Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.

BACKGROUND AND PURPOSE: Fatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS-CoV-2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions. METHODS: Sixty-seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and 'well-being' were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short-interval intracortical inhibition, intracortical facilitation, long-interval intracortical inhibition and short-latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks. RESULTS: Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and reduced mental well-being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long-interval intracortical inhibition and short-latency afferent inhibition were also impaired, indicating altered GABAB -ergic and cholinergic neurotransmission. Short-interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention. CONCLUSIONS: Patients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

Effects of Intermittent Theta Burst Stimulation on the Clock Drawing Test Performances in Patients with Alzheimer's Disease.

The clock drawing test (CDT) is widely used in clinical neuropsychological practice. However, its neuroanatomical correlates have not been well established. This study investigated the effects of theta burst stimulation (TBS) applied over different brain regions on CDT scores in patients with Alzheimer's disease (AD). The 10-20 positions F3, F4, T3, T4, TP3, TP4, P3, P4, as determined by a 10-20 positioning cap, were targeted. Excitatory intermittent TBS (iTBS) was given over the above-mentioned eight regions to ten AD patients and ten control subjects on separate days. CDT was administered at baseline (T0), during the 5 min following the TBS (T1) and 60 min after TBS (T2), with an inter-session interval of at least 4 days. iTBS over TP4 and P4 transiently increased Rouleau CDT score in AD patients. When targeting TP4 and P4, mainly the area of the supramarginal/angular gyrus and the inferior parietal lobe, corresponding respectively to the Brodmann areas 40/39 and 7/40, are reached. iTBS thus seems able to modulate activity of the right posterior parietal cortex in AD patients performing the CDT. Our results provide physiological evidence that those parietal regions are functionally important for the execution of the Rouleau CDT. This finding suggests that CDT has reliable neuroanatomical correlates, and support the notion that this test can be used as a good marker of right parietal brain dysfunction. The present study also highlights the therapeutic potential of the induction of neuromodulatory effects using non-invasive brain stimulation techniques.

Effects of intrathecal baclofen therapy in subjects with disorders of consciousness: a reappraisal.

Baclofen is a structural analogue of gamma-amino-butyric acid (GABA), which reduces spastic hypertonia of striated muscle due to a mechanism of GABAB-ergic inhibition of mono- and polysynaptic reflexes at the spinal level. There are reports of patients with severe disorders of consciousness that presented a substantial improvement following intrathecal baclofen (ITB) administration for severe spasticity. The neural mechanisms underlying the clinical recovery after ITB have not yet been clarified. Baclofen could modulate sleep-wake cycles that may be dysregulated and thus interfere with alertness and awareness. The diminished proprioceptive and nociceptive sensory inputs may relieve thalamo-cortical neural networks involved in maintaining the consciousness of the self and the world. ITB treatment might also promote the recovery of an impaired GABAergic cortical tone, restoring the balance between excitatory and inhibitory cortical activity. Furthermore, glutamatergic synapses are directly or indirectly modulated by GABAB-ergic receptors. Neurophysiological techniques (such as transcranial magnetic stimulation, electroencephalography, or the combination of both) can be helpful to explore the effects of intrathecal or oral baclofen on the modulation of neural cortical circuits in humans with disorders of consciousness.

Modulation of exteroceptive electromyographic responses in defensive peripersonal space.

The cutaneous silent period (CSP) to noxious finger stimulation constitutes a robust spinal inhibitory reflex that protects the hand from injury. In certain conditions, spinal inhibition is interrupted by a brief burst-like electromyographic activity, dividing the CSP into two inhibitory phases (I1 and I2). This excitatory component is termed long-loop reflex (LLR) and is presumed to be transcortical in origin. Efficient defense from environmental threats requires sensorimotor integration between multimodal sensory afferents and planning of defensive movements. In the defensive peripersonal space (DPPS) immediately surrounding the body, we interact with objects and persons with increased alertness. We investigated whether CSP differs when the stimulated hand is in the DPPS of the face compared with a distant position. Furthermore, we investigated the possible role of vision in CSP modulation. Fifteen healthy volunteers underwent CSP testing with the handheld either within 5 cm from the nose (near) or away from the body (far). Recordings were obtained from first dorsal interosseous muscle following index (D2) or little finger (D5) stimulation with varying intensities. A subgroup of subjects underwent CSP recordings in near and far conditions, both with eyes open and with eyes closed. No inhibitory CSP parameter differed between stimulation in near and far conditions. LLRs occurring following D2 stimulation were significantly larger in near than far conditions at all stimulus intensities, irrespective of subjects seeing their hand. Similar to the hand-blink reflex, spinally organized protective reflexes may be modulated by corticospinal facilitatory input when the hand enters the DPPS of the face. NEW & NOTEWORTHY The present findings demonstrate for the first time that a spinally organized protective reflex, the cutaneous silent period (CSP), may be modulated by top-down corticospinal facilitatory input when the stimulated hand enters the defensive peripersonal space (DPPS) of the face. In particular, the cortically mediated excitatory long-loop reflex, which may interrupt the CSP, is facilitated when the stimulated hand is in the DPPS, irrespective of visual control over the hand. No spinal inhibitory CSP parameter differs significantly in or outside the DPPS.

Cholinergic transmission is impaired in patients with idiopathic normal-pressure hydrocephalus: a TMS study.

The pathophysiological mechanisms of cognitive and gait disturbances in subjects with normal-pressure hydrocephalus (NPH) are still unclear. Cholinergic and other neurotransmitter abnormalities have been reported in animal models of NPH. The objective of this study was to evaluate the short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain, in subjects with idiopathic NPH (iNPH). We applied SAI technique in twenty iNPH patients before ventricular shunt surgery. Besides SAI, also the resting motor threshold and the short intracortical inhibition to paired stimulation were assessed. A significant reduction of the SAI (p = 0.016), associated with a less pronounced decrease of the resting motor threshold and the short latency intracortical inhibition to paired stimulation, were observed in patients with iNPH at baseline evaluation. We also found significant (p < 0.001) correlations between SAI values and the gait function tests, as well as between SAI and the neuropsychological tests. These findings suggest that the impairment of cholinergic neurons markedly contributes to cognitive decline and gait impairment in subjects with iNPH.

Cortical afferent inhibition abnormalities reveal cholinergic dysfunction in Parkinson's disease: a reappraisal.

Parkinson's disease (PD) is a multisystem neurodegenerative disorder affecting, besides the dopaminergic function, multiple neurotransmission systems, including the cholinergic system. Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation (TMS) of motor cortex; this test is named short latency afferent inhibition (SAI). SAI abnormalities have been reported in PD patients with gait disturbances and many non-motor symptoms, such as visual hallucinations (VHs), REM sleep behavior disorder (RBD), dysphagia, and olfactory impairment. The findings of these TMS studies strongly suggest that cholinergic degeneration is an important contributor to a number of clinical features of PD. TMS and neuropsychological raise the possibility that the presence of RBD, VHs and olfactory dysfunction indicate increased risk of cognitive impairment in patients with PD. Longitudinal studies of the patients are required to verify whether SAI abnormalities can predict a future severe cognitive decline. TMS can provide simple measures that may represent suitable biomarkers of cholinergic neurotransmission in PD. SAI studies enable an early recognition of PD patients with cholinergic system degeneration, and this might allow future targeted cholinergic treatment approaches, in addition to dopaminergic therapy, to ameliorate non-motor and motor clinical symptoms in PD patients.

Post-traumatic parkinsonism: The intricate twist between trauma, inflammation and neurodegeneration. A narrative review.

Post-traumatic Parkinsonism (PTP) is a complex neurological disorder that is often associated with the occurrence of a traumatic brain injury (TBI). PTP can occur either in the acute or chronic phase of TBI. There is still uncertainty about the mechanisms provoking PTP, which can be the result of the acute blast itself or secondary neurodegenerative process occurring months to years post the acute trauma. Currently there is an underestimation of the clinical importance of PTP and lack of specific and proven therapeutic interventions, both in the pharmacological and the neurorehabilitation field. This narrative review aims to summarize the actual knowledge about PTP in terms of its pathophysiology, clinical aspects, treatments and perspective of care in the neurorehabilitative setting.

Reduced TMS-evoked EEG oscillatory activity in cortical motor regions in patients with post-COVID fatigue.

OBJECTIVE: Persistent fatigue is a major symptom of the so-called 'long-COVID syndrome', but the pathophysiological processes that cause it remain unclear. We hypothesized that fatigue after COVID-19 would be associated with altered cortical activity in premotor and motor regions. METHODS: We used transcranial magnetic stimulation combined with EEG (TMS-EEG) to explore the neural oscillatory activity of the left primary motor area (l-M1) and supplementary motor area (SMA) in a group of sixteen post-COVID patients complaining of lingering fatigue as compared to a sample of age-matched healthy controls. Perceived fatigue was assessed with the Fatigue Severity Scale (FSS) and Fatigue Rating Scale (FRS). RESULTS: Post-COVID patients showed a remarkable reduction of beta frequency in both areas. Correlation analysis exploring linear relation between neurophysiological and clinical measures revealed a significant inverse correlation between the individual level of beta oscillations evoked by TMS of SMA with the individual scores in the FRS (r(15) = -0.596; p = 0.012). CONCLUSIONS: Post-COVID fatigue is associated with a reduction of TMS-evoked beta oscillatory activity in SMA. SIGNIFICANCE: TMS-EEG could be used to identify early alterations of cortical oscillatory activity that could be related to the COVID impact in central fatigue.

Lowered Delta Activity in Post-COVID-19 Patients with Fatigue and Cognitive Impairment.

In post-COVID-19 syndrome (PCS), neurocognitive symptoms and fatigue are often associated with alterations in electroencephalographic (EEG) activity. The present study investigates the brain source activity at rest in PCS patients (PCS-pts) perceiving cognitive deficits and fatigue. A total of 18 PCS-pts and 18 healthy controls (HCs) were enrolled. A Montreal Cognitive Assessment (MoCA), Perceived Cognitive Difficulties Scale (PDCS) and Fatigue Severity Scale (FSS) were administered for assessing the symptoms' severity. Brain activity at rest, both with open (OE) and closed eyes (CE), was recorded by high-density EEG (Hd-EEG) and localized by source estimation. Compared to HCs, PCS-pts exhibited worse performance in executive functions, language and memory, and reported higher levels of fatigue. At resting OE state, PCS-pts showed lower delta source activity over brain regions known to be associated with executive processes, and these changes were negatively associated with PDCS scores. Consistent with recent literature data, our findings could indicate a dysfunction in the neuronal networks involved in executive functions in PCS-pts complaining of fatigue and cognitive impairment.

Conscious agency vs. pre-conscious sensory filtering: Disparate suppression of trigeminal blink reflex by self-stimulation and by prepulses.

Modulation of the blink reflex (BR) to supraorbital nerve (SON) stimulation by a weak somatosensory prepulse (sPP) consists of inhibition of R2 and facilitation of R1. Similar BR changes occur with self-stimulation. Our aim was to compare neurophysiological processes underlying both effects. We assessed BR parameters in 18 healthy participants following right SON stimulation either performed by an experimenter (experiment 1A) or following self-stimulation (experiments 1B, 1C). In experiments 1A and 1C, sPPs to digit 2 preceded SON stimuli by 40, 100, 200 and 500 ms. In experiment 1B: self-stimulation was delayed by 40, 100, 200, and 500 ms. In experiment 2, BRs were elicited by an experimenter randomly during a 2-s period before participants applied self-stimulation. In experiment 1, as expected, sPPs caused facilitation of R1 and inhibition of R2, which peaked at 100 ms ISI, similarly in experiments 1A and 1C. Self-stimulation caused a decrease of R2, which was evident in a broad range of time intervals. In experiment 2, R2 was already inhibited at the onset of the 2-s period, while R1 began to rise significantly 1.4 s before self-stimulation. Both effects progressively increased until self-triggering. The results concur with a time-locked gating mechanism of prepulses at brainstem level, whereas self-stimulation modulates BR in a tonic manner, reflecting a cognitive influence due to self-agency.

Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome.

OBJECTIVE: Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI). Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI. METHODS: Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity. RESULTS: Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected. CONCLUSIONS: Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients. SIGNIFICANCE: This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.

Global slowness and increased intra-individual variability are key features of attentional deficits and cognitive fluctuations in post COVID-19 patients.

Fatigue, attentional deficits and cognitive fluctuations are the most characterizing symptoms of neurological involvement in Post COVID-19 syndrome (PCS). As the intraindividual variability (IIV) in cognitive performances has been recognized as a hallmark of brain-related disorders associated with cognitive deficits, it could be an interesting measure to elucidate the mechanisms subtending both the attentive impairment and the cognitive fluctuations in these patients. By referring to IIV analysis of Reaction Times (RTs), the present study aims to define the attentive impairment and its relation to fluctuations and fatigue, in patients suffering from Post COVID-19 neurological symptoms. 74 patients were enrolled. They underwent an extensive clinical and neuropsychological assessments, as well as computerized Sustained Attention and Stroop tasks. For studying IIV, RTs distributions of performances in computerized tasks were fitted with ex-Gaussian distribution, for obtaining the τ values. Finally, the Resting Motor Threshold (RMT) was also collected to estimate cortical excitability. 29 healthy volunteers served as controls. Patients showed poorer scores in Montreal Cognitive Assessment and higher RMT, in comparison with controls. In Sustained Attention Task, Mean, µ, σ and τ values were significantly higher in PCS patients (p value = < 0.0001; 0.001; 0.018 and < 0.0001, respectively). Repeated measures ANOVA comparing the RTs mean in Stroop task within-subject and between-subjects revealed significant condition and group effect (p < 0.0001 both) and significant interaction (p = 0.005), indicating worst performances in patients. The mean of the derived interference value was significantly higher in PCS patients than in controls (p = 0.036). Patients suffering from PCS show deficits in attention, both in the sustained and executive components. Both high RTs means and high IIV subtend these deficits and could explain the often-complained cognitive fluctuations in this population.

TMS for the functional evaluation of cannabis effects and for treatment of cannabis addiction: A review.

The knowledge about the effects of cannabis on human cortical brain processes is increasing. In this regard, transcranial magnetic stimulation (TMS) enables the evaluation of central nervous system function, including drug effects. Moreover, repetitive TMS (rTMS) has been used therapeutically in several substance use disorders. In this scoping review, we summarize and discuss studies that have employed TMS and rTMS techniques in users of cannabis for recreational purposes. In subjects with a history of persistent cannabis use, TMS studies showed reduced short-interval cortical inhibition (SICI). This observation points more at neurobiological changes of chronic cannabis use than to a direct effect of cannabis on gamma-aminobutyric acid (GABA) A receptors. Moreover, individuals vulnerable to becoming long-term users of cannabis may also have underlying pre-existing abnormalities in SICI. Of note, the use of cannabis is associated with an increased risk of schizophrenia, and the down-regulation of GABAergic function may play a role. Less frequent cannabis use and spontaneous craving were observed following rTMS applied to the dorsolateral prefrontal cortex (DLPFC). There is emerging evidence that the posterior cingulate cortex and the precuneus are potential targets for rTMS intervention in cannabis use disorder. However, larger and randomized trials should corroborate these encouraging findings.

Visuomotor integration in early Alzheimer's disease: A TMS study.

BACKGROUND AND PURPOSE: Cortical visuomotor integration is altered in Alzheimer's disease (AD), even at an early stage of the disease. The aim of this study was to assess the connections between the primary visual (V1) and motor (M1) areas in patients with early AD using a paired-pulse, twin-coil transcranial magnetic stimulation (TMS) technique. METHODS: Visuomotor connections (VMCs) were assessed in 13 subjects with probable AD and 16 healthy control subjects. A conditioning stimulus over the V1 phosphene hotspot was followed at interstimulus intervals (ISIs) of 18 and 40 ms by a test stimulus over M1, to elicit motor evoked potentials (MEPs) in the contralateral first dorsal interosseous muscle. RESULTS: Significant effects due to VMCs, consisting of enhanced MEP suppression at ISI of 18 and 40 ms, were observed in the AD patients. Patients with AD showed an excessive inhibitory response of the right M1 to inputs travelling from V1 at given ISIs. CONCLUSIONS: This study provides neurophysiological evidence of altered functional connectivity between visual and motor areas in AD.

Optimization of cognitive assessment in Parkinsonisms by applying artificial intelligence to a comprehensive screening test.

The assessment of cognitive deficits is pivotal for diagnosis and management in patients with parkinsonisms. Low levels of correspondence are observed between evaluations assessed with screening cognitive tests in comparison with those assessed with in-depth neuropsychological batteries. A new tool, we named CoMDA (Cognition in Movement Disorders Assessment), was composed by merging Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Frontal Assessment Battery (FAB). In total, 500 patients (400 with Parkinson's disease, 41 with vascular parkinsonism, 31 with progressive supranuclear palsy, and 28 with multiple system atrophy) underwent CoMDA (level 1-L1) and in-depth neuropsychological battery (level 2-L2). Machine learning was developed to classify the CoMDA score and obtain an accurate prediction of the cognitive profile along three different classes: normal cognition (NC), mild cognitive impairment (MCI), and impaired cognition (IC). The classification accuracy of CoMDA, assessed by ROC analysis, was compared with MMSE, MoCA, and FAB. The area under the curve (AUC) of CoMDA was significantly higher than that of MMSE, MoCA and FAB (p < 0.0001, p = 0.028 and p = 0.0007, respectively). Among 15 different algorithmic methods, the Quadratic Discriminant Analysis algorithm (CoMDA-ML) showed higher overall-metrics performance levels in predictive performance. Considering L2 as a 3-level continuous feature, CoMDA-ML produces accurate and generalizable classifications: micro-average ROC curve, AUC = 0.81; and AUC = 0.85 for NC, 0.67 for MCI, and 0.83 for IC. CoMDA and COMDA-ML are reliable and time-sparing tools, accurate in classifying cognitive profile in parkinsonisms.This study has been registered on ClinicalTrials.gov (NCT04858893).

The need for psychological, caregiver-centered intervention in the time of COVID-19.

We focus attention on problems that are affecting the informal caregivers of patients with neurodegenerative disorders in the time of COVID-19. The pandemic is increasing difficulties in the management of the frailest people and their isolation is actually even more tangible than it was in the past. The social restrictions and the lockdown of many activities are putting the system of care provided by informal caregivers on the edge of collapse. We incite the scientific community to face these concerns and provide clinicians clear indications for assisting and supporting caregivers in the care of their relatives during this period. We suggest that e-health programs could become the ideal "environment" to favor the continuity of care for patients with neurodegenerative conditions and guarantee the required support to their caregivers, both directly in terms of psychological management and indirectly for helping them in disease management.

Case Report: Myopathy in Critically Ill COVID-19 Patients: A Consequence of Hyperinflammation?

Introduction: COVID-19-associated muscular complications may comprise myalgia, weakness, wasting, and rhabdomyolysis. Skeletal muscle damage in COVID-19 may be due to direct infection by the virus SARS-CoV-2 through interaction with the ACE2 receptor, systemic hyper-inflammatory state with cytokine release and homeostatic perturbation, an autoimmune process, or myotoxic drugs. Disclosing the cause of weakness in an individual patient is therefore difficult. Case Description: We report two patients, who survived typical COVID-19 pneumonia requiring intensive care treatment and who developed early on myalgia and severe proximal weakness in all four limbs. Laboratory exams revealed elevated serum creatine kinase and markedly increased C-reactive protein and interleukin 6, concurring with a systemic inflammatory response. On admission in neurorehabilitation (4 and 7 weeks after COVID-19 onset, respectively), the patients presented with proximal flaccid tetraparesis and limb-girdle muscle atrophy. Motor nerve conduction studies showed decreased amplitude and prolonged duration of compound muscle action potentials (CMAPs) with normal distal motor latencies and normal conduction velocities in median and ulnar nerves. Needle electromyography in proximal muscles revealed spontaneous activity in one and myopathic changes in both patients. Discussion: Clinical, laboratory, and electrodiagnostic findings in these patients were unequivocally consistent with myopathy. Interestingly, increased distal CMAP duration has been described in patients with critical illness myopathy (CIM) and reflects slow muscle fiber conduction velocity due to membrane hypo-excitability, possibly induced by inflammatory cytokines. By analogy with CIM, the pathogenesis of COVID-19-related myopathy might also depend on hyperinflammation and metabolic pathways that may affect muscles in a pathophysiological continuum from hypo-excitability to necrosis.

Involvement of central sensory pathways in subjects with restless legs syndrome: A neurophysiological study.

In patients with restless legs syndrome (RLS) a motor cortical disinhibition has been reported in transcranial magnetic stimulation (TMS) studies, but the neuronal excitability in other cortical areas has been poorly explored. The aim of this study was the functional evaluation of thalamo-cortical circuits and inhibitory cortical responses in the sensory cortex in RLS. We assessed the high-frequency somatosensory evoked potentials (HF-SEP) in sixteen subjects suffering from RLS of different degrees of severity. In patients with severe or very severe RLS we found a significant desynchronization with amplitude reduction of both pre- and post-synaptic HF-SEP bursts, which suggest an impairment in the thalamo-cortical projections and in the cortical inhibitory interneurons activity, respectively. The assessment of the central sensory pathways by means of HF-SEP may shed light on the pathophysiological mechanisms of RLS.

TMS-EEG Co-Registration in Patients with Mild Cognitive Impairment, Alzheimer's Disease and Other Dementias: A Systematic Review.

An established method to assess effective brain connectivity is the combined use of transcranial magnetic stimulation with simultaneous electroencephalography (TMS-EEG) because TMS-induced cortical responses propagate to distant anatomically connected brain areas. Alzheimer's disease (AD) and other dementias are associated with changes in brain networks and connectivity, but the underlying pathophysiology of these processes is poorly defined. We performed here a systematic review of the studies employing TMS-EEG co-registration in patients with dementias. TMS-EEG studies targeting the motor cortex have revealed a significantly reduced TMS-evoked P30 in AD patients in the temporo-parietal cortex ipsilateral to stimulation side as well as in the contralateral fronto-central area, and we have demonstrated a deep rearrangement of the sensorimotor system even in mild AD patients. TMS-EEG studies targeting other cortical areas showed alterations of effective dorsolateral prefrontal cortex connectivity as well as an inverse correlation between prefrontal-to-parietal connectivity and cognitive impairment. Moreover, TMS-EEG analysis showed a selective increase in precuneus neural activity. TMS-EEG co-registrations can also been used to investigate whether different drugs may affect cognitive functions in patients with dementias.