Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease: a proof of concept study

Abstract

The current drug treatment for Alzheimer's disease (AD) is only partially and temporary effective. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current inducing modulation in cortical excitability. In addition, cognitive training (COG) may improve cognitive functions in AD. Our aim was to treat AD patients combining high-frequency repetitive TMS interlaced with COG (rTMS-COG). Eight patients with probable AD, treated for more than 2 months with cholinesterase inhibitors, were subjected to daily rTMS-COG sessions (5/week) for 6 weeks, followed by maintenance sessions (2/week) for an additional 3 months. Six brain regions, located individually by MRI, were stimulated. COG tasks were developed to fit these regions. Primary objectives were average improvement of Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) and Clinical Global Impression of Change (CGIC) (after 6 weeks and 4.5 months, compared to baseline). Secondary objectives were average improvement of MMSE, ADAS-ADL, Hamilton Depression Scale (HAMILTON) and Neuropsychiatric Inventory (NPI). One patient abandoned the study after 2 months (severe urinary sepsis). ADAS-cog (average) improved by approximately 4 points after both 6 weeks and 4.5 months of treatment (P < 0.01 and P < 0.05) and CGIC by 1.0 and 1.6 points, respectively. MMSE, ADAS-ADL and HAMILTON improved, but without statistical significance. NPI did not change. No side effects were recorded. In this study, rTMS-COG (provided by Neuronix Ltd., Yokneam, Israel) seems a promising effective and safe modality for AD treatment, possibly as good as cholinesterase inhibitors. A European double blind study is underway.

An overview of repetitive transcranial magnetic stimulation (rTMS) in Alzheimer’s disease

“…rTMS could offer a reliable method to characterize important neurophysiological and physiopathological aspects of AD, and a decrease in cortical plasticity and connectivity/reactivity has been identified in comparison with healthy persons and even with other dementias. As a result, rTMS can be proposed as a promising therapy for AD (Bentwich et al, 2011;Brem et al, 2013;Freitas et al, 2011).…”

“…Even considering the sample size, improvements were observed in the evaluation scales, but without statistical significance: Alzheimer´s Disease Assessment Scale (ADAS-cog), Clinical Global Impression of Change (CGI), Mini Mental State Examination (MMSE), Evaluation Scale of Daily Activities, and Hamilton Depression Scale. There were no changes in the Cummings neuropsychiatric inventory (NPI) (Bentwich et al, 2011).…”

Theoretical Validation of the Computational Unified Field Theory (CUFT)

“…Hence, according to the (current) probabilistic interpretation of Quantum Mechanics, the determination of the (complimentary) 'space-energy' (s/e) or 'temporal-mass' (t/m) values of any given subatomic 'target' phenomenon (or phenomena) can only be determined following its direct (or indirect) physical interaction/s with another subatomic 'probe' element; But, note that according to such (probabilistic interpretation of) Quantum Mechanical theory the subatomic 'target' element is dispersed 'all along' a 'probability wave function' prior to its interaction with the probe element -but "collapses" into a single (complimentary) 'space-energy' or 'temporal-mass' value immediately following its direct (or indirect) physical interaction with the 'probe' element. This means that according to current (probabilistic) quantum mechanical theory, there exists a clear "unidirectional" (asymmetrical) 'flow of time' -i.e., one in which the determination of any subatomic (target) phenomena can be determined only following the collapse of the probability wave function' which takes place as a result of the direct (or indirect) physical interaction between the (probability wave function's) 'target' and other subatomic 'probe' element (Born, 1954); Now, as shown previously (Bentwich, 2011b) the computational structure (implicitly) assumed by the (above) probabilistic interpretation of quantum mechanics produces a 'Self-Referential Ontological Computational System' (SROCS) -which was shown to inevitably lead to both 'logical inconsistency' and 'computational indeterminacy' that are contradicted by known quantum empirical findings and which therefore also pointed at the computational 'Duality Principle' (e.g., asserting the existence of a conceptually higher-ordered 'D2' computational level that is capable of computing the simultaneous "co-occurrence" of any exhaustive hypothetical 'probe-target' pairs series). But, even beyond the Duality Principle's challenging of the current (implicit SROCS computational structure underlying) the probabilistic interpretation of Quantum Mechanics, note that it is precisely this SROCS assumed computational structure -which prohibits the capacity of any "collapsed" target element (or phenomenon) to "revert back to its 'un-collapsed' probability wave function state"!…”

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

“…Knockout of p75NTR in APPtransgenic mice reduces the Aβ production in the brain, suggesting that activation of p75NTR in Aβ-related pa- Aβ Down-regulation of BDNF [9] , activation of inflammatory cells [10] , generation of reactive oxygen species [11] , inhibition of long-term potentiation [6] , impairment of synaptic structure and function [7,8] , acceleration of neurofibrillary tangle formation [12] Altered function of blood-brain barrier Decreased clearance of Aβ [13] , leakage of serum-derived components into brain leading to neuronal dysfunction [14] , promotion of aluminum accumulation in brain [15] Brain trauma Increased risk of AD [16,17] Chronic stress Induction of abnormal hyperphosphorylation of tau [18] , accelerated impairment of cognition [19] Decline in protein synthesis Further neuronal impairment caused by other factors [20,21] Decline in stimulation and acetylcholine Impaired memory circuitry [22,23] Decreased levels of neurotrophic factors Deficient support for neuronal survival [24,25] Depression Chronic inflammation, impairment in the signaling of neurotrophins [26] Diabetes Apoptosis of neurons, defects of long-term potentiation, changed synapse plasticity [27,28] Downregulation of neprilysin Promotion of Aβ deposits [29][30][31] Enhanced reactive oxygen species levels Contributes to mitochondrial dysfunction [32,33] and calcium overload…”