Friday, 19 January 2018

Symptoms update - toe walking and the need to sit

OK, so I go for months without a symptoms update and then several come along at once. This post comes from a comment made about my walking, and from my own observations going out in the evenings.

Firstly, the walking. My wife observed that I always seem to walk around at home on my toes rather than on my feet, and after she mentioned it I know that this is now a regular thing for me. I’m not sure when I moved from walking on feet to walking on toes, but it happens now. More detail: When we are at home we take our shoes off, so all of us walk around in our socks. I have noticed that I only walk on my toes at home, I don’t do this when wearing my shoes out an about. At home, walking on my feet feels more difficult, and therefore I wonder if this isn’t a bit more spasticity showing in my legs. The other observation is that with my insoles my heels are a couple of centimetres higher than without my insoles, so perhaps my feet are more used to walking with heels slightly higher.

Secondly, when I have had a busy day I feel the need to sit down towards the end of the evening. This was certainly true at my office Christmas do, where we were standing for a good while. I can feel that my legs are beginning to be more tired towards the end of the evening, and the need to sit gets stronger and stronger. Perhaps another example of more spasticity, or perhaps an example of physical fatigue starting to show itself. When I am at home there are many more reasons to sit down, so I don’t notice this as much – and I am often just putting in a few more flights of stairs or laps of the house to get to the next fitbit badge.

Wednesday, 27 December 2017

Review of 2017

As we draw to the end of 2017 it is time for me to reflect on this years goings on.


This year has seen less new knowledge going in, but there have been several times when I've needed to look back at knowledge gained previously, thereby fulfilling one of this blogs purposes: to act as a memory dump. During the year I've looked back on my posts on depression and my work on misdiagnosis. I've also been contributing to the knowledge of others in a new way by taking part in the HSP falls study for Plymouth University (UK) and the CREATE Daily Living Scale study.


Generally it has been another year of no significant change. I think that my distance may be becoming limited due to HSP, but I've not tested that properly yet. 2017 has seen the continuation of tracking my cycling with Strava and I've started tracking plenty of things with FitBit, so there is plenty of data for me to look at and see if I can spot any patterns. On the other side of the coin, during the year PatientsLikeMe changed their website so I've lost a couple of trackers I found useful there. The main 'big' thing this year has been the MRI scan, but nothing on the results of that yet.

This Blog

I'm really pleased with the continuing growth in readership of this blog! My audience remains broadly the same (predominantly US, UK, Russia, Ukraine, France, Germany, Canada). The most popular posts continue to be the results of my survey, the various presentations/posters given at meetings and my general posts on research and particular HSP symptoms. I now have a full year of Google Analytics tracking to compare with the blogger tracking, so expect some analysis on that in the new year! Various blog posts are being linked to and used within other HSP and RareDisease publications, so I feel like a bit of an information conduit now. Thank you to all my readers.

I've had various comments from people appreciating what I have to say, which I'm very pleased to receive. Feedback like this gives me another reason why this is a worthwhile thing to do. Thank you to anyone that makes a comment or connects up with me in some other way. A couple of my favourite comments about the blog from this years survey are:

"I'm interested to hear how you are progressing with symptoms as I feel like the only guy on earth that has this condition. Your blogs make me feel like I'm not alone"
"Great to read how you approach every day problems"
"It is superb and very informative - I have gleaned a lot of useful info over the past few months and hope to be able to put much of it into practice now I know what I am dealing with."


The now annual pattern of my surveys is well established. Each year I get more responses than previously, and this year is no exception. I've now got around 190 responses to start analysing in 2018, which is brilliant! If you're reading this and want to take part then (providing it is still 2017) please do! Results will be out on 28th Feb after the majority of analysis during January.

Similarly, its good to get feedback on this. Two of my favourite comments from this year are:
"I felt like your questions were right on target for capturing most of the issues I'm facing."
"It is nice to be asked relevant questions!"

Community Contribution

HSP Community activities for 2017 included:
  • Being elected chairman of the UK Support Group!
  • Taking part in research projects (as described above)
  • Starting to talk with people from other HSP groups
  • Convincing the UK HSP group to join EuroHSP
  • Analysing and reporting the results of my survey to share with the HSP world
  • Seeking out other on-line HSP communities principally to spread the word of my survey
  • Continuing this blog and posting/discussing HSP things on twitter.

Obviously, becoming chair of the HSP group is a big change for me, and I'm working with the rest of the committee to ensure that the group continues to support its members in the most appropriate way. There are several channels of discussion going on.

HSP in the news

There have been a couple of people with HSP in the UK news during 2017, both children. 

Firstly, Lily Rice became the first female from Europe to perform a backflip in a wheelchair - and

Secondly, right at the end of the year, Archie Blomfield has been chosen to play the lead role of William Trundle in the Christmasaurus alongside McFly's Tom Fletcher at the Hammersmith Apollo in London.
My youngest son is a dinosaur fan, and we read this great story last Christmas.

Friday, 22 December 2017

A brief history of HSP

I was having a brief look at papers in the "new research tool" I became aware of at the drug repurposing conference in 2016.

This pointed me to this article which is a brief history of HSP.

I have copied and pasted the article below, and shortened for this aspects most of interest to me - which is principally understanding the earlier part of the HSP story. If you're interested in the more recent aspects, the click the link and read away!

The article is called: Hereditary spastic paraplegia from 1880 to 2017: an historical review

It is written by: Ingrid Faber, Eduardo Rafael Pereira, Alberto R. M. Martinez, Marcondes França Jr and Hélio Afonso Ghizoni Teive from Universidade Estadual de Campinas and Universidade Federal do Paraná in Brasil.

The diagnosis of an inherited spastic paraplegia is based essentially on the clinical picture, together with the investigation of other, potentially affected, members of the kindred. 

In the last three decades, advances in molecular genetics have revealed that HSPs constitute a large and heterogeneous group of diseases. These frequently overlap clinically and/or genetically with other degenerative disorders such as ataxias, leukodystrophies, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and peripheral neuropathies. Historically, the differentiation between HSPs and inherited ataxias has been the most challenging. The key to differentiating complicated HSP from ataxias with associated corticospinal tract dysfunction is to focus on the patient's main disabilities. As a rule, individuals with HSP are overtly spastic and have mild or no complaints relating to the upper limbs. Whereas, in the ataxia group, there is no pronounced dissociation between upper and lower limbs. 

Hereditary spastic paraplegia - first descriptions
In 1880, the Baltic-German (region known today as Estonia and Latvia) neurologist Ernst Adolf Gustav Gottfried von Strümpell published the first case series of patients with HSP. Strümpell reported on two siblings with a probable AD-HSP whose symptoms manifested at 37 and 56 years of age. Clinically, these patients showed a pure form of spastic paraplegia. After the death of one of the siblings, neuropathology showed degeneration of the lateral corticospinal tract, fasciculus gracilis and spinocerebellar tract. In 1888, Maurice Lorrain, a French neurologist, published a more detailed contribution to the anatomical and clinical study of HSPs; hence HSP also being known as Strümpell-Lorrain disease.

Clinical phenotype
Rhein was the first, in 1916, to drive attention to the exquisite clinical heterogeneity some families with HSP displayed. His observations were accompanied by many case series describing pleomorphic clinical pictures encompassing: retinal degeneration, dementia, extrapyramidal symptoms, mental handicap, hand amyotrophy and other features. The term Strumpell's familial spastic paraplegia was reserved for families that displayed only spastic paraparesis, a condition that was thought to be much rarer. Currently, it is recognized that pure forms are more prevalent than complicated ones, their relatively benign clinical course, not affecting life expectancy, greatly contributed to their underdiagnosis at that time. Most epidemiological studies were based on postmortem or hospitalization records.

Anita Harding, a professor of neurology at the University of London, was an important pioneer in the field of molecular neurogenetics. In the 1980s, she published a series of groundbreaking works addressing HSP. In 1981, she presented what was, at the time, the largest investigation into pure HSP, with 22 families studied. She also reinforced the knowledge that spasticity, and not weakness, is the main source of disability in this scenario, an aspect that remains useful in differentiating HSP from other myelopathies. Harding's major contribution to the field of HSP was published in The Lancet journal in 1983. Entitled “Classification of the hereditary ataxias and paraplegias”, this paper established an accurate differentiation between ataxias and HSP, providing a workable base for the etiological investigations that would come. Harding defined that, besides the spastic paraparesis, additional mild signs such as vibration and segmental position sense deficits, slight distal amyotrophy and sphincter dysfunction were also conceivably present in the pure phenotype. This work also provided refinement of the HSP phenotype, emphasizing the variability of disease progression, even within the same family. Sadly, Harding's outstanding career ended prematurely at the age 42 when she succumbed to a cancer. 

In 2006, the German Network for Hereditary Spastic Paraplegia presented the spastic paraplegia rating scale, developed to quantify the disease progression clinically. Validated measures of disease severity are essential to understanding the disease's natural history. Additionally, by their ability to measure treatment impact, they are decisive in the development of future clinical trials.
Structural characterization
While the clinical descriptions of HSP flourished during the 1980s, the pathological comprehension of the disease saw flourishing moments 100 years before. We return to Adolf von Strümpell, the first to identify the disease clinically, who was also the first to describe its pathological hallmarks six years later, in 1886. An unrelated case was also documented by him in 1904. Both pathological specimens showed degeneration of the corticospinal tract in the spinal cord with a distal-proximal gradient. Since then, the disease has been understood as a distal axonopathy of the longest large myelinated fibers of the spinal tract. 

In 1952, Schwarz gave an extensive review of the pathologic literature, highlighting the contributions of Newmark (1904, 1906, 1911), Jakob and Kahlstorf, that culminated with the differentiation of Strümpell's disease from other conditions such as cerebellar ataxias and motor neuron disorders, establishing that, at first, lesions are restricted to the spinal cord and affecting the corticospinal and posterior tracts

Advances in genetics
After the accurate clinical classification developed by Harding, the research involving HSP evolved from anecdotal case descriptions to the systematic study of families alike. Numerous HSP genetic studies have been published since the 1980s. Several genetic subtypes of HSP have been described and numbered sequentially, based on the order of the gene discovery (SPG1, SPG2, SPG3, etc. In 1994, Jouet et al., reported that three disorders; X-linked spastic paraplegia, MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and X-linked hydrocephalus were, in fact, allelic conditions, all resulting from mutations in the gene for neural cell adhesion molecule (L1CAM or SPG1). This was the first gene discovered that caused HSP; Also in 1994, Hazan et al., identified the locus implicated in the majority of cases of dominantly inherited HSP.

In 1998, the first gene for autosomal recessive HSP was identified, when the HSP-SPG7 gene was cloned. In 2007, SPG11 was identified as the gene most commonly related to spastic paraplegia with mental impairment and thin corpus callosum. HSP-SPG11 has been recognized as the most common AR-HSP. Surprisingly, SPG11 mutations can also primarily present with other phenotypes, such as parkinsonism or ALS.

Friday, 1 December 2017

Symptoms Update - Walking

So, it looks like there hasn't been many symptoms updates, and then two come along in quick succession!

Observations from the last couple of months are that my walking speed has dropped, but I'm not really sure over low long this has taken place. Certainly before I was living in Bristol I was quite a fast walker, and easily found myself at the front of groups walking. When I was visiting the Lake District (and other similar places) to go walking I know that I was able to average about 5km/hour overall, the uphill bits being the slower part of the average. I used to be able to comfortably achieve 5km/hour on other walks.

These days I notice that I am now walking slower than most people - a walk along the street will see people passing me, and I have to speed up if I want to keep up with a group of people. Recently I went to meet a friend for a couple of drinks which involved a 1.8km walk which I managed in about 23 mins, slightly downhill - about 4.7km/hr, which felt like quite a pace.

The main new thing to note, however, is that about 3/4 of the way back home at the end of the evening my legs were feeling really tired, and I suspect that I shouldnt say that my walking distance is unlimited any more. According to fitbit I had a 15km day, which is one of my busier days. You should note that I treat the distance on fitbit as a measure of activity rather than a measure of distance because fitbit counts some steps whilst I am cycling, but my average distance/busyness is about 9km per day.

Saturday, 18 November 2017

Hyperactive reflexes and Clonus

Two of the HSP symptoms which are mentioned reasonably often are hyperactive reflexes and clonus, but I wasnt sure what they are, so it was time to do some investigation. And, actually its quite tricky to work out. It appears that hyperactive reflexes and clonus are related - both are grouped together under the heading Hyperreflexia. It is very easy to find plenty of references to these as being symptoms of something else. Apologies for a very link heavy post!

Looking at HSP, I find: spasticity is an increase in muscle tone with resulting stiffness. Muscle tone refers to the mild contraction that muscles continue to exhibit even when at rest (ie, resting muscle tone). A reflex between nerve endings in the muscle and spinal cord regulates muscle tone. Normally, the corticospinal nerves control and reduce sensitivity of this reflex. Because HSP causes deterioration of the corticospinal nerves, the reflex is not reduced as it should be, the result being an exaggerated (ie, hyperactive) reflex and increased muscle tone. Essentially, HSP prevents the muscles from relaxing properly.

Clonus is relatively easy to trackdown - it is alternate involuntary muscular contraction and relaxation in rapid succession. This can also be described as rhythmic. Clonus is a larger motion than a twitch, and the muscles will contract and relax between 3 adn 8 times a second, for between a few seconds and a few minutes. The connection is that these are often caused by a reflex. gives some info.  Once more there are videos of this, for example on the ankle: and a faster one here, and for the legs and here You can also see plenty of people with their legs shaking - Here's a description: This all reminds me of things I was told back in my 2013 survey about people being misdiagnosed with restless leg syndrome.

Hyperactive reflexes are more tricky to track down, and it is difficult to know what level of reflex is considered normal (although there is a scale of 0 to 4 with 2 being normal If a reflex is hyperactive then the muscles have a larger movement than normal when they are tested on the reflexes (and the score would be more than 2). You can see that some people have both hyperactive reflexes and clonus: and

There are plenty of websites and medical papers which describe people with HSP who have either or both hyperactive reflexes and clonus, but these papers tend to assume that the reader knows what they are!

(p.s. I had previously looked up clonus myself in 2012, reflecting on my jumping legs back at school:, and borrowing the clonus text from the SP Foundation website)

Sunday, 12 November 2017

New! Fitbit data (and some symptom updates)

Earlier in the year I got myself a fitbit (part of a gift from work to celebrate my working there for 20 years). If you dont know, this is a watch with a motion detector and a heart-rate detector. It allows me to track how active I am and how well I sleep (among other things). The data tracks over time. I'm hoping to be able to use it as another monitor for the slow progress of HSP.

So, first things first, what am I tracking?

  • Steps per day (along with distance & height)
  • Exercise/activity levels
  • Heart-rate
  • Sleep levels

I've got in my personal data spreadsheet various columns which track these things on a weekly basis. I'm hoping to be able to use this data in parallel with the data from strava ( and from patientslikeme ( and see if there are any trends. Perhaps between level of activity and fatigue

After looking at the first few months worth of data I note:

Stretching time - I hadn't been accurately timing the overall duration of my stretches. As I have been going to the physio regularly various extra stretches have been added in to my routine, and I had mentally chalked this up as "10-15 mins". However, using fitbit my typical stretching session is about 8-9mins. If I'm in a rush I'm in the 5-6mins and sessions over 10mins are unusual (for now).

Heart-rate - two things to note here. Firstly, my heart rate when walking goes up higher than my heart rate when cycling, which perhaps suggests that walking requires more effort than cycling. Also my resting heart rate goes up for a few days after I've consumed a fair bit of alcohol. Resting heart rate doesn't appear to be related to my level of exercise. Overall, the walking update is that I feel a bit slower now, and walking is beginning to require a bit more effort to do. I used to be a quick walker, and now I'm heading towards the slow end of normal/typical walking speeds. I notice this the most when I'm walking with other adults rather than out with my kids.

Stair counting - My fitbit counts number of flights of stairs climbed, which it does through sensing the change in air pressure. This is one of the aspects that I find frustrating as the count is not always accurate, and so sometimes I'll have gone up more flights of stairs then the fitbit says. My 'fix' for this is to raise my hand up in the air when I get to the top of the stairs and this normally registers the climb. I find that stair climbing is beginning to get more tricky - a bit slower, and having to use the banister. I expect that it will get more tricky as time goes on, so every step counts!

Step counting - This is generally good. As the watch is worn on the wrist it gets is step count by detecting the motion of the wrist rather than actually counting steps. So, it doesnt work well when I push a supermarket trolley around a supermarket for example, which leads me to suspect that a fitbit wouldn't work work well for someone with a walking frame. On the other hand, I can get quite a bit step count from doing tasks like unloading the dishwasher or ironing clothes, so for me I'm using step count as a measure of activity level rather than specifically a count of the number of steps I've taken. Having said that I've set myself a daily step target, and if I'm close to it at the end of the day I'll just a few more steps to get to the target or to the next badge level. (

Toilet counting! Fitbit can remind/nag you take 250 steps per hour, to avoid staying stationary for long periods of time ( At work I find that if I use the toilets that are not nearest my desk then a round trip is just over 250 steps. I find that once an hour is about right for urinating. Worth noting that I'm not desperate to go after an hour, so I'm going to the toilet more frequently than my bladder demands, and sometimes I'm in meetings or on telephone calls that are more than an hour in length without a problem. but it helps to understand how often I'm going. If my calls/meetings get on for about 2 hours long then I do need to go, urgently!

When it comes to my end of year review next month I'll work out what new health tracking stats i want to add to my symptoms tracker - I have more than a full year of bike/strava data already. On this front, there are a few alterations to my usual routine as well. Back in April I began going out for more leisure/social bike rides as well as my regular commute, so the first third of the year has shorter distances than the second two thirds. I suspect I'll need a graph to see if there are any trends.

Sunday, 5 November 2017

International HSP names

Part of the promotion for my online HSP survey has been finding HSP groups on Facebook and letting them know. I spent some time translating a post about my survey into different languages. (I used Google translate). It comes as no surprise that the name HSP is different in each language. This post puts down what I have found:

Hereditary Spastic Paraplegia
Hereditary Spastic Paraparesis
Familial Spastic Paraplegia
Familial Spastic Paraparesis

French: Paraplégie Spastique Familiale (PSF)
Portuguese: Paraparesia Espástica Familiar (PEF)
Spanish: Paraparesia Espástica Familiar (PEF)
Italian: Paraparesi Spastiche Ereditarie (PSE)
Italian: Paraparesi Spastica Familiare (PSF)
Swedish: Hereditär Spastisk Parapares (HSP)
Dutch: Hereditaire Spastische Paraparese (HSP)
German: Hereditären Spastischen Spinalparalysen (HSS)
Danish: Hereditær Spastisk Paraplegi (HSP)
Danish: Hereditær Spastisk Paraparese (HSP)
Greek: Κληρονομική Σπαστική Παραπληγία (ΚΣΠ)

Strümpell-Lorrain disease
La maladie de Strümpell-Lorrain
Strümpell-Lorrain`s sygdom

If you know any more, do let me know!

Also, when thinking of a list of HSP names, i know there are also names for certain types of HSP, found on OMIM

SPG1: MASA Syndrome / CRASH Syndrome
SPG3A: Strumpell Disease
SPG9A: Cataracts with Motor Neuronopathy, Short Stature, and Skeletal Abnormalities
SPG15: Kjellin Syndrome
SPG17: Silver Syndrome
SPG18: Intellectual Disability, Motor Dysfunction, And Joint Contractures; IDMDC
SPG20: Troyer Syndrome
SPG21: Mast Syndrome
SPG23: Lison Syndrome
SPG35: Fatty Acid Hydroxylase-Associated Neurodegeneration
SPG39: NTE-Related Motor Neuron Disorder
SPG47: Cerebral Palsy, Spastic Quadriplegic, 5, Formerly; CPSQ5
SPG50: Cerebral Palsy, Spastic Quadriplegic, 3, Formerly; CPSQ3
SPG51: Cerebral Palsy, Spastic Quadriplegic, 4, Formerly; CPSQ4
SPG52: Cerebral Palsy, Spastic Quadriplegic, 6, Formerly; CPSQ6

This tells me that there is no SPG22 or 40, and the list gets a bit fragmented in the high 50's and beyond. At the time of writing the last one is SPG79.

Saturday, 21 October 2017

Comments about my walking

In the last year or so i've started to get the occasional comment about my walking.

Some of these are from colleagues at work who I don't see very often. They all know about my HSP, but I have also had some comments from strangers. I wasn't expecting this to happen! It is a bit unsettling, and i've not yet worked out how I should react.

I realise that this must mean that my spasticity is beginning to be more visible, and I'll probably have a few answers lined up which I can just give. Reciting my story to strangers is not really my style, so initially I'll probably go for something like "my legs are just a bit stiff". (I realise that comment about not reciting my life story is a bit contrary to you reading my life story here!)

One person made a comment once that I should use the lift, when my foot scuffed on the way up some stairs. I automatically thought "no! I need to use the stairs to keep my muscles working, you don't understand" - but of course I didn't say this. It was just a quick comment with no context, and my mental reaction was a bit strong and I need to watch that - part of the stress management toolkit.

Saturday, 14 October 2017


Fatigue seems to be a reasonably common symptom with HSP - my 2013 survey identified that fatigue was the third most commonly occurring symptom (after loss of balance and getting more stiff in the cold). 62% of respondents reported that fatigue was significant (occuring frequently, regularly, most of the time or all of the time), 20% of respondents indicated that fatigue was minor or affected them occasionally, with 8% of respondents not being affected. Full report here:

So, what information can I found out about fatigue in HSP? - Not much.

People with HSP on patients like me also report fatigue, with 20% reporting severe, 40% moderate, 33% mild and 7%  without fatigue. Grouping severe and moderate together (60%) this is the same result I showed in 2013. Data here (although you have to be signed in to see this).

There are two papers:
One from 1999: - with no abtract here. Some hunting shows the start of the article here: This paper appears to cover the aspects of HSP as they were at the time. There is no mention of fatigue on the first page.

The other paper is from 2016: This paper compared 30 people with SPG4 HSP with 30 controls in Brazil. This paper reports that patients with HSP had higher levels of fatigue than controls (as well as more pain and more depression).

The lack of published information, and comments about fatigue from others led me to include this in my 2016 survey, I asked people to complete 3 different fatigue surveys and these results showed;

  • 11% of people had mild fatigue, 62% had moderate fatigue and 27% had severe fatigue. 
  • Fatigue is generally independent of mobility.
  • Whilst the physical factors of HSP contribute the most to fatigue there is also an important cognitive aspect. 
  • Those with SPG7 tend to have a higher level of fatigue than those with SPG4. 

I compared my results with the Brazil results and found they were comparable.

If you have a low mood/depression and wish to do something about it, you could look here: - I found this on this podcast - plenty of other interesting similar podcasts here!

Friday, 6 October 2017

Summary of depression posts

I've been keeping an eye out on my blog statistics, and one of my posts on depression is getting quite a bit of interest in the last few weeks.

This post simply summarises the main depression posts I've put up, here together for handy reference.

Stress and depression tests (March 14)
In this post I report the Generalised Anxiety Disorder Questionnaire (GAD-7) questionnaire and the Patient Health Questionnaire (PHQ-9) tests after encountering them at my referral to the local psychology unit. The post includes links to both and a summary of how scores are interpreted.

The depression paper! (September 11)
This post is where I first found the paper describing the prevalence of depression in people with HSP from Estonia. I then use this paper in 2015 as a comparison with my own results.

Stress and mood management course notes (April 2014)
This post is a precis of my notes from the stress and mood management course I went on. The course introduced cognitive behavioural therapy, descriptions of the normal cycles of stress/anxiety and low mood/depression, and various tricks to help break out of those cycles, rules for living, communication, and problem solving.

Assessing your own depression (January 16)
This post was written after a conversation with a friend who had been suffering from depression and described an alternative approach to assessing yourself than the two questionnaires from the 2014 post. This self assessment considers well-being and aligns it with depression. You score yourself on how well you are living within your own values.

Presentation at the 2013 AGM
At the 2013 UK AGM Liz Redmond gave a talk called "Looking After Yourself" which covered low mood, another term for depression. The talk gave various techniques to help look after your mental health. (On a similar theme, see also;

Part of my 2015 survey:
In my 2015 survey I asked respondents to complete the PHQ-2 questionaire which can be used as a screening tool for depression. Overall 63% of respondents had some symptoms of depression and 37% were without those symptoms. Additionally, the results suggest that around one quarter of people with HSP may require further assessment for depression, particularly for those who are using walking frames all or most of the time to get around. There are further details in the link on my analysis of these results.

A symptom included in my 2013 survey
Depression was one of the symptoms mentioned in my 2013 survey, which showed roughly 1/3 with no depression, 1/3 with mild depression and 1/3 with significant depression.