Despite improved definition of the problem and better understanding of its phenomenology, freezing of gait (FoG) remains a therapeutic enigma for clinicians and neuroscientists alike. Patients with Parkinson disease (PD) or other neurological disorders experiencing FoG are similarly frustrated, despite the benefits that levodopa and other medications provide for control of PD's primary motor features. For those burdened by episodes of FoG, current therapeutic options are quite limited. Some patients achieve improvements from pharmacotherapy-for example, by adjunctive use of an oral dopaminergic agonist or by subcutaneous infusion of apomorphine. If needed, deep brain stimulation sometimes offers symptomatic improvements. Certain interventions devised by physical therapists (or discovered by patients themselves) can improve FoG. However, successful pharmacotherapy for FoG has lagged behind, though the future holds some promising leads for therapies acting on dopaminergic, adenosinergic, noradrenergic, glutamatergic, and cholinergic circuitry.

Interactions among brain networks support cognition and behavior. Oscillatory activity may contribute by coordinating distant neuronal populations, and identifying mechanisms that dynamically modulate this connectivity is crucial for understanding brain function. Dopamine (DA) is a well-positioned candidate, given its role in altering neuronal excitability and regulating oscillatory cognitive networks connecting the hippocampus (HPC) and prefrontal cortex (PFC). However, how DA modulates HPC-PFC synchrony remains mostly unknown. Here, we recorded HPC and PFC activity in urethane-anesthetized rats while manipulating DA levels. Our results show that DA dose-dependently induces HPC-PFC theta coupling, including non-zero-lag phase synchrony. In PFC single units, DA reduced firing rates while strengthening spike-theta phase locking and shifting the preferred firing phase. Preferential stimulation of D1-like receptors with SKF-38393 or D2-like receptors with quinpirole did not reproduce the complete DA-induced oscillatory pattern, whereas systemic apomorphine, a non-selective DA receptor agonist, produced a distinct dose-dependent modulation of theta phase synchrony. Together, these findings demonstrate that DA rapidly reorganizes HPC-PFC network dynamics, enhancing interareal theta phase coordination and the temporal organization of prefrontal neuronal activity. This network response was not fully reproduced by preferential activation of either D1-like or D2-like receptors alone, pointing to a more complex dopaminergic modulation of HPC-PFC network dynamics.

Patients with Parkinson's disease now live for decades after deep brain stimulation, and many develop recurrent symptoms while the stimulator still functions. A continuous infusion is sometimes added, but the circumstances justifying it are undefined, and the two modalities are still viewed as competing rather than complementary. This review examines the addition of the four infusion therapies after stimulation. A search of three databases identified fifteen reports, almost all small and retrospective. They report 118 patients and 119 infusion courses: 68 with intestinal levodopa gel, 23 with apomorphine, 28 with foslevodopa/foscarbidopa, and none with entacapone. Off time fell in every study that measured it, though fewer than half did. The on-state motor examination improved significantly only in the largest series to test it. In a post hoc trial subgroup, off time improved similarly with and without previous stimulation, while activities of daily living and speech improved significantly less in those with prior stimulation. Severe adverse events were more frequent after prior stimulation. The combination is uncommon: 1% to 2% of patients in larger cohorts, under 0.1% in a national apomorphine cohort. Stimulation parameters are reported or unchanged in only 10 of the 118 patients, and primary failure cannot be separated from secondary failure in 29. We propose a structured assessment separating correctable device problems, recurrent dopaminergic symptoms, stimulation-induced effects and levodopa-resistant progression. Infusion therapy may help recurrent levodopa-responsive complications after stimulation has been re-evaluated and optimized. Its use in late axial or cognitive decline is untested rather than disproven.

Background/Objectives: Intranasal delivery is a promising noninvasive approach to enhance central nervous system drug delivery in Parkinson's disease (PD), potentially bypassing the blood-brain barrier and minimizing gastrointestinal side effects. This review summarizes clinical trials and translational evidence for intranasal PD therapies by treatment options and intent, highlighting key challenges in efficacy, pharmacokinetics, and safety. Methods: We reviewed human clinical trials, preclinical and pilot studies, and pharmacokinetic investigations of intranasal therapies for PD. Comparisons to established treatments were included in context. Only PD-specific clinical studies were analyzed. Therapies were grouped by rescue, antioxidant/metabolic/hormonal, and biologic or cell-based approaches, with continuous-delivery systems reviewed separately. Results: Intranasal rescue therapies, such as apomorphine, provide rapid improvement during OFF episodes (periods when the effects of PD medications fade and symptoms reappear), but tolerability issues and nasal irritation limit usage. Early-phase studies suggest intranasal delivery enables quick symptom relief and favorable pharmacokinetics, though most trials are small and focus on feasibility. New approaches include antioxidants, neurotrophic factors, gene therapy, and cell-based methods, with advanced formulations enhancing nasal retention and brain uptake. However, more translational evidence and long-term safety data are needed. Conclusions: Intranasal therapies for PD offer rapid rescue and expand options beyond standard drugs. Large, well-designed trials are needed to confirm efficacy, long-term safety, and optimal formulations. Intranasal delivery remains an emerging but potentially transformative strategy requiring further clinical research.

Fluctuations represent a major therapeutic challenge in Parkinson's disease (PD) and become increasingly prevalent with disease progression. While oral and device-aided therapies (DAT) improve symptom control, patients continue to experience disabling OFF episodes, in particular early morning OFFs, delayed ON, and no-ON phenomena. Increasing evidence suggests that both motor and non-motor fluctuations are more common than previously recognized and contribute substantially to impaired quality of life. Fluctuations affect up to 50% of patients within five years of disease onset to eventually affect almost all patients with longer duration. Beside altered central pharmacodynamics, peripheral mechanisms such as dysphagia, gastroparesis, altered intestinal absorption, and microbiome-mediated levodopa degradation, contribute to fluctuations. Although oral adjunct medication and DAT reduce daily OFF-time, clinically meaningful OFF periods often persist. This is where on-demand therapies provide rapid symptom relief and address the limitations of conventional oral medication and DAT. Hence, more regular, even daily use of on-demand therapies may improve quality of life in patients with PD. However, the potential impact of on-demand therapies on non-motor OFF periods needs further investigation. Side effects, handling and economic considerations should be taken into account. This expert perspective concludes that given the high prevalence and clinical relevance of fluctuations, on-demand therapies may be considered as an integral component of standard PD management rather than solely as a rescue option in rare emergency situations. Implementation may be particularly beneficial for patients experiencing early-morning-OFFs, delayed and no-ONs but also predictable and unpredictable OFFs.

Recovery of consciousness after brain injury remains a major challenge in the intensive care unit (ICU), and pharmacological treatments that directly promote awakening from coma and other disorders of consciousness (DoC) are lacking. We hypothesise that simultaneously targeting the two core components of consciousness by pharmacological means-arousal with apomorphine and awareness with psilocybin-is safe in the ICU and may facilitate evidence of cerebral reserves after brain injury.

BackgroundSeveral studies have demonstrated the clinical benefit of apomorphine subcutaneous infusion in Parkinson's disease (PD). However, it remains unclear whether apomorphine infusion also modulates the abnormal motor cortical excitability and plasticity that contribute to PD pathophysiology and progression.MethodsWe investigated the effects of continuous apomorphine infusion on cortical excitability and plasticity in patients with moderate-advanced PD, assessed at baseline and after 1, 12, and 24 weeks of treatment. Transcranial magnetic stimulation (TMS) was used to evaluate: i) motor cortex excitability (via input-output (I-O) recruitment curves and motor evoked potentials (MEPs) at 100-140% of resting motor threshold); ii) intracortical inhibition/facilitation (SICI; ICF), and plasticity using intermittent theta-burst stimulation (iTBS). Kinematic analysis of finger movements quantified bradykinesia. Eighteen healthy controls (HC) underwent baseline assessments for comparison.ResultsAt baseline, PD patients showed increased cortical excitability and reduced iTBS-induced plasticity compared to HC. After 24 weeks of continuous apomorphine infusion, cortical excitability decreased (reduced I-O slope and MEP amplitudes at 120-140% rMT), and plasticity improved (greater MEP facilitation 30 min post-iTBS). Clinically, motor and non-motor symptoms improved paralleled by a significant reduction in oral levodopa dose. Changes in excitability correlated with changes in motor performance.ConclusionsWe found that continuous apomorphine infusion was associated with progressive modulation of selected cortical markers in PD, in parallel with clinical improvement. These findings also highlight the potential value of cortical markers for monitoring treatment response in advanced PD.

Gastrointestinal (GI) dysfunction is a well-recognized prodromal feature of Parkinson's disease (PD), yet the mechanisms linking central dopaminergic (DA) neurodegeneration to gut pathology remain unclear. Previous studies have reported intestinal permeability and microbiome changes in toxin-based PD models, but the specific contribution of nigrostriatal injury to these outcomes is unknown. Here, we used the 6-hydroxydopamine (6-OHDA) rat model to determine whether selective loss of substantia nigra pars compacta (SNc) DA neurons disrupt gut barrier integrity and microbial homeostasis. Neurodegeneration was confirmed by progressive apomorphine-induced rotations and reduced tyrosine hydroxylase (TH) expression in the SNc and Dorsal Lateral Striatum (DLS). 6-OHDA lesioning led to increased circulating lipopolysaccharide (LPS) and intestinal fatty acid-binding protein (iFABP), consistent with impaired gut barrier function. Immunostaining for Villin, an actin-binding protein in microvilli, revealed no changes to the enterocyte brush border in either the ileum or colon. However, the tight junction protein zona occludens-1 (ZO-1) had marked reductions in both the ileum and more profoundly in the colon, indicating regional vulnerability. 6-OHDA-lesioned rats also exhibited alterations in specific gram-negative bacterial classes and reduced short-chain fatty acid levels (SCFAs). Together, these findings demonstrate that neurotrauma in the DA system can compromise gut integrity and microbial composition, supporting a brain-to-gut axis in PD pathophysiology and identifying gut barrier protection as a potential therapeutic target.

Prenatal stress has recently become known as one of the major factors influencing neurodevelopmental changes resulting in higher susceptibility to drug abuse in adults. The current investigation is aimed at evaluation of the effect of prenatal unpredictable chronic mild stress on susceptibility to apomorphine reward and functioning of 5HT-1A receptors in adulthood in male rats. The female rats were subjected to chronic mild stress from gestational day 6 until parturition. In adult animals, the place preference (CPP), as well as behavioral sensitization to repeated apomorphine (1.0 mg/kg) administration was measured, and the animals underwent behavioral testing and measurement of 5-HT syndrome, followed by analysis of 5HT and 5HIAA content in the hippocampus, hypothalamus, midbrain, and caudate nucleus after injection of 5HT-1A receptor agonist 8-OH-DPAT (1.0 mg/kg). The prenatally stressed animals demonstrated increased preference for the compartment paired with apomorphine and increased behavioral sensitization as compared to control rats, which indicates increased reward susceptibility. Furthermore, prenatally stressed animals displayed increased 5-HT syndrome behavior and lower content of 5HT and 5HIAA in some regions following 8-OH-DPAT challenge. Thus, the prenatal stress increases susceptibility to apomorphine reward through 5HT-1A receptors.