in 2010 , there were an estimated 35.6 million people in the world suffering from dementia .
this is an increasing problem ; 65.7 million dementia cases are expected by 2030 and 115.4 million by 2050 .
this growing problem presents a pressing need for ad treatments . repetitive transcranial magnetic stimulation ( rtms )
is a noninvasive technique that has been used as a treatment for several major neurological and psychotic disorders such as parkinson 's disease , depression , and schizophrenia in the last decade ; it is currently being investigated as a treatment for ad .
the process of applying rtms involves a rapidly varying magnetic field , which can be used to modulate the firing of neurons on the outer surface of the brain .
it has been shown that rtms can either stimulate or inhibit cortical areas within the focal area of the coil [ 3 , 4 ] .
often , rtms treatments can be separated into two groups : high - frequency rtms ( 1020  hz ) and low - frequency rtms ( 1  hz ) .
the high - frequency rtms is generally considered to be more excitatory , while the low - frequency rtms is inhibitory , although this may vary between individuals .
the mechanism through which rtms affects the brain is thought to be long - term potentiation / depression ( ltp / ltd ) .
there have been a number of studies investigating rtms as a treatment for cognitive decline in ad .
a comprehensive review of these studies can be found in [ 7 , 8 ] .
these papers conclude that there is promise for the use of rtms to treat ad , but that further study is required .
specifically , action and object naming has been shown to improve during rtms treatments [ 9 , 10 ] , auditory sentence comprehension is improved up to eight weeks after rtms treatment , high - frequency rtms can improve cognitive skills in patients for up to 3 months , and rtms combined with cognitive training produces long - lasting improvements in a variety of cognitive measures .
while these results are promising , they are still preliminary , and much further research is needed to confirm their results .
the purpose of this paper is to discuss the complications of comorbid depression on investigations of rtms as a treatment for ad .
the prevalence of comorbid depression among dementia patients has been reported as 19% in one study   and up to 68% in another . while some previous studies explicitly excluded depressed patients [ 911 ] , others did not [ 12 , 13 ] perhaps due to lack of subjects excluding the comorbid syndrome . in order to properly understand the effects of rtms on ad patients ,
in the studies of rtms treatments for ad patients , the dorsolateral prefrontal cortex ( dlpfc ) has been commonly used as the stimulation site [ 912 ] , although at least one study also stimulated other brain regions . due to its interconnectedness with other brain regions
this region coordinates functions with the rest of the brain , knows where specific information is stored , and can assess when information is needed .
the dlpfc also helps to shift between tasks and therefore has a role in working memory .
further , it has a role in choice and decision - making . in early dementia
, there are often problems with both working memory and adaptive decision - making , leading to the conclusion that the dlpfc is affected by dementia .
the most common application of rtms clinically is for treatment of major depression . as with ad , the dlpfc
this is because in depressed patients there is often a decrease in glucose uptake and blood flow in the left dlpfc , and by stimulating the left side or inhibiting the right side , the activity on both sides of the brain is equalized , producing antidepressant effects .
a review published in 2011 suggested the optimal specifications for the use of rtms as a treatment for depression .
these specifications are very similar to those used in the rtms studies to treat ad ( see table 2 ) .
the motor threshold intensities used to treat dementia vary from 90% to 110% , similar to the suggested 90%120% intensity range for depression .
the suggested frequency for depression treatment is 520  hz , and frequencies of 10  hz   and 20  hz [ 912 ] have been used for dementia treatment . for depression , 5 treatments per week for 29 weeks are recommended .
the studies for dementia have implemented similar treatment schedules , including 5 sessions per week for one week , 24 weeks , and 6 weeks , occasionally with maintenance treatments   and follow - up assessments [ 11 , 12 ] . due to similar rtms treatment protocols , antidepressant effects
for instance , in a comparative study of high - frequency and low - frequency rtms for ad patients , high - frequency rtms yielded significant improvements in the geriatric depression scale , in addition to improvements in the mini - mental state examination and instrumental daily living activity scale . in three of the five studies considered in this paper [ 911 ] ,
patients with major depression were excluded , and therefore the positive effects were likely not caused by the antidepressant nature of the treatments . in a study that incorporated cognitive training ,
these cases were mild and controlled by medication , and 4 of these patients were in remission from their depression .
a comparative study between high - frequency and low - frequency rtms as a treatment for ad   did not specify the inclusion or exclusion of depressed patients , but the authors noted that approximately 40% of ad patients experienced depressive symptoms .
furthermore , one of the rating scales used for that study was the geriatric depression scale ( gds ) , and the patients improved in the gds as a result of treatments .
five studies which apply rtms to patients with alzheimer 's disease have been conducted [ 913 ] and are described below .
the first studies [ 9 , 10 ] considered the effects of rtms on action and object naming , while the third   considered the effects on language production and comprehension .
another study   aimed to treat ad using rtms combined with cognitive training , and the fifth study   investigated the cognitive improvements associated with rtms . in a study in 2006 , rtms was applied to 15 patients with mild - to - moderate cognitive decline ( probable dementia ) , and the effects were assessed by testing object and action naming during stimulation .
the results showed that action naming performance was better during both left and right dlpfc stimulation compared to the sham stimulation .
there was no significant increase in the performance seen for object naming . in a follow up
study in 2008 by the same group , rtms was applied to 24 ad patients : 12 with moderate - to - severe ad , and 12 with mild ad .
the results showed that rtms application to the dlpfc improved both action and object naming for moderate and severe ad patients but improved only action naming for mild ad patients . the same group conducted a further study   to assess whether rtms caused cognitive improvements in language production and/or comprehension in ad patients , and also to observe whether or not the improvements persisted after stimulation .
ten patients with probable moderate ad , and without major depression , were recruited and separated into two groups : one receiving 2 weeks of treatment and the other receiving 4 weeks of treatment .
the study also found that the patients with 4 weeks of treatment did not show significantly higher improvements than patients with 2 weeks of treatment .   in a recent study ,
high - frequency rtms was applied in conjunction with cognitive training ( cog ) , with the goal of treating ad patients .
this treatment ( rtms - cog ) was applied to 8 patients with probable early or moderate ad .
the trial consisted of daily treatments ( 5 days per week ) for 6 weeks , followed by maintenance sessions ( 2 days per week ) for 3 months .
six brain regions were stimulated : broca and wernicke , right and left dlpfc , and right and left parietal somatosensory association cortex ( r - psac , l - psac ) .
the brain areas were stimulated separately , 3 regions per day , every other day . the results showed a significant improvement in ad assessment scale - cognitive ( adas - cog ) scores after the 6 weeks of treatments .
it should also be noted that 6 of the 8 patients had a history of depression , although 4 of these were in remission . in another recent study ,
another group carried out a comparison of high - frequency ( 20  hz ) and low - frequency ( 1  hz ) rtms in probable ad patients applied bilaterally over the dlpfc .
forty - five patients diagnosed with probable ad ( 32 mild to moderate , 13 severe ) were randomly separated into 3 groups : 15 patients received high - frequency treatments ( 20  hz ) , 15 patients received low - frequency treatments ( 1  hz ) , and 15 received sham treatments .
depressed patients were not explicitly excluded ; however , measures of depression were evaluated during the study .
assessments took place before and after the treatment plan , in addition to 1 month and 3 months after the last session .
the results showed a significant improvement in the mini - mental state examination ( mmse ) , instrumental daily living activity scale ( iadl ) , and geriatric depression scale ( gds ) for high - frequency treatments with moderate - to - mild ad patients .
the high - frequency rtms treatment yielded significantly more improvement in all rating scales compared to the low - frequency rtms treatment and sham treatment .
a comparison summary of the rtms protocols for the five aforementioned studies can be found in table 1 .
there is some concern that the beneficial results observed in ad patients undergoing rtms treatments are due to the antidepressant effects of rtms .
as outlined in the previous section , the use of rtms to treat depression is very similar to the protocol used to treat ad .
therefore , it is likely that for patients with comorbid depression the depression was treated during rtms sessions .
however , some of the aforementioned studies excluded patients with major depression [ 911 ] , which may address this concern .
several studies have considered the frequency of comorbid depression and dementia and the relationship between the two symptoms .
a recent study conducted in dutch psychogeriatric nursing home wards   found that , out of 496 psychogeriatric residents , 96 ( or 19% ) were found to have comorbid depression and dementia ( stages 26 ) .
another study followed 670 outpatients with probable ad   and found that 26% of the patients had major depression , 26% had minor depression , and 48% were not depressed .
a comparison of depression patients with reversible cognitive impairment ( rci ) and with no cognitive impairment ( nci )   found that , within 57 years , 71.4% of the rci group developed dementia , compared to only 18.2% of the nci individuals .
( rci describes depressed patients who are first diagnosed with dementia but , upon treating for depression , show significant cognitive improvement . )
the authors suggest that chronic depression may lead to dementia because of its effects on the brain ( vascular effects , excessive release of corticosteroids , and hippocampal deterioration ) .
another study   following 1,239 older individuals ( baseline age 55.5  18.8 years ) found that the risk of developing dementia increased by 87% for participants who had experienced 1 episode of elevated depressive symptoms ( eds ) over the years of followup ( median of 24.7 years ) , and nearly doubled for participants who had experienced 2 or more eds .
as noted by the authors , these results support the hypothesis that , in some cases of major depression , there is an excessive release of glucocorticoid ( a type of corticosteroid ) , causing overstimulation of hippocampal glucocorticoid receptors , leading to the death of neurons in the hippocampus .
further , a study of 949 framingham heart study participants   found that , over a 17-year follow - up period , 164 participants developed dementia ( 136 cases of ad ) . among those depressed at baseline ,
21.6% had developed dementia , compared to 16.6% of the participants who were not depressed at the baseline .
the authors propose that chronic inflammatory changes associated with depression may increase the likelihood of developing dementia and ad .
vascular factors may also play a role , as well as lifestyle factors associated with depression .
from the five studies that have applied rtms to ad patients , it seems clear that high - frequency rtms applied to the dlpfc presents a possible treatment tool for ad .
more studies should be conducted with larger populations to verify the results of these studies , and take into consideration the antidepressant effects of rtms and how they may be causing the observed cognitive improvements . in particular ,
care should be taken in all future studies to separate the results from patients with depression or a history of depression from other results .
this will ensure that any confounding factors relating to cognitive improvements from the treatment of depression are fully understood .
in addition , it seems likely that some cases of depression may lead to dementia later in life .
positive results have been found using rtms as a treatment for both depression and dementia patients with similar application techniques .
therefore , treating dementia patients with rtms may not only improve cognitive abilities , but also have antidepressant effects for those who are suffering from comorbid depression .
in addition , it is possible that by also treating the depressive symptoms of dementia patients , further damage to the brain from depressive effects could be slowed . in order for these exciting possibilities to be explored , we should ensure that we fully understand both the cognitive and antidepressant potential of rtms .
 with an ever - increasing population of alzheimer 's disease ( ad ) patients worldwide , a noninvasive treatment for ad is needed . in this paper , the application of repetitive transcranial magnetic stimulus ( rtms ) as a treatment for patients with probable ad is compared to the application of rtms as a treatment for depression . 
 comorbidity of depression and dementia is discussed , as well as possible links between the two diseases . 
 the possible confounding antidepressant effects of rtms on cognitive improvements in ad patients are discussed . 
1. Introduction
2. Similarities in rTMS Protocols for Treatment of Dementia and Depression 
3. rTMS Study Protocols and Results
4. Comorbidity of Depression and Dementia
5. Conclusion