Neuroimaging and serum biomarkers of neurodegeneration and neuroplasticity in Parkinson's disease patients treated by intermittent theta-burst stimulation over the bilateral primary motor area: a randomized, double-blind, sham-controlled, crossover trial study.

Background and objectives: Intermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson's disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent corticostriatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induced clinical enhancement. Here, our primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective as an add-on treatment at reducing scores for both motor functional impairment and nonmotor symptoms in PD. We hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striato-cortico-cerebellar functional connectivity and positively impacting neuroglia and neuroplasticity. Methods: A total of 24 PD patients will be assessed in a randomized, double-blind, sham-controlled crossover study involving the application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 consecutive sessions (5 days) of iTBS over the bilateral M1 separated by a 3-month washout period. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment; evaluation of M1 excitability; combined structural magnetic resonance imaging (MRI), resting-state electroencephalography and functional MRI; and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS. Discussion: The findings of this study will help to clarify the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations than previous studies while using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate the structural and functional mechanisms of M1 iTBS-induced plasticity in the cortico-basal ganglia circuitry. Our approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD.

Subthalamic Beta Activity in Parkinson's Disease May Be Linked to Dorsal Striatum Gray Matter Volume and Prefrontal Cortical Thickness: A Pilot Study.

Background: Excessive oscillations at beta frequencies (13-35 Hz) in the subthalamic nucleus (STN) represent a pathophysiological hallmark of Parkinson's disease (PD), which correlates well with parkinsonian symptoms and is reduced in response to standard disease treatments. However, the association of disease-specific regional gray matter (GM) atrophy or cortical thickness (CT) with the presence of STN beta oscillatory activity has been poorly investigated but is of relevance given the potential of these variables for extracting information about PD pathophysiology. This exploratory study investigated the involvement of regional GM volume and CT in the basal ganglia-cortical network and its potential association with the presence of STN beta oscillatory activity in PD. Methods: We acquired preoperative GM densities on T1-weighted magnetic resonance imaging scans and we carried out regional estimation of GM volume and CT. LFP activities from the STN were recorded post-operatively in 7 cognitively preserved PD patients off dopaminergic medication undergoing deep-brain stimulation surgery. Oscillatory beta power was determined by power spectral density of 4-min resting state STN LFP activity. Spearman partial correlations and regression analysis were used to screen the presence of STN beta power for their relationship with GM volume and CT measurements. Results: After controlling for the effects of age, educational level, and disease duration, and after correcting for multiple testing, enhanced STN beta power showed significant and negative correlations between, first, volume of the right putamen and left caudate nucleus, and second, smaller CT in frontal regions involving the left rostral middle frontal gyrus (MFG) and left medial orbitofrontal gyrus. A lower volume in the right putamen and a lower CT in the left MFG demonstrated the strongest associations with increased STN beta power. Conclusions: These tentative results seem to suggest that STN LFP beta frequencies may be mainly linked to different but ongoing parallel neurodegenerative processes, on the one hand, to GM volume reduction in dorsal striatum, and on the other hand, to CT reduction of prefrontal-"associative" regions. These findings could further delineate the brain structural interactions underpinning the exaggerated STN beta activity commonly observed in PD patients.

A ventromedial prefrontal dysrhythmia in obsessive-compulsive disorder is attenuated by nucleus accumbens deep brain stimulation.

BACKGROUND: Obsessive-compulsive disorder (OCD) has consistently been linked to abnormal frontostriatal activity. The electrophysiological disruption in this circuit, however, remains to be characterized. OBJECTIVE/HYPOTHESIS: The primary goal of this study was to investigate the neuronal synchronization in OCD patients. We predicted aberrant oscillatory activity in frontal regions compared to healthy control subjects, which would be alleviated by deep brain stimulation (DBS) of the nucleus accumbens (NAc). METHODS: We compared scalp EEG recordings from nine patients with OCD treated with NAc-DBS with recordings from healthy controls, matched for age and gender. Within the patient group, EEG activity was compared with DBS turned off vs. stimulation at typical clinical settings (3.5 V, frequency of stimulation 130 Hz, pulse width 60 µs). In addition, intracranial EEG was recorded directly from depth macroelectrodes in the NAc in four OCD patients. RESULTS: Cross-frequency coupling between the phase of alpha/low beta oscillations and amplitude of high gamma was significantly increased over midline frontal and parietal electrodes in patients when stimulation was turned off, compared to controls. Critically, in patients, beta (16-25 Hz) -gamma (110-166 Hz) phase amplitude coupling source localized to the ventromedial prefrontal cortex, and was reduced when NAc-DBS was active. In contrast, intracranial EEG recordings showed no beta-gamma phase amplitude coupling. The contribution of non-sinusoidal beta waveforms to this coupling are reported. CONCLUSION: We reveal an increased beta-gamma phase amplitude coupling in fronto-central scalp sensors in patients suffering from OCD, compared to healthy controls, which may derive from ventromedial prefrontal regions implicated in OCD and is normalized by DBS of the nucleus accumbens. This aberrant cross-frequency coupling could represent a biomarker of OCD, as well as a target for novel therapeutic approaches.

Nucleus Accumbens Stimulation Modulates Inhibitory Control by Right Prefrontal Cortex Activation in Obsessive-Compulsive Disorder.

Inhibitory control is considered a compromised cognitive function in obsessive-compulsive (OCD) patients and likely linked to corticostriatal circuitry disturbances. Here, 9 refractory OCD patients treated with deep brain stimulation (DBS) were evaluated to address the dynamic modulations of large-scale cortical network activity involved in inhibitory control after nucleus accumbens (NAc) stimulation and their relationship with cortical thickness. A comparison of DBS "On/Off" states showed that patients committed fewer errors and exhibited increased intraindividual reaction time variability, resulting in improved goal maintenance abilities and proactive inhibitory control. Visual P3 event-related potentials showed increased amplitudes during Go/NoGo performance. Go and NoGo responses increased cortical activation mainly over the right inferior frontal gyrus and medial frontal gyrus, respectively. Moreover, increased cortical activation in these areas was equally associated with a higher cortical thickness within the prefrontal cortex. These results highlight the critical role of NAc DBS for preferentially modulating the neuronal activity underlying sustained speed responses and inhibitory control in OCD patients and show that it is triggered by reorganizing brain functions to the right prefrontal regions, which may depend on the underlying cortical thinning. Our findings provide updated structural and functional evidence that supports critical dopaminergic-mediated frontal-striatal network interactions in OCD.

A fast pathway for fear in human amygdala.

A fast, subcortical pathway to the amygdala is thought to have evolved to enable rapid detection of threat. This pathway's existence is fundamental for understanding nonconscious emotional responses, but has been challenged as a result of a lack of evidence for short-latency fear-related responses in primate amygdala, including humans. We recorded human intracranial electrophysiological data and found fast amygdala responses, beginning 74-ms post-stimulus onset, to fearful, but not neutral or happy, facial expressions. These responses had considerably shorter latency than fear responses that we observed in visual cortex. Notably, fast amygdala responses were limited to low spatial frequency components of fearful faces, as predicted by magnocellular inputs to amygdala. Furthermore, fast amygdala responses were not evoked by photographs of arousing scenes, which is indicative of selective early reactivity to socially relevant visual information conveyed by fearful faces. These data therefore support the existence of a phylogenetically old subcortical pathway providing fast, but coarse, threat-related signals to human amygdala.

Dynamic risk control by human nucleus accumbens.

Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established.