Spectral exponent assessment and neurofilament light chain: a comprehensive approach to describe recovery patterns in stroke.

Introduction: Understanding the residual recovery potential in stroke patients is crucial for tailoring effective neurorehabilitation programs. We propose using EEG and plasmatic Neurofilament light chain (NfL) levels as a model to depict longitudinal patterns of stroke recovery. Methods: We enrolled 13 patients (4 female, mean age 74.7 ± 8.8) who underwent stroke in the previous month and were hospitalized for 2-months rehabilitation. Patients underwent blood withdrawal, clinical evaluation and high-definition EEG at T1 (first week of rehabilitation) and at T2 (53 ± 10 days after). We assessed the levels of NfL and we analyzed the EEG signal extracting Spectral Exponent (SE) values. We compared our variables between the two timepoint and between cortical and non-cortical strokes. Results: We found a significant difference in the symmetry of SE values between cortical and non-cortical stroke at both T1 (p = 0.005) and T2 (p = 0.01). SE in the affected hemisphere showed significantly steeper values at T1 when compared with T2 (p = 0.001). EEG measures were consistently related to clinical scores, while NfL at T1 was related to the volume of ischemic lesions (r = 0.75; p = 0.003). Additionally, the combined use of NfL and SE indicated varying trends in longitudinal clinical recovery. Conclusion: We present proof of concept of a promising approach for the characterization of different recovery patterns in stroke patients.

Italian translation and cultural adaptation of the Agitated Behavior Scale (ABS-I) in patients with acquired brain injuries.

OBJECTIVE: The objective of this study was to produce a cross-cultural adaptation in Italian of the Agitated Behavior Scale (ABS), originally developed in English, as the first of two stages that also include cross-cultural validation and allow a clinical scale to be used in the proper setting such as rehabilitation units. METHODS: In order to adapt the ABS scale to a different cultural environment, five consecutive steps were performed: (1) forward translations (n = 8), (2) synthesis of the 8 forward translations to obtain a first shared italian version (ABS_I_trial), (3) back translations (n = 3), (4) creation of an expert committee to evaluate forward and back translations and finally (5) the cognitive debriefing. RESULTS: After the five steps, including forward translations and back translations, the process of committee verification and judgement and the evaluative step of cognitive debriefing, high comprehensibility of all items was found, resulting in an Italian translation version of ABS suitable for application in a clinical setting. CONCLUSION: ABS translation was produced by means of a standardized procedure aimed at minimizing cross-cultural gaps. The expert committee evaluated the version produced as highly understandable in Italian. Further steps, such as the subsequent validation of its psychometric properties, are needed to employ this translation in a clinical setting.

Neurophysiological investigations in a case of primary paroxysmal hemicrania-tic syndrome.

BACKGROUND: The association between paroxysmal hemicrania (PH) and trigeminal neuralgia-the so-called PH-tic syndrome-has rarely been described. However, a correct diagnosis is crucial since both disorders require specific treatments. Little is known about pathophysiological mechanisms, and, to date, there are no electrophysiological studies in patients with PH-tic syndrome. CASE: We describe the case of a 52-year-old man with a PH-tic syndrome successfully treated with an association of carbamazepine (1200 mg/day) and indomethacin (150 mg/die). Patient underwent trigeminal reflex testing, including blink and masseter inhibitory reflex, and laser-evoked potential (LEP) recording after supraorbital region stimulation in the affected and unaffected side. Both neurophysiological investigations resulted normal; LEPs failed to detect any latency asymmetry between both sides. CONCLUSIONS: Neurophysiological findings demonstrate for the first time the integrity of somatosensory system in a primary PH-tic syndrome case. Central pathophysiological mechanisms and hypothalamic dysregulation may contribute to the development of this rare syndrome.

Dissociations between spontaneous electroencephalographic features and the perturbational complexity index in the minimally conscious state.

The analysis of spontaneous electroencephalogram (EEG) is a cornerstone in the assessment of patients with disorders of consciousness (DoC). Although preserved EEG patterns are highly suggestive of consciousness even in unresponsive patients, moderately or severely abnormal patterns are difficult to interpret. Indeed, growing evidence shows that consciousness can be present despite either large delta or reduced alpha activity in spontaneous EEG. Quantifying the complexity of EEG responses to direct cortical perturbations (perturbational complexity index [PCI]) may complement the observational approach and provide a reliable assessment of consciousness even when spontaneous EEG features are inconclusive. To seek empirical evidence of this hypothesis, we compared PCI with EEG spectral measures in the same population of minimally conscious state (MCS) patients (n = 40) hospitalized in rehabilitation facilities. We found a remarkable variability in spontaneous EEG features across MCS patients as compared with healthy controls: in particular, a pattern of predominant delta and highly reduced alpha power-more often observed in vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients-was found in a non-negligible number of MCS patients. Conversely, PCI values invariably fell above an externally validated empirical cutoff for consciousness in all MCS patients, consistent with the presence of clearly discernible, albeit fleeting, behavioural signs of awareness. These results confirm that, in some MCS patients, spontaneous EEG rhythms may be inconclusive about the actual capacity for consciousness and suggest that a perturbational approach can effectively compensate for this pitfall with practical implications for the individual patient's stratification and tailored rehabilitation.

Exploring the Therapeutic Potential of Quadripulse rTMS over the Visual Cortex: A Proof-of-Concept Study in Healthy Volunteers and Chronic Migraine Patients with Medication Overuse Headache.

In chronic migraine with medication overuse (CM-MOH), sensitization of visual cortices is reflected by (i) increased amplitude of stimulus-evoked responses and (ii) habituation deficit during repetitive stimulation. Both abnormalities might be mitigated by inhibitory transcranial neurostimulation. Here, we tested an inhibitory quadripulse repetitive transcranial magnetic stimulation (rTMS-QPI) protocol to decrease durably visual cortex excitability in healthy subjects (HS) and explored its therapeutic potential in CM-MOH patients. Pattern-reversal visual evoked potentials (VEP) were used as biomarkers of effect and recorded before (T1), immediately after (T2), and 3 h after stimulation (T3). In HS, rTMS-QPI durably decreased the VEP 1st block amplitude (p < 0.05) and its habituation (p < 0.05). These changes were more pronounced for the P1N2 component that was modified already at T2 up to T3, while for N1P1 they were significant only at T3. An excitatory stimulation protocol (rTMS-QPE) tended to have an opposite effect, restricted to P1N2. In 12 CM-MOH patients, during a four-week treatment (2 sessions/week), rTMS-QPI significantly reduced monthly headache days (p < 0.01). In patients reversing from CM-MOH to episodic migraine (n = 6), VEP habituation significantly improved after treatment (p = 0.005). rTMS-QPI durably decreases visual cortex responsivity in healthy subjects. In a proof-of-concept study of CM-MOH patients, rTMS-QPI also has beneficial clinical and electrophysiological effects, but sham-controlled trials are needed.

Neuroimaging markers of Alice in Wonderland syndrome in patients with migraine with aura.

Background: The Alice in Wonderland syndrome (AIWS) is a transient neurological disturbance characterized by sensory distortions most frequently associated with migraine in adults. Some lines of evidence suggest that AIWS and migraine might share common pathophysiological mechanisms, therefore we set out to investigate the common and distinct neurophysiological alterations associated with these conditions in migraineurs. Methods: We conducted a case-control study acquiring resting-state fMRI data from 12 migraine patients with AIWS, 12 patients with migraine with typical aura (MA) and 24 age-matched healthy controls (HC). We then compared the interictal thalamic seed-to-voxel and ROI-to-ROI cortico-cortical resting-state functional connectivity between the 3 groups. Results: We found a common pattern of altered thalamic connectivity in MA and AIWS, compared to HC, with more profound and diffuse alterations observed in AIWS. The ROI-to-ROI functional connectivity analysis highlighted an increased connectivity between a lateral occipital region corresponding to area V3 and the posterior part of the superior temporal sulcus (STS) in AIWS, compared to both MA and HC. Conclusion: The posterior STS is a multisensory integration area, while area V3 is considered the starting point of the cortical spreading depression (CSD), the neural correlate of migraine aura. This interictal hyperconnectivity might increase the probability of the CSD to directly diffuse to the posterior STS or deactivating it, causing the AIWS symptoms during the ictal phase. Taken together, these results suggest that AIWS in migraineurs might be a form of complex migraine aura, characterized by the involvement of associative and multisensory integration areas.

Imaging Correlates between Headache and Breast Cancer: An [18F]FDG PET Study.

This study aimed to examine brain metabolic patterns on [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) in breast cancer (BC), comparing patients with tension-type headache (TTH), migraine (MiG), and those without headache. Further association with BC response to neoadjuvant chemotherapy (NAC) was explored. In this prospective study, BC patients eligible for NAC performed total-body [18F]FDG PET/CT with a dedicated brain scan. A voxel-wise analysis (two-sample t-test) and a multiple regression model were used to compare brain metabolic patterns among TTH, MiG, and no-headache patients and to correlate them with clinical covariates. A single-subject analysis compared each patient's brain uptake before and after NAC with a healthy control group. Primary headache was diagnosed in 39/46 of BC patients (39% TTH and 46% MiG). TTH patients exhibited hypometabolism in specific brain regions before NAC. TTH patients with a pathological complete response (pCR) to NAC showed hypermetabolic brain regions in the anterior medial frontal cortex. The correlation between tumor uptake and brain metabolism varied before and after NAC, suggesting an inverse relationship. Additionally, the single-subject analysis revealed that hypometabolic brain regions were not present after NAC. Primary headache, especially MiG, was associated with a better response to NAC. These findings suggest complex interactions between BC, headache, and hormonal status, warranting further investigation in larger prospective cohorts.

Electrophysiological findings in migraine may reflect abnormal synaptic plasticity mechanisms: A narrative review.

BACKGROUND: The cyclical brain disorder of sensory processing accompanying migraine phases lacks an explanatory unified theory. METHODS: We searched Pubmed for non-invasive neurophysiological studies on migraine and related conditions using transcranial magnetic stimulation, electroencephalography, visual and somatosensory evoked potentials. We summarized the literature, reviewed methods, and proposed a unified theory for the pathophysiology of electrophysiological abnormalities underlying migraine recurrence. RESULTS: All electrophysiological modalities have determined specific changes in brain dynamics across the different phases of the migraine cycle. Transcranial magnetic stimulation studies show unbalanced recruitment of inhibitory and excitatory circuits, more consistently in aura, which ultimately results in a substantially distorted response to neuromodulation protocols. Electroencephalography investigations highlight a steady pattern of reduced alpha and increased slow rhythms, largely located in posterior brain regions, which tends to normalize closer to the attacks. Finally, non-painful evoked potentials suggest dysfunctions in habituation mechanisms of sensory cortices that revert during ictal phases. CONCLUSION: Electrophysiology shows dynamic and recurrent functional alterations within the brainstem-thalamus-cortex loop varies continuously and recurrently in migraineurs. Given the central role of these structures in the selection, elaboration, and learning of sensory information, these functional alterations suggest chronic, probably genetically determined dysfunctions of the synaptic short- and long-term learning mechanisms.

Where do we look for the next breakthrough in sleep research?

The wakefulness-sleep cycle sets the pace of our life. Sleep research examines the transition between wakefulness and sleep, its hormonal regulation, and its pathological disruption. Understanding sleep mechanisms would improve quality-of-life well beyond sleep itself. To this aim, we invite contributions for the Collection "sleep physiology and circadian rhythms".

The Role of Female Reproductive Hormones in the Association between Migraine and Breast Cancer: An Unanswered Question.

Accumulating epidemiological studies have investigated a possible interconnection between migraine (Mi) and breast cancer (BC) because of the strong link between these diseases and female reproductive hormones. This review aims to consolidate findings from epidemiological studies and explore biologically plausible hypothetical mechanisms related to hormonal pathways. Current evidence suggests a protective role of Mi in BC development, particularly in case-control studies but not in cohort ones. The inconsistency among studies may be due to several reasons, including diagnostic criteria for Mi and the age gap between the development of these two diseases. Furthermore, recent research has challenged the concept of a net beneficial effect of Mi on BC, suggesting a more complex relationship between the two conditions. Many polymorphisms/mutations in hormone-related pathways are involved in at least one of the two conditions. The most promising evidence has emerged for a specific alteration in the estrogen receptor 1 gene (rs2228480). However, the possible specific mutation or polymorphism involved in this association has not yet been identified. Further studies with robust methodologies are needed to validate the protective role of Mi in BC and fully elucidate the precise nature of this causal relationship.

Profiling the Spectrum of Headache Disorders on 440 Breast Cancer Patients: Highlights on Clinical and Pathological Mechanisms.

Although widely studied, the association between migraines (M) and breast cancer (BC) risk remains evasive. In this prospective single-center study, 440 early or locally advanced BC patients were enrolled at IRCCS Humanitas Research Hospital. Clinical and demographical data were collected. Those who suffered from headaches were evaluated with the International Classification of Headache Disorders. M was found to be significantly more prevalent in BC patients: 56.1% versus an expected prevalence of 17% in the global population. M patients showed a higher risk of having stage II or III BC than stage I, which was more frequently found in the non-headache population. Interestingly, the frequency of headache attacks was positively correlated with estrogen (r = 0.11, p = 0.05) and progesterone (r = 0.15, p = 0.007) expression, especially in patients with migraine without aura. The higher the expression of hormone receptors in BC, the higher the headache frequency. Moreover, patients suffering from headaches showed an overall earlier onset of BC. Our findings challenge the idea of a net preventive role of M on BC, suggesting a rather complex interaction in which M mostly influences some BC subtypes and vice versa. Further multi-center studies with extended follow-up are needed.

Unconsciousness or unresponsiveness in akinetic mutism? Insights from a multimodal longitudinal exploration.

The clinical assessment of patients with disorders of consciousness (DoC) relies on the observation of behavioural responses to standardised sensory stimulation. However, several medical comorbidities may directly impair the production of reproducible and appropriate responses, thus reducing the sensitivity of behaviour-based diagnoses. One such comorbidity is akinetic mutism (AM), a rare neurological syndrome characterised by the inability to initiate volitional motor responses, sometimes associated with clinical presentations that overlap with those of DoC. In this paper, we describe the case of a patient with large bilateral mesial frontal lesions, showing prolonged behavioural unresponsiveness and severe disorganisation of electroencephalographic (EEG) background, compatible with a vegetative state/unresponsive wakefulness syndrome (VS/UWS). By applying an unprecedented multimodal battery of advanced imaging and electrophysiology-based techniques (AIE) encompassing spontaneous EEG, evoked potentials, event-related potentials, transcranial magnetic stimulation combined with EEG and structural and functional MRI, we provide the following: (i) a demonstration of the preservation of consciousness despite unresponsiveness in the context of AM, (ii) a plausible neurophysiological explanation for behavioural unresponsiveness and its subsequent recovery during rehabilitation stay and (iii) novel insights into the relationships between DoC, AM and parkinsonism. The present case offers proof-of-principle evidence supporting the clinical utility of a multimodal hierarchical workflow that combines AIEs to detect covert signs of consciousness in unresponsive patients.

Habituation deficit of visual evoked potentials in migraine patients with hypermobile Ehlers-Danlos syndrome.

Objectives: Migraine is one of the most frequent clinical manifestations of hypermobile Ehlers-Danlos syndrome (hEDS). The comorbidity between these two diseases has been only partially investigated. We aimed to observe whether neurophysiological alterations described in migraineurs in visual evoked potentials (VEPs) were present in hEDS patients with migraine. Methods: We enrolled 22 hEDS patients with migraine (hEDS) and 22 non-hEDS patients with migraine (MIG), with and without aura (according to ICHD-3), as well as 22 healthy controls (HC). Repetitive pattern reversal (PR)-VEPs were recorded in basal conditions in all participants. During uninterrupted stimulation, 250 cortical responses were recorded (4,000 Hz sample rate) and divided into epochs of 300 ms after the stimulus. Cerebral responses were divided into five blocks. The habituation was calculated as the slope interpolating the amplitudes in each block, for both the N75-P100 and P100-N145 components of PR-VEP. Results: We observed a significant habituation deficit of the P100-N145 component of PR-VEP in hEDS compared to HC (p = 0.002), unexpectedly more pronounced than in MIG. We observed only a slight habituation deficit of N75-P100 in hEDS, with a slope degree that was intermediate between MIG and HC. Discussion: hEDS patients with migraine presented an interictal habituation deficit of both VEPs components like MIG. Pathophysiological aspects underlying the pathology could account for the peculiar pattern of habituation in hEDS patients with migraine characterized by a pronounced habituation deficit in the P100-N145 component and a less clear-cut habituation deficit in the N75-P100 component with respect to MIG.

Beyond alpha power: EEG spatial and spectral gradients robustly stratify disorders of consciousness.

Neurophysiological markers can overcome the limitations of behavioural assessments of Disorders of Consciousness (DoC). EEG alpha power emerged as a promising marker for DoC, although long-standing literature reported alpha power being sustained during anesthetic-induced unconsciousness, and reduced during dreaming and hallucinations. We hypothesized that EEG power suppression caused by severe anoxia could explain this conflict. Accordingly, we split DoC patients (n = 87) in postanoxic and non-postanoxic cohorts. Alpha power was suppressed only in severe postanoxia but failed to discriminate un/consciousness in other aetiologies. Furthermore, it did not generalize to an independent reference dataset (n = 65) of neurotypical, neurological, and anesthesia conditions. We then investigated EEG spatio-spectral gradients, reflecting anteriorization and slowing, as alternative markers. In non-postanoxic DoC, these features, combined in a bivariate model, reliably stratified patients and indexed consciousness, even in unresponsive patients identified as conscious by an independent neural marker (the Perturbational Complexity Index). Crucially, this model optimally generalized to the reference dataset. Overall, alpha power does not index consciousness; rather, its suppression entails diffuse cortical damage, in postanoxic patients. As an alternative, EEG spatio-spectral gradients, reflecting distinct pathophysiological mechanisms, jointly provide a robust, parsimonious, and generalizable marker of consciousness, whose clinical application may guide rehabilitation efforts.

The Relationship among Bowel [18]F-FDG PET Uptake, Pathological Complete Response, and Eating Habits in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy.

Recently, the impact of patients' eating habits on both breast cancer (BC) management and inflammation have been proven. Here, we investigated whether inflammatory habits could correlate with baseline bowel [18]F-fluorodeoxyglucose (FDG) uptake and the latter, in turn, with pathological Complete Response (pCR) to neoadjuvant chemotherapy (NAC). We included stage I−III BC undergoing standard NAC at IRCCS Humanitas Research Hospital, Italy. Patients fulfilled a survey concerning eating/lifestyle behaviors and performed a staging [18]F-FDG positrone emission tomography/computed tomography (PET/CT). In the absence of data on the effects of individual foods, we aggregated drink and food intake for their known inflammatory properties. Data were recorded for 82 women (median age, 48). We found positive correlations between colon mean standardized uptake value (SUVmean) and pro-inflammatory drinks (alcohol and spirits; r = +0.33, p < 0.01) and foods (red and cured meats; r = +0.25, p = 0.04), and a significant negative correlation between rectum SUVmean and anti-inflammatory foods (fruits and vegetables; r = −0.23, p = 0.04). Furthermore, colon SUVmean was significantly lower in patients with pCR compared to non pCR (p = 0.02). Our study showed, for the first time, that patients' eating habits affected bowel [18]F-FDG uptake and that colon SUVmean correlated with pCR, suggesting that PET scan could be an instrument for identifying patients presenting unhealthy behaviors.

Functional connectivity alterations in migraineurs with Alice in Wonderland syndrome.

BACKGROUND AND PURPOSE: Alice in Wonderland syndrome (AIWS) is a neurological disorder characterized by erroneous perception of the body schema or surrounding space. Migraine is the primary cause of AIWS in adults. The pathophysiology of AIWS is largely unknown, especially regarding functional abnormalities. In this study, we compared resting-state functional connectivity (FC) of migraine patients experiencing AIWS, migraine patients with typical aura (MA) and healthy controls (HCs). METHODS: Twelve AIWS, 12 MA, and 24 HCs were enrolled and underwent 3 T MRI scanning. Independent component analysis was used to identify RSNs thought to be relevant for AIWS: visual, salience, basal ganglia, default mode, and executive control networks. Dual regression technique was used to detect between-group differences in RSNs. Finally, AIWS-specific FC alterations were correlated with clinical measures. RESULTS: With respect to HCs, AIWS and MA patients both showed significantly lower (p < 0.05, FDR corrected) FC in lateral and medial visual networks and higher FC in salience and default mode networks. AIWS patients alone showed higher FC in basal ganglia and executive control networks than HCs. When directly compared, AIWS patients showed lower FC in visual networks and higher FC in all other investigated RSNs than MA patients. Lastly, AIWS-specific FC alterations in the executive control network positively correlated with migraine frequency. CONCLUSIONS: AIWS and MA patients showed similar FC alterations in several RSNs, although to a different extent, suggesting common pathophysiological underpinnings. However, AIWS patients showed additional FC alterations, likely due to the complexity of AIWS symptoms involving high-order associative cortical areas.

A Propensity Score Matching Study on the Effect of OnabotulinumtoxinA Alone versus Short-Term Psychodynamic Psychotherapy Plus Drug-of-Choice as Preventive Therapy in Chronic Migraine: Effects and Predictive Factors.

OBJECTIVE: The objective of this study was to test the superiority of multidisciplinary approach, that is, Short-Term Psychodynamic Psychotherapy (STPP) plus drug of choice, versus monotherapy, that is, OnabotulinumtoxinA (OnaBoNT-A). METHOD: We consecutively recorded data from chronic migraine (CM) patients, with or without medication overuse headache (MOH), who underwent STPP or OnaBoNT-A, with a 3-month follow-up schedule. Headache days and analgesics intake were monitored as primary outcome measures. Propensity score matching (PSM) was used to eliminate discrepancies between groups. Discriminant function analysis (DFA) was used to pinpoint predictive factors associated with the clinical response. RESULTS: 96 patients with CM (64% with MOH) were treated with STPP and 54 (59% with MOH) with OnaBoNT-A. At baseline, OnaBoNT-A patients had more failed preventive therapies, more years of illness and chronicity, and were older; STPP patients were more depressed and had a higher HIT-6. Both STPP and OnaBoNT-A patients showed a significant reduction of headache days (STPP: -14 vs. OnaBoNT-A:-14.3) and analgesics intake (STPP: -12,3 vs. OnaBoNT-A -13.5 pills/month), respectively. MOH diminished more in STPP, adherence was higher in OnaBoNT-A. Results were confirmed after PSM balancing of the groups for those variables that resulted as different (but age). CONCLUSION: OnaBoNT-A monotherapy produced similar results to psychotherapy plus medication, after correcting for baseline differences.

A pilot analysis of headache disorders in breast cancer patients.

INTRODUCTION: The interaction between breast cancer and migraine is complex and not fully elucidated. Large epidemiological studies point towards a beneficial effect of migraines on breast cancer (BC). We aimed to investigate the BC-migraine relationship, with strict data checks and clinical evaluations of both BC and common headache forms. METHODS: Consecutive BC patients were evaluated with the International Classification of Headache Disorders. Clinical data on the BC subtypes and treatments were collected. Parametric and nonparametric statistics were used according to data distributions. RESULTS: Fifty patients were recruited. The mean age was 53.5 ± 12.5 years; 42% were postmenopausal, 52% were premenopausal, and 6% were peri-menopausal. Eleven patients were diagnosed as luminal A, nine as luminal B, 24 as HER2-positive (HER2 +), six as triple-negative BC. Thirty-eight (76%) patients had hormone receptor-positive disease. Ninety-two percent received chemotherapy, 66% received endocrine therapy, and 52% received radiotherapy. Nine out of 50 reported a worsening of headache after systemic treatment. Migraine was diagnosed in 29 patients (18 with menstrual migraine), tension-type headache (TTH) in nine, and no headache in 12. Patients with migraine were younger (48.4 ± 10.7 vs. 60.5 ± 12; p < 0.01). Patients with migraine and TTH had a higher chance of having a HER2 + BC (p < 0.05). Active migraine was associated with a higher expression of estrogen receptors (p = 0.04). CONCLUSIONS: Patients with active migraine had higher estrogen receptor expression, while migraine and TTH patients mainly had HER2 + BC. This association was not known earlier and could be helpful to understand deeper the relationship between BC and headache.