A comprehensive review of transcranial magnetic stimulation in secondary dementia.

Although primary degenerative diseases are the main cause of dementia, a non-negligible proportion of patients is affected by a secondary and potentially treatable cognitive disorder. Therefore, diagnostic tools able to early identify and monitor them and to predict the response to treatment are needed. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological technique capable of evaluating in vivo and in "real time" the motor areas, the cortico-spinal tract, and the neurotransmission pathways in several neurological and neuropsychiatric disorders, including cognitive impairment and dementia. While consistent evidence has been accumulated for Alzheimer's disease, other degenerative cognitive disorders, and vascular dementia, to date a comprehensive review of TMS studies available in other secondary dementias is lacking. These conditions include, among others, normal-pressure hydrocephalus, multiple sclerosis, celiac disease and other immunologically mediated diseases, as well as a number of inflammatory, infective, metabolic, toxic, nutritional, endocrine, sleep-related, and rare genetic disorders. Overall, we observed that, while in degenerative dementia neurophysiological alterations might mirror specific, and possibly primary, neuropathological changes (and hence be used as early biomarkers), this pathogenic link appears to be weaker for most secondary forms of dementia, in which neurotransmitter dysfunction is more likely related to a systemic or diffuse neural damage. In these cases, therefore, an effort toward the understanding of pathological mechanisms of cognitive impairment should be made, also by investigating the relationship between functional alterations of brain circuits and the specific mechanisms of neuronal damage triggered by the causative disease. Neurophysiologically, although no distinctive TMS pattern can be identified that might be used to predict the occurrence or progression of cognitive decline in a specific condition, some TMS-associated measures of cortical function and plasticity (such as the short-latency afferent inhibition, the short-interval intracortical inhibition, and the cortical silent period) might add useful information in most of secondary dementia, especially in combination with suggestive clinical features and other diagnostic tests. The possibility to detect dysfunctional cortical circuits, to monitor the disease course, to probe the response to treatment, and to design novel neuromodulatory interventions in secondary dementia still represents a gap in the literature that needs to be explored.

Diagnostic contribution and therapeutic perspectives of transcranial magnetic stimulation in dementia.

Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such asexcitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of thepathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention. The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment. To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer's disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression. In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.

Participation of the left inferior frontal gyrus in human originality.

Human creative cognition is commonly described as a twofold cyclic process that involves an idea generation phase and an idea evaluation phase. Although the evaluation phase makes a crucial contribution to originality, its underlying mechanisms have not received sufficient research attention. Here, we suggest that the left inferior frontal gyrus (lIFG) plays a major role in the interplay between the evaluation and generation networks and that inhibiting this region's activity may have an effect on "releasing" the generation neural network, resulting in greater originality. To examine the neural networks that mediate the generation and evaluation of ideas, we conducted an fMRI experiment on a group of healthy human participants (Study 1), in which we compared an idea generation task to an idea evaluation task. We found that evaluating the originality of ideas is indeed associated with a relative increase in lIFG activation, as opposed to generating original ideas. We further showed that temporarily inhibiting the lIFG using continuous theta-burst stimulation (Study 2) results in less strict evaluation on the one hand and increased originality scores on the other. Our findings provide converging evidence from multiple methods to show that the lIFG participates in evaluating the originality of ideas.

Bi-phasic activation of the primary motor cortex by pain and its relation to pain-evoked potentials - an exploratory study.

The primary motor cortex (M1) is a known target for brain stimulation aimed at pain alleviation in chronic pain patients, yet the mechanisms through which analgesia occurs, and the exact pain-motor interrelations are not fully understood. We used noxious contact heat evoked potentials (CHEPs) and cortical source analysis to further explore the relevance of M1 in pain processing. Twenty-four healthy young females received brief noxious heat stimuli to their left non-dominant volar forearm, simultaneously with CHEPs recordings. Thereafter, the pain-evoked activity of M1 and a control area in the occipital cortex (OC) was analyzed and estimated using sLORETA (standardized low-resolution brain electromagnetic tomography). This analysis revealed two phases of M1 pain-evoked activation (phase 1: the peak at 261.5±25.7ms; phase 2: the peak at 381.3±28.3ms). Canonical correlations revealed that M1, but not the OC, was the main factor contributing to the relation with the CHEPs components. In detail, the activity magnitude of M1 first and second phases was related to the N2 and P2 amplitude, respectively. The latency of the second phase was associated with both N2 and P2 latencies. In relation to pain, the latency of M1's first activity phase was positively correlated with pain ratings, suggesting pain interference to synchronized activity in M1. Our results confirm the established relevance of the primary motor cortex to pain processing.

Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: a double-blind sham-controlled study.

BACKGROUND: Theta-burst transcranial magnetic stimulation (TBS) has been shown to induce potent and long lasting effects on cortical excitability. In a previous open study, we demonstrated safety, tolerability and antidepressant properties of continuous TBS (cTBS) in major depression (MD). The present study was aimed to evaluate the therapeutic efficacy of cTBS in depressed patients using a double-blind, sham-controlled design. METHODS: Twenty nine patients with MD were randomized to receive either active cTBS to the right dorsolateral prefrontal cortex (n=15) or sham cTBS (n=14) for 10 consecutive work days. After the 10th session, patients who received sham TBS were crossed over to active cTBS which consisted of 10 daily sessions. Patients who received active cTBS continued with the same treatment protocol for additional 10 treatments. Each treatment session consisted of 3600 stimuli at an intensity of 100% of the active motor threshold. Severity of depression was assessed weekly. RESULTS: Overall, there was no significant difference in the degree of clinical improvement between active and sham cTBS groups. However, in patients whose medication status remained unchanged before the trial (n=8) and in those who were medication-free (n=3), active cTBS resulted in a significantly greater reduction of Hamilton depression scores as compared to sham cTBS. LIMITATIONS: A small sample size, confounding effect of medication and short treatment period. CONCLUSIONS: Our results suggest that the antidepressant effect of cTBS is modest, yet it might be beneficial to patients nonresponsive to ongoing pharmacological treatment. A direct comparison between cTBS and conventional rTMS protocols is warranted.

Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study.

OBJECTIVE: To compare the ability of an H-coil and figure-8 coil to stimulate different motor cortex regions. METHODS: The resting (rMT) and active (aMT) motor thresholds were measured for the right hand APB and leg AHB muscles in 10 subjects, using an H-coil and a figure-8 coil. The electric field distribution induced by the coils was measured in a head model. The combination of the hand and leg MTs with the field measurements was used to determine the depth of hand and leg motor areas via the intersection points. RESULTS: The rMT and aMT of both APB and AHB were significantly lower for the H-coil. The ratio and difference between the leg and hand rMT and aMT were significantly lower for the H-Coil. Electric field measurements revealed significantly more favorable depth profile and larger volume of stimulation for the H-coil. The averaged intersection for the APB was at a distance from coil of 1.83±0.54cm and at an intensity of 97.8±21.4V/m, while for the AHB it was at a distance of 2.73±0.44cm and at an intensity of 118.6±21.3V/m. CONCLUSION: The results suggest a more efficient activation of deeper motor cortical regions using the H-coil. SIGNIFICANCE: The combined evaluation of MTs by H- and figure-8 coils allows measurement of the individual depth of different motor cortex regions. This could be helpful for optimizing stimulation parameters for TMS treatment.

Motor cortex disinhibition in normal-pressure hydrocephalus.

OBJECT: Previous studies have shown a close association between frontal lobe dysfunction and gait disturbance in idiopathic normal-pressure hydrocephalus (iNPH). A possible mechanism linking these impairments could be a modulation of corticospinal excitability. The aim of this study was 2-fold: 1) to determine whether iNPH affects corticospinal excitability; and 2) to evaluate changes in corticospinal excitability following ventricular shunt placement in relation to clinical outcome. METHODS: Twenty-three patients with iNPH were examined using single- and paired-pulse transcranial magnetic stimulation of the leg motor area before and 1 month after ventricular shunt surgery. The parameters of corticospinal excitability assessed were the resting motor threshold (rMT), motor evoked potential/M-wave area ratio, central motor conduction time, intracortical facilitation, and short intracortical inhibition (SICI). The results were compared with those obtained in 8 age-matched, healthy volunteers, 19 younger healthy volunteers, and 9 age-matched patients with peripheral neuropathy. RESULTS: Significant reduction of the SICI associated with a decrease of the rMT was observed in patients with iNPH at baseline evaluation. Ventricular shunt placement resulted in significant enhancement of the SICI and increase of the rMT in patients who markedly improved, but not in those who failed to improve. CONCLUSIONS: This study demonstrates that iNPH affects corticospinal excitability, causing disinhibition of the motor cortex. Recovery of corticospinal excitability following ventricular shunt placement is correlated with clinical improvement. These findings support the view that reduced control of motor output, rather than impairment of central motor conduction, is responsible for gait disturbances in patients with iNPH.

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression.

The aim of this open study was to evaluate the safety and tolerability of theta-burst transcranial magnetic stimulation (TBS) and to assess preliminarily its therapeutic efficacy in patients with major depression. A total of 33 patients were assigned to receive one of four TBS protocols for 10 consecutive work days. TBS consisted of triple-pulse 50-Hz bursts given at a rate of 5 Hz to the left or right dorsolateral prefrontal cortex at different stimulation parameters. Severity of depression was assessed by the Hamilton Depression Rating Scale. Our results indicate that TBS as applied in this study is safe and well tolerated in depressed patients and seems to have antidepressant properties. Increase of stimulation parameters is not associated with more side-effects and adds to its therapeutic effect.

Effect of electroconvulsive therapy on cortical excitability in patients with major depression: a transcranial magnetic stimulation study.

OBJECTIVE: The antidepressant action of electro-convulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) may be related to their ability to modulate cortical excitability. The aim of this study was to investigate changes in cortical excitability following ECT in patients with major depression (MD) and to compare therapeutic efficacy of ECT combined with rTMS to that of ECT alone. METHODS: Twenty-two patients with MD were assigned to receive ECT and right prefrontal 1 Hz rTMS (n=12) or ECT with sham rTMS (n=10). ECT was given twice weekly and rTMS was applied on the remaining 4 days, throughout 3 weeks. The resting motor threshold (rMT) and motor evoked potential (MEP)/M-wave area ratio were evaluated before and 6 h after the first, third and sixth ECT session. The active motor threshold (aMT), intra-cortical inhibition (ICI) and intra-cortical facilitation (ICF) were measured at baseline and 24 h after the last ECT. RESULTS: There were no significant differences in the degree of clinical improvement and measures of cortical excitability in the ECT+active rTMS group as compared to the ECT+sham rTMS group. Marked clinical improvement observed in 19 out of the 22 patients was associated with a significant increase of the MEP/M-wave area ratio, decrease of the aMT and reduction of the ICI in the left hemisphere. CONCLUSIONS: The antidepressant effect of ECT was associated with an enhancement of left hemispheric excitability. rTMS did not add to the beneficial effect of ECT. However, the small sample size and the robust effect of ECT might have obscured a potential therapeutic effect of rTMS. SIGNIFICANCE: Measures of cortical excitability may provide insight to our understanding of the mechanism of action of ECT and might be useful for the assessment of treatment response.

Evidence for cortical hyperexcitability of the affected limb representation area in CRPS: a psychophysical and transcranial magnetic stimulation study.

Functional alterations in noxious, sensory and motor circuits within the central nervous system may play an important role in the pathophysiology of complex regional pain syndrome (CRPS). The aim of the present study was to search for further evidence of hyperexcitability in the hemisphere contralateral to the affected limb in patients with CRPS by employing both psychophysical and transcranial magnetic stimulation (TMS) methods. Twelve patients with CRPS type I, confined to the distal part of a limb (six in an upper-limb and six in a lower-limb), were enrolled in the study. The quantitative thermal, mechanical and 'wind-up' like pain testing was performed at the most painful site in the affected limb and in the ipsilateral limb. Results were then compared to those found at mirror sites in the contralateral limbs. TMS was used to assess the inter-hemispheric difference in parameters of corticospinal excitability, intracortical inhibition, and intracortical facilitation. The quantitative thermal and mechanical testing showed significant differences in cold, heat and mechanical pain thresholds, as well as in the first and last 'wind-up' stimuli between the affected and the contralateral limbs of the CRPS patients. No significant differences between the ipsilateral unaffected limbs and their contralateral pair limbs were found. A significant reduction in the short intracortical inhibition associated with a significant increase of the I-wave facilitation was found in the hemisphere contralateral to the affected side in the upper-limb CRPS group. No significant inter-hemispheric asymmetry between the affected and the non-affected sides was revealed in the lower-limb CRPS group. Taken together, these results suggest that in patients with well-localized CRPS, there is evidence for sensory and motor CNS hyperexcitability, though it seems to involve only corresponding regions within the CNS rather than the entire hemisphere.

Antidepressant effects of different schedules of repetitive transcranial magnetic stimulation vs. clomipramine in patients with major depression: relationship to changes in cortical excitability.

The antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) that have been demonstrated in recent studies could be related to its ability to modulate cortical excitability. Yet, the relationship between stimulus location and frequency and treatment outcome has not been established. The aim of the present study was to compare efficacy of rTMS in various configurations and clomipramine treatment in patients with major depression (MD) and to evaluate the relationship between clinical outcome and changes in cortical excitability. Fifty-nine MD patients were randomized to receive (1) left (n = 12) or right (n = 12) 3 Hz rTMS with placebo medication; (2) left (n = 10) or right (n = 9) 10 Hz rTMS with placebo medication; (3) active medication (clomipramine) with sham rTMS (n = 16). Both 3 Hz and 10 Hz rTMS were administered to the prefrontal cortex by a circular coil at an intensity of 110% and 100% of the resting motor threshold (rMT) respectively. Measurements of cortical excitability were performed prior to and 24 h after completion of 2 wk of daily rTMS or pharmacological treatments. These included the rMT, silent period threshold (SPT), inter-threshold difference (ITD), MEP/M-wave amplitude ratio and silent period duration (SPD). Severity of depression was blindly assessed by the Hamilton Depression Rating Scale (HDRS). The best improvement scores were seen in patients who received left 3 Hz rTMS. The 10 Hz rTMS treatment was less tolerated resulting in a significantly higher dropout rate. A significant increase of the MEP/M wave amplitude ratio accompanied by a shortening of the SPD was evidenced in patients who showed marked clinical improvement (reduction in HDRS by 50% or more) following left rTMS regardless of stimulation frequency. Our results suggest that 3 Hz left rTMS has a higher therapeutic efficacy and tolerability in patients with MD. The enhancement of cortical excitability may be related to the antidepressant action of rTMS.

The value of motor and somatosensory evoked potentials in evaluation of cervical myelopathy in the presence of peripheral neuropathy.

STUDY DESIGN: Patterns and rates of motor-evoked potential (MEP) and somatosensory-evoked potential (SEP) abnormalities were evaluated in 9 patients with combined cervical cord compression and diabetic neuropathy and 15 patients with asymptomatic cervical cord compression. The results were compared with those of 8 patients with pure cervical myelopathy and 7 patients with pure diabetic neuropathy. OBJECTIVE: To assess the efficacy of MEPs and SEPs in the evaluation of cervical myelopathy in the presence of peripheral neuropathy. SUMMARY OF BACKGROUND DATA: Previous studies have demonstrated a high sensitivity of MEPs and SEPs in documenting a functional involvement of motor and somatosensory pathways in pure or preclinical cervical myelopathy. However, there have been no detailed reports on MEPs and SEPs in cervical cord compression associated with peripheral neuropathy. METHODS: Central somatosensory conduction was assessed by median and tibial SEPs using peak-to-peak and onset-to-onset methods. Central motor conduction was measured by MEPs and F-waves elicited from upper and lower limb muscles in response to transcranial magnetic stimulation, magnetic stimulation of cervical motor roots, and electrical stimulation of peripheral nerves. RESULTS: MEPs were more sensitive than SEPs in detecting central conduction impairments in patients with either pure or preclinical or combined forms of cervical myelopathy. The rate of MEP abnormalities suggesting the corticospinal tract involvement in the combined cervical cord compression-neuropathy group did not differ significantly from that in the asymptomatic cervical cord compression group but was lower than in the pure cervical myelopathy group. Combined MEP and SEP analysis improved the test sensitivity in detecting clinically "silent" cervical cord dysfunctions. CONCLUSIONS: MEPs associated with SEPs are a valuable tool for assessing the presence and severity of cervical cord involvement in combined cervical cord compression and peripheral neuropathy lesions.