODS: In a community based multiethnic birth cohort, dietary caffeine intake (coffee, caffeinated tea, and cola) was measured (maternal self-report, n = 8202) around the 16th week of gestation. At age 5, children's overall problem behavior, emotional problems, conduct problems, hyperactivity/inattention problems, peer relationship problems, and prosocial behavior were rated by both mother and teacher (n = 3439) with the Strengths and Difficulties Questionnaire. Analyses were adjusted for maternal age, ethnicity, cohabitant status, education, smoking and alcohol consumption during pregnancy, child's gender, family size, and prenatal maternal anxiety. RESULTS: Caffeine intake was not associated with a higher risk for behavior problems or with suboptimal prosocial behavior. No evidence was found for mediation by fetal growth restriction or gestational age, nor for effect modification by the child's gender. CONCLUSIONS: Results did not provide evidence for developmental programming influences of intrauterine exposure to caffeine on offspring's problem behavior at age 5. Present results give no indication to advise pregnant women to reduce their caffeine intake to prevent behavior problems in their children.

Relations among intelligence, executive function, and P300 event related potentials in schizophrenia.

Prior research has demonstrated that the P300 response may be related to neuropsychological functioning in nonclinical samples. However, the nature of this relation is unclear, and its characteristics in schizophrenia are unexplored. We assessed estimated IQ, neuropsychological tests that assess components of executive functioning, and the P300 component of the event-related brain potential elicited by auditory and visual oddball paradigms in individuals with and without schizophrenia. We observed modest relations between P300 indices and neuropsychological tests purported to assess aspects of executive functioning in both diagnostic groups. Furthermore, multiple regression analyses revealed that whereas control participants with higher estimated IQs demonstrated larger P3 amplitudes to attended auditory targets, the opposite relation appeared evident in schizophrenic participants when variance due to Trailmaking A or a continuous performance task was held constant. Additionally, control participants with higher estimated IQs demonstrated shorter P3 latencies to attended visual targets whereas schizophrenic participants did not when variance due to the Tower of London was held constant. These results suggest diagnostic group differences in the association between P300 and IQ and indicate that investigations designed to explore P300-IQ relations should include measures of executive functioning in their models.

Neurochemical markers of alcoholism vulnerability in humans.

This review considers several neurochemical characteristics or trait markers that may be related to a genetic vulnerability to alcoholism. These potential neurochemical markers of alcoholism vulnerability include indices of activity of five neurotransmitter systems, namely gamma-aminobutyric acid, serotonin, dopamine, noradrenaline and beta-endorphin. This review evaluates whether potential abnormalities in these neurochemical indices, as assessed in alcoholics and in the children of alcoholics, meet three criteria for the identification of a vulnerability marker of alcoholism: (1). heritable; (2). associated with alcoholism in the general population; (3). state independent. It is concluded that, at present, indices of increased baseline activity of the serotonin transporter in platelets and of increased responsiveness of the pituitary beta-endorphin system may fulfil each of these three criteria. Additional research efforts should be devoted to the evaluation of trait marker properties of neurochemical indices in individuals at high risk for alcoholism.